MicroRNA-125b transforms myeloid cell lines by repressing multiple mRNA

Background: We previously described a t(2;11)(p21;q23) chromosomal translocation found in patients with myelodysplasia or acute myeloid leukemia that leads to over-expression of the microRNA miR-125b, and we showed that transplantation of mice with murine stem/progenitor cells overexpressing miR-125b is able to induce leukemia. In this study, we investigated the mechanism of myeloid transformation by miR-125b. Design and Methods: To investigate the consequences of miR-125b over-expression on myeloid differentiation, apoptosis and proliferation, we used the NB4 and HL60 human promyelocytic cell lines and the 32Dclone3 murine promyelocytic cell line. To test whether miR-125b is able to transform myeloid cells, we used the non-tumorigenic and interleukin-3-dependent 32Dclone3 cell line over-expressing miR-125b, in xenograft experiments in nude mice and in conditions of interleukin-3 deprivation. To identify new miR-125b targets, we compared, by RNA-sequencing, the transcriptome of cell lines that do or do not over-express miR-125b. Results: We showed that miR-125b over-expression blocks apoptosis and myeloid differentiation and enhances proliferation in both species. More importantly, we demonstrated that miR-125b is able to transform the 32Dclone3 cell line by conferring growth independence from interleukin-3; xenograft experiments showed that these cells form tumors in nude mice. Using RNA-sequencing and quantitative real-time polymerase chain reaction experiments, we identified multiple miR-125b targets. We demonstrated that ABTB1, an anti-proliferative factor, is a new direct target of miR-125b and we confirmed that CBFB, a transcription factor involved in hematopoiesis, is also targeted by miR-125b. MiR-125b controls apoptosis by down-regulating genes involved in the p53 pathway including BAK1 and TP53INP1. Conclusions: This study demonstrates that in a myeloid context, miR-125b is an oncomiR able to transform cell lines. miR-125b blocks myeloid differentiation in part by targeting CBFB, blocks apoptosis through down-regulation of multiple genes involved in the p53 pathway, and confers a proliferative advantage to human and mouse myeloid cell lines in part by targeting ABTB1.Leukemia & Lymphoma Society of AmericaNational Institutes of Health (U.S.) (NIH grant DK068348)National Institutes of Health (U.S.) (NIH grant 5P01 HL066105

Control of cellular automata

We study the problem of master-slave synchronization and control of totalistic cellular automata (CA) by putting a fraction of sites of the slave equal to those of the master and finding the distance between both as a function of this fraction. We present three control strategies that exploit local information about the CA, mainly, the number of nonzero Boolean derivatives. When no local information is used, we speak of synchronization. We find the critical properties of control and discuss the best control strategy compared with synchronization

Spatial curvature effects on molecular transport by diffusion

For a substance diffusing on a curved surface, we obtain an explicit relation valid for very small values of the time, between the local concentration, the diffusion coefficient, the intrinsic spatial curvature and the time. We recover the known solution of Fick's law of diffusion in the flat space limit. In the biological context, this result would be useful in understanding the variations in the diffusion rates of integral proteins and other molecules on membranes.Comment: 10 page

How to determine local elastic properties of lipid bilayer membranes from atomic-force-microscope measurements: A theoretical analysis

Measurements with an atomic force microscope (AFM) offer a direct way to probe elastic properties of lipid bilayer membranes locally: provided the underlying stress-strain relation is known, material parameters such as surface tension or bending rigidity may be deduced. In a recent experiment a pore-spanning membrane was poked with an AFM tip, yielding a linear behavior of the force-indentation curves. A theoretical model for this case is presented here which describes these curves in the framework of Helfrich theory. The linear behavior of the measurements is reproduced if one neglects the influence of adhesion between tip and membrane. Including it via an adhesion balance changes the situation significantly: force-distance curves cease to be linear, hysteresis and nonzero detachment forces can show up. The characteristics of this rich scenario are discussed in detail in this article.Comment: 14 pages, 9 figures, REVTeX4 style. New version corresponds to the one accepted by PRE. The result section is restructured: a comparison to experimental findings is included; the discussion on the influence of adhesion between AFM tip and membrane is extende

A spatial model of autocatalytic reactions

Biological cells with all of their surface structure and complex interior stripped away are essentially vesicles - membranes composed of lipid bilayers which form closed sacs. Vesicles are thought to be relevant as models of primitive protocells, and they could have provided the ideal environment for pre-biotic reactions to occur. In this paper, we investigate the stochastic dynamics of a set of autocatalytic reactions, within a spatially bounded domain, so as to mimic a primordial cell. The discreteness of the constituents of the autocatalytic reactions gives rise to large sustained oscillations, even when the number of constituents is quite large. These oscillations are spatio-temporal in nature, unlike those found in previous studies, which consisted only of temporal oscillations. We speculate that these oscillations may have a role in seeding membrane instabilities which lead to vesicle division. In this way synchronization could be achieved between protocell growth and the reproduction rate of the constituents (the protogenetic material) in simple protocells.Comment: Submitted to Phys. Rev.

Analytical study of the effect of recombination on evolution via DNA shuffling

We investigate a multi-locus evolutionary model which is based on the DNA shuffling protocol widely applied in \textit{in vitro} directed evolution. This model incorporates selection, recombination and point mutations. The simplicity of the model allows us to obtain a full analytical treatment of both its dynamical and equilibrium properties, for the case of an infinite population. We also briefly discuss finite population size corrections

Michaelis-Menten Relations for Complex Enzymatic Networks

All biological processes are controlled by complex systems of enzymatic chemical reactions. Although the majority of enzymatic networks have very elaborate structures, there are many experimental observations indicating that some turnover rates still follow a simple Michaelis-Menten relation with a hyperbolic dependence on a substrate concentration. The original Michaelis-Menten mechanism has been derived as a steady-state approximation for a single-pathway enzymatic chain. The validity of this mechanism for many complex enzymatic systems is surprising. To determine general conditions when this relation might be observed in experiments, enzymatic networks consisting of coupled parallel pathways are investigated theoretically. It is found that the Michaelis-Menten equation is satisfied for specific relations between chemical rates, and it also corresponds to the situation with no fluxes between parallel pathways. Our results are illustrated for simple models. The importance of the Michaelis-Menten relationship and derived criteria for single-molecule experimental studies of enzymatic processes are discussed.Comment: 10 pages, 4 figure