Regulation of B cell fate by chronic activity of the IgE B cell receptor.

IgE can trigger potent allergic responses, yet the mechanisms regulating IgE production are poorly understood. Here we reveal that IgE+ B cells are constrained by chronic activity of the IgE B cell receptor (BCR). In the absence of cognate antigen, the IgE BCR promoted terminal differentiation of B cells into plasma cells (PCs) under cell culture conditions mimicking T cell help. This antigen-independent PC differentiation involved multiple IgE domains and Syk, CD19, BLNK, Btk, and IRF4. Disruption of BCR signaling in mice led to consistently exaggerated IgE+ germinal center (GC) B cell but variably increased PC responses. We were unable to confirm reports that the IgE BCR directly promoted intrinsic apoptosis. Instead, IgE+ GC B cells exhibited poor antigen presentation and prolonged cell cycles, suggesting reduced competition for T cell help. We propose that chronic BCR activity and access to T cell help play critical roles in regulating IgE responses

HFE and transferrin directly compete for transferrin receptor in solution and at the cell surface

Transferrin receptor (TfR) is a dimeric cell surface protein that binds both the serum iron transport protein transferrin (Fe-Tf) and HFE, the protein mutated in patients with the iron overload disorder hereditary hemochromatosis. HFE and Fe-Tf can bind simultaneously to TfR to form a ternary complex, but HFE binding to TfR lowers the apparent affinity of the Fe-Tf/TfR interaction. This apparent affinity reduction could result from direct competition between HFE and Fe-Tf for their overlapping binding sites on each TfR polypeptide chain, from negative cooperativity, or from a combination of both. To explore the mechanism of the affinity reduction, we constructed a heterodimeric TfR that contains mutations such that one TfR chain binds only HFE and the other binds only Fe-Tf. Binding studies using a heterodimeric form of soluble TfR demonstrate that TfR does not exhibit cooperativity in heterotropic ligand binding, suggesting that some or all of the effects of HFE on iron homeostasis result from competition with Fe-Tf for TfR binding. Experiments using transfected cell lines demonstrate a physiological role for this competition in altering HFE trafficking patterns

Dynamic competition between transcription initiation and repression: Role of nonequilibrium steps in cell-to-cell heterogeneity

Transcriptional repression may cause transcriptional noise by a competition between repressor and RNA polymerase binding. Although promoter activity is often governed by a single limiting step, we argue here that the size of the noise strongly depends on whether this step is the initial equilibrium binding or one of the subsequent unidirectional steps. Overall, we show that nonequilibrium steps of transcription initiation systematically increase the cell-to-cell heterogeneity in bacterial populations. In particular, this allows also weak promoters to give substantial transcriptional noise.Comment: 5 pages, 3 fiugres. Figure and text update

Analysis of B cell selection mechanisms in the adaptive immune response

The essential task of a germinal centre reaction is the selection of those B cells that bind the antigen with high affinity. The exact mechanisms of B cell selection is still unknown and rather difficult to be accessed in experiment. With the help of an already established agent-based model for the space-time-dynamics of germinal centre reactions [1,2] we compare the most important hypotheses for what the limiting factor for B cell rescue may be. We discuss competition for antigen sites on follicular dendritic cells, a refractory time for centrocytes after every encounter with follicular dendritic cells, competition for the antigen itself, the role of antigen masking with soluble antibodies, and competition for T cell help. The unexpected result is that neither competition for interaction sites nor competition for antigen nor antigen masking are in agreement with present experimental data on germinal centre reactions. We show that these most popular selection mechanisms do not lead to sufficient affinity maturation and do not respect the observed robustness against changes of initial conditions. However, the best agreement with data was found for the newly hypothesized centrocyte refractory time and for competition for T cell help. Thus the in silico experiments point towards selection mechanisms that are not in the main focus of current germinal centre research. Possible experiments to test these hypotheses are proposed

Active wetting of epithelial tissues

Development, regeneration and cancer involve drastic transitions in tissue morphology. In analogy with the behavior of inert fluids, some of these transitions have been interpreted as wetting transitions. The validity and scope of this analogy are unclear, however, because the active cellular forces that drive tissue wetting have been neither measured nor theoretically accounted for. Here we show that the transition between 2D epithelial monolayers and 3D spheroidal aggregates can be understood as an active wetting transition whose physics differs fundamentally from that of passive wetting phenomena. By combining an active polar fluid model with measurements of physical forces as a function of tissue size, contractility, cell-cell and cell-substrate adhesion, and substrate stiffness, we show that the wetting transition results from the competition between traction forces and contractile intercellular stresses. This competition defines a new intrinsic lengthscale that gives rise to a critical size for the wetting transition in tissues, a striking feature that has no counterpart in classical wetting. Finally, we show that active shape fluctuations are dynamically amplified during tissue dewetting. Overall, we conclude that tissue spreading constitutes a prominent example of active wetting --- a novel physical scenario that may explain morphological transitions during tissue morphogenesis and tumor progression

