Is the Initial Event in Carcinogenesis An Enhancement of the Mutation Rate?

The age-specific incidence rates of adult cancer indicate that the carcinogenic process is a power function of elapsed time. If the malignant clone arises by a series of mutations, and each mutation is regarded as an independent event with a small instantaneous probability of occurrence, then the slope of the age-specific incidence gives an indication of the number of genes involved. In most cases, the epidemiological data exhibit an age-specific incidence the slope of which is between a fourth and a seventh power of age. Assuming that the mutations involved are deletions and must occur in otherwise viable and proliferative cells, the mutation rate required to generate enough mutant cells to fit the cancer incidence data must be remarkably high in the pre-malignant cell population. The initiation process may thus be an event that results in a raised mutation rate in the affected cell and its progeny. It is proposed that the process of induction involves one or more mutations that induce a metabolic lesion that has the effect of increasing the subsequent mutation rate in the affected clone. A possible mechanism involving free radical generation is suggested and some of the biological implications of the proposal examined.     

Labelling strategy and membrane characterization of marine bacteria Vibrio splendidus by in vivo 2H NMR

Vibrio splendidus is a marine bacterium often considered as a threat in aquaculture hatcheries where it is responsible for mass mortality events, notably of bivalves' larvae. This bacterium is highly adapted to dynamic salty ecosystems where it has become an opportunistic and resistant species. To characterize their membranes as a first and necessary step toward studying bacterial interactions with diverse molecules, we established a labelling protocol for in vivo ²H solid-state nuclear magnetic resonance (SS-NMR) analysis of V. splendidus. ²H SS-NMR is a useful tool to study the organization and dynamics of phospholipids at the molecular level, and its application to intact bacteria is further advantageous as it allows probing acyl chains in their natural environment and study membrane interactions. In this study, we showed that V. splendidus can be labelled using deuterated palmitic acid, and demonstrated the importance of surfactant choice in the labelling protocol. Moreover, we assessed the impact of lipid deuteration on the general fitness of the bacteria, as well as the saturated-to-unsaturated fatty acid chains ratio and its impact on the membrane properties. We further characterize the evolution of V. splendidus membrane fluidity during different growth stages and relate it to fatty acid chain composition. Our results show larger membrane fluidity during the stationary growth phase compared to the exponential growth phase under labelling conditions - an information to take into account for future in vivo SS-NMR studies. Our lipid deuteration protocol optimized for V. splendidus is likely applicable other microorganisms for in vivo NMR studies.     

Inversion of terrestrial ecosystem model parameter values against eddy covariance measurements by Monte Carlo sampling

Effective measures to counter the rising levels of carbon dioxide in the Earth's atmosphere require that we better understand the functioning of the global carbon cycle. Uncertainties about, in particular, the terrestrial carbon cycle's response to climate change remain high. We use a well‐known stochastic inversion technique originally developed in nuclear physics, the Metropolis algorithm, to determine the full probability density functions (PDFs) of parameters of a terrestrial ecosystem model. By thus assimilating half‐hourly eddy covariance measurements of CO₂ and water fluxes, we can substantially reduce the uncertainty of approximately five model parameters, depending on prior uncertainties. Further analysis of the posterior PDF shows that almost all parameters are nearly Gaussian distributed, and reveals some distinct groups of parameters that are constrained together. We show that after assimilating only 7 days of measurements, uncertainties for net carbon uptake over 2 years for the forest site can be substantially reduced, with the median estimate in excellent agreement with measurements.     

Caging experiment in the deep sea: Efficiency and artefacts from a case study at the Arctic long-term observatory HAUSGARTEN

Present theories of deep-sea community organization recognize the importance of small-scale biological disturbances, originated partly from the activities of epibenthic megafaunal organisms, in maintaining high benthic biodiversity in the deep sea. However, due to technical difficulties, in situ experimental studies to test hypotheses in the deep sea are lacking. The objective of the present study was to evaluate the potential of cages as tools for studying the importance of epibenthic megafauna for deep-sea benthic communities. Using the deep-diving Remotely Operated Vehicle (ROV) “VICTOR 6000”, six experimental cages were deployed at the sea floor at 2500 m water depth and sampled after 2 years (2y) and 4 years (4y) for a variety of sediment parameters in order to test for caging artefacts. Photo and video footage from both experiments showed that the cages were efficient at excluding the targeted fauna. The cage also proved to be appropriate to deep-sea studies considering the fact that there was no fouling on the cages and no evidence of any organism establishing residence on or adjacent to it. Environmental changes inside the cages were dependent on the experimental period analysed. In the 4y experiment, chlorophyll a concentrations were higher in the uppermost centimeter of sediment inside cages whereas in the 2y experiment, it did not differ between inside and outside. Although the cages caused some changes to the sedimentary regime, they are relatively minor compared to similar studies in shallow water. The only parameter that was significantly higher under cages at both experiments was the concentration of phaeopigments. Since the epibenthic megafauna at our study site can potentially affect phytodetritus distribution and availability at the seafloor (e.g. via consumption, disaggregation and burial), we suggest that their exclusion was, at least in part, responsible for the increases in pigment concentrations. Cages might be suitable tools to study the long-term effects of disturbances caused by megafaunal organisms on the diversity and community structure of smaller-sized organisms in the deep sea, although further work employing partial cage controls, greater replication, and evaluating faunal components will be essential to unequivocally establish their utility.     

