Forward induction and the excess capacity puzzle: An experimental investigation

While the theoretical industrial organization literature has long arguedthat excess capacity can be used to deter entry into markets, there islittle empirical evidence that incumbent firms effectively behave in thisway. Bagwell and Ramey (1996) propose a game with a specific sequence ofmoves and partially-recoverable capacity costs in which forward inductionprovides a theoretical rationalization for firm behavior in the field. Weconduct an experiment with a game inspired by their work. In our data theincumbent tends to keep the market, in contrast to what the forwardinduction argument of Bagwell and Ramey would suggest. The results indicatethat players perceive that the first mover has an advantage without havingto pre-commit capacity. In our game, evolution and learning do not driveout this perception. We back these claims with data analysis, atheoretical framework for dynamics, and simulation results.

How T cell receptors interact with peptide-MHCs: A multiple steered molecular dynamics study.

The T-cell receptor (TCR) interaction with antigenic peptides (p) presented by the major histocompatibility complex (MHC) molecule is a key determinant of immune response. In addition, TCR-pMHC interactions offer examples of features more generally pertaining to protein-protein recognition: subtle specificity and cross-reactivity. Despite their importance, molecular details determining the TCR-pMHC binding remain unsolved. However, molecular simulation provides the opportunity to investigate some of these aspects. In this study, we perform extensive equilibrium and steered molecular dynamics simulations to study the unbinding of three TCR-pMHC complexes. As a function of the dissociation reaction coordinate, we are able to obtain converged H-bond counts and energy decompositions at different levels of detail, ranging from the full proteins, to separate residues and water molecules, down to single atoms at the interface. Many observed features do not support a previously proposed two-step model for TCR recognition. Our results also provide keys to interpret experimental point-mutation results. We highlight the role of water both in terms of interface resolvation and of water molecules trapped in the bound complex. Importantly, we illustrate how two TCRs with similar reactivity and structures can have essentially different binding strategies. Proteins 2011; © 2011 Wiley-Liss, Inc.

Brownian dynamics simulation of DNA condensation.

DNA condensation observed in vitro with the addition of polyvalent counterions is due to intermolecular attractive forces. We introduce a quantitative model of these forces in a Brownian dynamics simulation in addition to a standard mean-field Poisson-Boltzmann repulsion. The comparison of a theoretical value of the effective diameter calculated from the second virial coefficient in cylindrical geometry with some experimental results allows a quantitative evaluation of the one-parameter attractive potential. We show afterward that with a sufficient concentration of divalent salt (typically approximately 20 mM MgCl(2)), supercoiled DNA adopts a collapsed form where opposing segments of interwound regions present zones of lateral contact. However, under the same conditions the same plasmid without torsional stress does not collapse. The condensed molecules present coexisting open and collapsed plectonemic regions. Furthermore, simulations show that circular DNA in 50% methanol solutions with 20 mM MgCl(2) aggregates without the requirement of torsional energy. This confirms known experimental results. Finally, a simulated DNA molecule confined in a box of variable size also presents some local collapsed zones in 20 mM MgCl(2) above a critical concentration of the DNA. Conformational entropy reduction obtained either by supercoiling or by confinement seems thus to play a crucial role in all forms of condensation of DNA.

Experimental evidence that intra-specific competition in seagrass meadows reduces reproductive potential in the sea urchin Paracentrotus lividus (Lamarck)

To better understand the biological controls that regulate sea urchin dynamics, we studied the effects of potential inter- and intra-specific competition for food on several biological variables of the main sea urchin in the Mediterranean (Paracentrotus lividus). We carried out a caging experiment in which we manipulated sea urchin density (natural vs. high density) and herbivorous fish (Sarpa salpa) accessibility (free access vs. exclusion) in a Posidonia oceanica meadow. No evidence of competition between fish and urchins was detected. Neither density-dependent mortality nor changes in the somatic variables were found; however, we detected that intra-specific competition affected the reproductive potential of P. lividus. The gonad index of urchins at high population densities was ca. 30% lower than that of urchins at natural densities. As a spawning event had just occurred when urchins were collected, these differences probably reflect differences in reserve content, which may compromise the following reproductive period and decrease survival in the long term, as the gonads are also used as storage organs. For the time period studied, mortality rates appeared to be independent of local densities. The results indicate that a long-term negative feedback mechanism appears to take place in P. lividus in response to increased population density.