Function of Bmpr1a in ES cell differentiation and cell competition

Bone morphogenetic protein (BMP) 4 signalling via BMPR1A is required for the maintenance of the epiblast in the early embryo, and for self-renewal of pluripotent mouse embryonic stem (ES) cells by inhibiting neural differentiation. In this study, the self-renewal and differentiation abilities of ES cells lacking BMPR1A were investigated. Bmpr1a-null ES cells did not respond to BMP4 but retained a degree of SMAD1/5/8 activation and Id1 expression. This activation was likely due to BMP7 signalling via ACVR1. The observation that Bmpr1a-/- ES cells showed no selfrenewal or pluripotency defects suggested that signalling by BMPs of the 60a subgroup (such as BMP7) can also maintain pluripotency. When Bmpr1a-/- ES cells were differentiated, although they did form derivatives of the three germ layers, they displayed a higher propensity to undergo neurectodermal specification than control cells, likely due to their lower levels of BMP signalling. Cell Competition is the process by which viable cells are eliminated in the presence of metabolically more active or fitter cells. In Drosophila this process depends on dMyc levels and on limiting amounts of the survival factor Decapentaplegic (homologous to the mammalian BMPs). When Bmpr1a-/- ES cells were co-cultured with wild-type cells, they gradually disappeared from the culture and were therefore out-competed. This cell competition was enhanced by limiting the amounts of survival and growth factors and could be rescued by restoring BMP4 signalling in Bmpr1a-/- cells. In co-culture, Bmpr1a-/- ES cells showed no significant changes in apoptosis but had a decreased cell cycle rate and increased levels of differentiation. Concomitantly, higher c-MYC levels were observed in wild-type cells due to increased protein stability. The out-competition of Bmpr1a-/- cells was dependent on differentiation as it could be prevented by inhibiting this process. These results suggest that during development cell competition may be an important mechanism controlling cell fate and survival

STOCHASTIC DYNAMICS OF CELL LINEAGE IN TISSUE HOMEOSTASIS.

During epithelium tissue maintenance, lineages of cells differentiate and proliferate in a coordinated way to provide the desirable size and spatial organization of different types of cells. While mathematical models through deterministic description have been used to dissect role of feedback regulations on tissue layer size and stratification, how the stochastic effects influence tissue maintenance remains largely unknown. Here we present a stochastic continuum model for cell lineages to investigate how both layer thickness and layer stratification are affected by noise. We find that the cell-intrinsic noise often causes reduction and oscillation of layer size whereas the cell-extrinsic noise increases the thickness, and sometimes, leads to uncontrollable growth of the tissue layer. The layer stratification usually deteriorates as the noise level increases in the cell lineage systems. Interestingly, the morphogen noise, which mixes both cell-intrinsic noise and cell-extrinsic noise, can lead to larger size of layer with little impact on the layer stratification. By investigating different combinations of the three types of noise, we find the layer thickness variability is reduced when cell-extrinsic noise level is high or morphogen noise level is low. Interestingly, there exists a tradeoff between low thickness variability and strong layer stratification due to competition among the three types of noise, suggesting robust layer homeostasis requires balanced levels of different types of noise in the cell lineage systems

Joint fitting reveals hidden interactions in tumor growth

Tumor growth is often the result of the simultaneous development of two or more cancer cell populations. Their interaction between them characterizes the system evolution. To obtain information about these interactions we apply the recently developed vector universality (VUN) formalism to various instances of competition between tumor populations. The formalism allows us: (a) to quantify the growth mechanisms of a HeLa cell colony, describing the phenotype switching responsible for its fast expansion, (b) to reliably reconstruct the evolution of the necrotic and viable fractions in both in vitro and in vivo tumors using data for the time dependences of the total masses, and (c) to show how the shedding of cells leading to subspheroid formation is beneficial to both the spheroid and subspheroid populations, suggesting that shedding is a strong positive influence on cancer dissemination

Discrete breathers in a nonlinear electric line: Modeling, Computation and Experiment

We study experimentally and numerically the existence and stability properties of discrete breathers in a periodic nonlinear electric line. The electric line is composed of single cell nodes, containing a varactor diode and an inductor, coupled together in a periodic ring configuration through inductors and driven uniformly by a harmonic external voltage source. A simple model for each cell is proposed by using a nonlinear form for the varactor characteristics through the current and capacitance dependence on the voltage. For an electrical line composed of 32 elements, we find the regions, in driver voltage and frequency, where $n$-peaked breather solutions exist and characterize their stability. The results are compared to experimental measurements with good quantitative agreement. We also examine the spontaneous formation of $n$-peaked breathers through modulational instability of the homogeneous steady state. The competition between different discrete breathers seeded by the modulational instability eventually leads to stationary $n$-peaked solutions whose precise locations is seen to sensitively depend on the initial conditions

Effect of external electric field on the charge density waves in one dimensional Hubbard superlattices

We have studied the ground state of the one dimensional Hubbard superlattice structures with different unit cell sizes in the presence of electric field. Self consistent Hartree-Fock approximation calculation is done in the weak to intermediate interaction regime. Studying the charge gap at the Fermi level and the charge density structure factor, we get an idea how the charge modulation on the superlattice is governed by the competition between the electronic correlation and the external electric field.Comment: 6 pages, 8 figures. accepted in Journal of Physics: Condensed Matte