Trends in trappability and stop-over duration can confound interpretations of population trajectories from long-term migration ringing studies

We examined ringing data for three common passerines at a migration monitoring site with the objective of determining how closely the numbers of birds captured reflected the actual numbers of birds passing through this site. Mark–recapture analyses were used, fitting smooth inter-annual changes in re-trapping probability and apparent survival (continued presence within the study area). For all three species we found systematic declines in re-trapping probability over the roughly three decades of our study; one species showed systematic increases in daily apparent survival over this same time period. Within individual years, daily variation in wind and rainfall were found to affect re-trapping probability and apparent survival. The result of all of these effects was that long-term trends in the numbers of unique individual birds captured systematically over-estimated the declines for all three species, providing clear indication that the biological interpretation of these raw capture totals from ringing stations will not necessarily reflect actual changes in the abundance of species passing through these sites.     

Using complementary approaches to estimate survival of juvenile and adult Eastern Kingbirds

ABSTRACT Survival rates of young birds during the period between nest departure and their first breeding season is an important but difficult statistic to measure because of low natal site fidelity, especially for long‐distance migrants. From 2002 to 2008, we conducted a capture‐mark‐resight study of Eastern Kingbirds (Tyrannus tyrannus), a Nearctic‐Neotropical migrant, at Malheur National Wildlife Refuge, Oregon, to estimate juvenile (S_J) and adult (S_A) survival. The return rate of juvenile kingbirds was high (0.224) and not significantly different from program MARK's estimate of S_J (0.291). On average, and for both sexes, program MARK's estimate of S_A for birds banded as nestlings (0.64) was similar to that for birds first banded as adults (0.65). Enumeration methods and MARK yielded similar estimates of S_A, especially for males banded as adults. We attribute the similarity of resighting rate of birds banded as nestlings to S_J and the similarity of S_A estimated using program MARK and by enumeration methods to the high site fidelity of most juvenile and adult kingbirds at our ecologically isolated study site. An independent estimate of S_J calculated using local estimates of population growth and average annual production of young per year suggested that true S_J and S_A were probably slightly higher than program MARK's estimates because of undocumented permanent emigration, especially of birds first banded as adults. Demographic balancing suggests that true S_A and S_J were roughly 0.70 and 0.30, respectively. In general, our multiple estimates of S_J were similar. However, program MARK estimates of S_J tended to be lower than those produced by demographic balancing. Because of the difficulty in differentiating permanent emigration and mortality, and the affect it has on empirical estimates of survival, we urge researchers to use multiple methods of survival estimation, when possible, to validate the precision of their estimates.     

Receptor-Agonist Interactions in Service-Theoretic Perspective,Effects of Molecular Timing on the Shape of Dose-Response Curves

Service-theoretic concepts and methods, widely used in other fields (e.g., telecommunication and operations research), are useful also in a biochemical setting because the treatment of biocatalysts (enzymes, receptors) as servers and their ligands as customers, based on the established formal methods of service or queuing theory, may lead to insights and results unobtainable by conventional, mass-action-law-based theories. In this article, we apply the service-theoretic approach to receptor-agonist systems and show how by changing the stochastic time pattern of “operationally relevant” point events (e.g., instants of agonist arrival, instants of postclimax agonist departure) a great variety of dose-response curves may be generated, even in very simple reaction schemes, which, according to mass action kinetics, invariably lead to hyperbolic r(A) curves (r and A stand for response and agonist concentration, respectively). The molecular timing inherent to a hyperbolic response system is not optimal: for instance, at the agonist concentration A₅₀, half of the agonist molecules are rejected (“lost”) because of unfortunate timing of the arrival events. The fraction of lost arrivers can be diminished considerably if the arrivals are better timed: “sub-Poisson” arrivals improve the timing and, thus, convert hyperbolic r(A) curves into “lifted” nonhyperbolic ones. Conversely, “super-Poisson” arrivals make the nonoptimal timing in hyperbolic response systems even worse and, thus, convert hyperbolic r(A) curves into “depressed” nonhyperbolic ones. Furthermore, under special timing conditions, nonhyperbolic r(A) curves can be generated, which are partly lifted, partly depressed relative to the reference hyperbola, and which resemble in shape well-known nonhyperbolic forms of enzyme and receptor kinetics (negatively cooperative, positively cooperative, and sigmoidal kinetics). In addition unusual (undulatory and sawtooth-like) r(A) curves can be generated solely by changing the temporal pattern of arrival and service completion instants. Virtually any shape of dose-response curves may be obtained by allowing for probability distributions whose characteristic shape varies with their mean; we call such distributions “variomorphic” and apply them to the arrival process of agonist molecules.     

An optimal Bayesian predictive probability design for phase II clinical trials with simple and complicated endpoints

Most existing phase II clinical trial designs focus on conventional chemotherapy with binary tumor response as the endpoint. The advent of novel therapies, such as molecularly targeted agents and immunotherapy, has made the endpoint of phase II trials more complicated, often involving ordinal, nested, and coprimary endpoints. We propose a simple and flexible Bayesian optimal phase II predictive probability (OPP) design that handles binary and complex endpoints in a unified way. The Dirichlet-multinomial model is employed to accommodate different types of endpoints. At each interim, given the observed interim data, we calculate the Bayesian predictive probability of success, should the trial continue to the maximum planned sample size, and use it to make the go/no-go decision. The OPP design controls the type I error rate, maximizes power or minimizes the expected sample size, and is easy to implement, because the go/no-go decision boundaries can be enumerated and included in the protocol before the onset of the trial. Simulation studies show that the OPP design has satisfactory operating characteristics.