Thermal activation and ATP dependence of the cytoskeleton remodeling dynamics

The cytoskeleton (CSK) is a nonequilibrium polymer network that uses hydrolyzable sources of free energy such as adenosine triphosphate (ATP) to remodel its internal structure. As in inert nonequilibrium soft materials, CSK remodeling has been associated with structural rearrangements driven by energy-activated processes. We carry out particle tracking and traction microscopy measurements of alveolar epithelial cells at various temperatures and ATP concentrations. We provide the first experimental evidence that the remodeling dynamics of the CSK is driven by structural rearrangements over free-energy barriers induced by thermally activated forces mediated by ATP. The measured activation energy of these forces is ~40kBTr (kB being the Boltzmann constant and Tr being the room temperature). Our experiments provide clues to understand the analogy between the dynamics of the living CSK and that of inert nonequilibrium soft materials.

Influence of the driving mechanism on the response of systems with athermal dynamics: The example of the random-field Ising model

We investigate the influence of the driving mechanism on the hysteretic response of systems with athermal dynamics. In the framework of local mean-field theory at finite temperature (but neglecting thermally activated processes), we compare the rate-independent hysteresis loops obtained in the random field Ising model when controlling either the external magnetic field H or the extensive magnetization M. Two distinct behaviors are observed, depending on disorder strength. At large disorder, the H-driven and M-driven protocols yield identical hysteresis loops in the thermodynamic limit. At low disorder, when the H-driven magnetization curve is discontinuous (due to the presence of a macroscopic avalanche), the M-driven loop is reentrant while the induced field exhibits strong intermittent fluctuations and is only weakly self-averaging. The relevance of these results to the experimental observations in ferromagnetic materials, shape memory alloys, and other disordered systems is discussed.

Nitrogen dynamics in soil management systems. I - flux of inorganic nitrogen (NH4+ and NO3-)

In agricultural systems the N-NH4+ and N-NO3- contents is significantly affected by soil management. This study investigated the dynamics of inorganic nitrogen (N; NH4+ and NO3-) in an experimental evaluation of soil management systems (SMSs) adopted in 1988 at the experimental station of the ABC Foundation in Ponta Grossa, in the Central South region of the State of Paraná. The objective of this study was to evaluate the changes in N-NH4+ and N-NO3- flux in the surface layer of a Red Latosol arising from SMSs over a 12-month period. The experiment was arranged in a completely randomized block design in split plots, in three replications. The plots consisted of the following SMSs: 1) conventional tillage (CT); 2) minimum tillage (MT); 3) no-tillage with chisel plow every three years (NT CH); and 4) continuous no-tillage (CNT). To evaluate the dynamics of inorganic N, the subplots represented samplings (11 sampling times, T1 - T11). The ammonium N (N-NH4+) and nitric N (N-NO3-) contents were higher in systems with reduced tillage (MT and NT CH) and without tillage (CNT) than in the CT system. In the period from October 2003 to February 2004, the N-NH4+ was higher than the N-NO3- soil content. Conversely, in the period from May 2004 to July 2004, the N-NO3- was higher than the N-NH4+ content. The greatest fluctuation in the N-NH4+ and N-NO3- contents occurred in the 0-2.5 cm layer, and the highest peak in the N-NH4+ and N-NO3- concentrations occurred after the surface application of N. Both N-NH4+ and N-NO3- were strongly correlated with the soil organic C content, which indicated that these properties vary together in the system.

Nitrogen dynamics in soil management systems: II - mineralization and nitrification rates

Nitrogen is the main limiting factor in crop productivity and thereby soil management systems may change the mineralization and nitrification rates. In an experiment on soil management systems implemented in 1988 at the experimental station Fundação ABC, Ponta Grossa, in the central South region of the State of Paraná, inorganic N dynamics were examined to find a soil management strategy with a view to a sustainable environment. The objective of this study was to calculate the net mineralization and nitrification rates of soil N and the correlation with soil pH under management systems. Randomized complete block design was used, in split plots, in three replications. The following soil management systems (SMSs) were adopted in the plots: 1) conventional tillage (CT); 2) minimum tillage (MT); 3) no-tillage with chisel plow every three years (NT CH); and 4) continuous no-tillage (CNT). To evaluate the dynamics of inorganic N, samples were collected from sub-plots at different times (11 sampling times - T1 to T11). In the CNT and NT CH, the net mineralization rates were higher in the MT and CT systems in the 0-2.5 cm soil layer, while the nitrification rate was higher in the 2.5-5 cm layer. Soon after implementing the white oat management, the mineralization and nitrification rates in all soil layers were higher in the MT and CT systems. In the period of soybean development, in the 0-2.5 and 2.5-5 cm soil layers, the mineralization and nitrification rates were higher in the CNT and NT CH than in the MT and CT systems.

Cost-effective experimental design to support modeling of concentration-response functions

Modeling concentration-response function became extremely popular in ecotoxicology during the last decade. Indeed, modeling allows determining the total response pattern of a given substance. However, reliable modeling is consuming in term of data, which is in contradiction with the current trend in ecotoxicology, which aims to reduce, for cost and ethical reasons, the number of data produced during an experiment. It is therefore crucial to determine experimental design in a cost-effective manner. In this paper, we propose to use the theory of locally D-optimal designs to determine the set of concentrations to be tested so that the parameters of the concentration-response function can be estimated with high precision. We illustrated this approach by determining the locally D-optimal designs to estimate the toxicity of the herbicide dinoseb on daphnids and algae. The results show that the number of concentrations to be tested is often equal to the number of parameters and often related to the their meaning, i.e. they are located close to the parameters. Furthermore, the results show that the locally D-optimal design often has the minimal number of support points and is not much sensitive to small changes in nominal values of the parameters. In order to reduce the experimental cost and the use of test organisms, especially in case of long-term studies, reliable nominal values may therefore be fixed based on prior knowledge and literature research instead of on preliminary experiments

Estimating dormant and active hematopoietic stem cell kinetics through extensive modeling of bromodeoxyuridine label-retaining cell dynamics.

Bone marrow hematopoietic stem cells (HSCs) are responsible for both lifelong daily maintenance of all blood cells and for repair after cell loss. Until recently the cellular mechanisms by which HSCs accomplish these two very different tasks remained an open question. Biological evidence has now been found for the existence of two related mouse HSC populations. First, a dormant HSC (d-HSC) population which harbors the highest self-renewal potential of all blood cells but is only induced into active self-renewal in response to hematopoietic stress. And second, an active HSC (a-HSC) subset that by and large produces the progenitors and mature cells required for maintenance of day-to-day hematopoiesis. Here we present computational analyses further supporting the d-HSC concept through extensive modeling of experimental DNA label-retaining cell (LRC) data. Our conclusion that the presence of a slowly dividing subpopulation of HSCs is the most likely explanation (amongst the various possible causes including stochastic cellular variation) of the observed long term Bromodeoxyuridine (BrdU) retention, is confirmed by the deterministic and stochastic models presented here. Moreover, modeling both HSC BrdU uptake and dilution in three stages and careful treatment of the BrdU detection sensitivity permitted improved estimates of HSC turnover rates. This analysis predicts that d-HSCs cycle about once every 149-193 days and a-HSCs about once every 28-36 days. We further predict that, using LRC assays, a 75%-92.5% purification of d-HSCs can be achieved after 59-130 days of chase. Interestingly, the d-HSC proportion is now estimated to be around 30-45% of total HSCs - more than twice that of our previous estimate.

Static structure and dynamics of the liquid Li-Na and Li-Mg alloys

We present calculations for the static structure and ordering properties of two lithium-based s-p bonded liquid alloys, Li-Na and Li-Mg. Our theoretical approach is based on the neutral pseudoatom method to derive the interatomic pair potentials, and on the modified-hypernetted-chain theory of liquids to obtain the liquid static structure, leading to a whole combination that is free of adjustable parameters. The study is complemented by performing molecular dynamics simulations which, besides checking the theoretical static structural results, also allow a calculation of some dynamical properties. The obtained results are compared with the available experimental data.

Inference of chromosomal inversion dynamics from Pool-Seq data in natural and laboratory populations of Drosophila melanogaster.

Sequencing of pools of individuals (Pool-Seq) represents a reliable and cost-effective approach for estimating genome-wide SNP and transposable element insertion frequencies. However, Pool-Seq does not provide direct information on haplotypes so that, for example, obtaining inversion frequencies has not been possible until now. Here, we have developed a new set of diagnostic marker SNPs for seven cosmopolitan inversions in Drosophila melanogaster that can be used to infer inversion frequencies from Pool-Seq data. We applied our novel marker set to Pool-Seq data from an experimental evolution study and from North American and Australian latitudinal clines. In the experimental evolution data, we find evidence that positive selection has driven the frequencies of In(3R)C and In(3R)Mo to increase over time. In the clinal data, we confirm the existence of frequency clines for In(2L)t, In(3L)P and In(3R)Payne in both North America and Australia and detect a previously unknown latitudinal cline for In(3R)Mo in North America. The inversion markers developed here provide a versatile and robust tool for characterizing inversion frequencies and their dynamics in Pool-Seq data from diverse D. melanogaster populations.

Functional responses and heterogeneities: an experimental test with cladocerans

The functional response of predators is usually modelled as a function of absolute prey density. Arditi and Ginzburg have suggested that it should often depend instead on the prey available per capita of predators, i.e. on the prey/predator ratio. Theory suggests that these two forms of dependence are related to the degree of spatial and temporal heterogeneity. Experiments using four filter-feeding cladoceran species were designed to test this hypothesis and to investigate the relation between individual behaviour and population dynamics. The patterns of population abundance that the cladocerans reached at equilibrium match the expectation that species with homogeneous spatial behaviour follow prey-dependent dynamics while those with heterogeneous behaviour follow ratio-dependent dynamics.

Experimental evidence that intra-specific competition in seagrass meadows reduces reproductive potential in the sea urchin Paracentrotus lividus (Lamarck)

To better understand the biological controls that regulate sea urchin dynamics, we studied the effects of potential inter- and intra-specific competition for food on several biological variables of the main sea urchin in the Mediterranean (Paracentrotus lividus). We carried out a caging experiment in which we manipulated sea urchin density (natural vs. high density) and herbivorous fish (Sarpa salpa) accessibility (free access vs. exclusion) in a Posidonia oceanica meadow. No evidence of competition between fish and urchins was detected. Neither density-dependent mortality nor changes in the somatic variables were found; however, we detected that intra-specific competition affected the reproductive potential of P. lividus. The gonad index of urchins at high population densities was ca. 30% lower than that of urchins at natural densities. As a spawning event had just occurred when urchins were collected, these differences probably reflect differences in reserve content, which may compromise the following reproductive period and decrease survival in the long term, as the gonads are also used as storage organs. For the time period studied, mortality rates appeared to be independent of local densities. The results indicate that a long-term negative feedback mechanism appears to take place in P. lividus in response to increased population density.

MMPBSA decomposition of the binding energy throughout a molecular dynamics simulation of Amyloid-Beta (Aß10-35) aggregation

Recent experiments with amyloid-beta (Aß) peptides indicate that the formation of toxic oligomers may be an important contribution to the onset of Alzheimer's disease. The toxicity of Aß oligomers depend on their structure, which is governed by assembly dynamics. However, a detailed knowledge of the structure of at the atomic level has not been achieved yet due to limitations of current experimental techniques. In this study, replica exchange molecular dynamics simulations are used to identify the expected diversity of dimer conformations of Aß10-35 monomers. The most representative dimer conformation has been used to track the dimer formation process between both monomers. The process has been characterized by means of the evolution of the decomposition of the binding free energy, which provides an energetic profile of the interaction. Dimers undergo a process of reorganization driven basically by inter-chain hydrophobic and hydrophilic interactions and also solvation/desolvation processes.