On the discrete Peyrard-Bishop model of DNA: stationary solutions and stability

As a first step in the search of an analytical study of mechanical denaturation of DNA in terms of the sequence, we study stable, stationary solutions in the discrete, finite and homogeneous Peyrard-Bishop DNA model. We find and classify all the stationary solutions of the model, as well as analytic approximations of them, both in the continuum and in the discrete limits. Our results explain the structure of the solutions reported by Theodorakopoulos {\em et al.} [Phys. Rev. Lett. {\bf 93}, 258101 (2004)] and provide a way to proceed to the analysis of the generalized version of the model incorporating the genetic information.Comment: 15 pages, 12 figure

Kink dynamics in spatially inhomogeneous media: the role of internal modes

The phenomenon of length-scale competition in soliton-bearing equations perturbed by spatially dependent terms A. Sánchez and A. R. Bishop, SIAM Rev. 40, 579 1998 is analyzed from a general viewpoint. We show that the perturbation gives rise to an effective potential for solitons, which consists of wells and barriers. We calculate the effect of these potential features on the solitons, establishing a direct relationship between the maxima, minima, and curvature of the potential with soliton deformations. When the typical wavelength of the perturbation is of the order of the soliton width, these deformations are seen to correspond to the excitation of shape modes and can lead to the dissipation of the soliton kinetic energy and, further, to the impossibility of soliton propagation. Thus, we demonstrate that the mechanism for length-scale competition is related to changes in the dynamics of the internal modes. We study different examples where the perturbation is introduced parametrically and nonparametrically to make it clear that our results apply to a wide class of equations.This work was supported by MEC Spain under Grants MOSAICO and No. NAN2004-9087-C03-03 and by the Comunidad Autónoma de Madrid (Spain) under Grants No. UC3M-FI-05-007 and SIMUMAT-CM. The work by J.G. was done in part during a stay at Universidad Carlos III de Madrid, whose financial support is acknowledged, and S.C. is supported by the Consejería de Educación de la Comunidad Autónoma de Madrid and the Fondo Social Europeo.Publicad

Competitive dominance in plant communities: Modeling approaches and theoretical predictions

Quantitative predictions about the processes that promote species coexistence are a subject of active research in ecology. In particular, competitive interactions are known to shape and maintain ecological communities, and situations where some species out-compete or dominate over some others are key to describe natural ecosystems. Here we develop ecological theory using a stochastic, synthetic framework for plant community assembly that leads to predictions amenable to empirical testing. We propose two stochastic continuous-time Markov models that incorporate competitive dominance through a hierarchy of species heights. The first model, which is spatially implicit, predicts both the expected number of species that survive and the conditions under which heights are clustered in realized model communities. The second one allows spatially-explicit interactions of individuals and alternative mechanisms that can help shorter plants overcome height-driven competition, and it demonstrates that clustering patterns remain not only locally but also across increasing spatial scales. Moreover, although plants are actually height-clustered in the spatially-explicit model, it allows for plant species abundances not necessarily skewed to taller plants

A signal of competitive dominance in mid-latitude herbaceous plant communities

Understanding the main determinants of species coexistence across space and time is a central question in ecology. However, ecologists still know little about the scales and conditions at which biotic interactions matter and how these interact with the environment to structure species assemblages. Here we use recent theoretical developments to analyse plant distribution and trait data across Europe and find that plant height clustering is related to both evapotranspiration (ET) and gross primary productivity. This clustering is a signal of interspecies competition between plants, which is most evident in mid-latitude ecoregions, where conditions for growth (reflected in actual ET rates and gross primary productivities) are optimal. Away from this optimum, climate severity probably overrides the effect of competition, or other interactions become increasingly important. Our approach bridges the gap between species-rich competition theories and large-scale species distribution data analysisThis work was funded by the Spanish ‘Ministerio de Economía y Competitividad’ under the projects CGL2012-39964 and CGL2015-69043-P (D.A. and J.A.C.), by the Spanish ‘Ministerio de Ciencia, Innovación y Universidades’ under the project PGC2018-096577-B-I00 (D.A. and J.A.C.), and the Ramón y Cajal Fellowship program (RYC-2010-06545, D.A.). J.A.C. acknowledges partial financial support from the Department of Applied Mathematics (Universidad Politécnica de Madrid). S.C. acknowledges financial support from Banco Santander through grant no. PR87/19-2258

Estrogens and genomic instability in human cancer cells-involvement of Src/Raf/Erk signaling in micronucleus formation by estrogenic chemicals

This article is available open access through the publisher’s website. Copyright @ 2008 The Authors.Reports of the ability of estrogenic agents such as 17β-estradiol (E2), estriol (E3) and bisphenol A (BPA) to induce micronuclei (MN) in MCF-7 breast cancer cells have prompted us to investigate whether these effects are linked to activation of the estrogen receptor (ER) α. Coadministration of tamoxifen and the pure ER antagonist ICI 182 780 to cells treated with E2 and E3 did not lead to significant reductions in micronucleus frequencies. Since these antiestrogens interfere with the transcriptional activity of the ER and block promotion of ER-dependent gene expression, it appears that this process is not involved in micronucleus formation. However, ER activation also triggers rapid signaling via the Src/Raf/extracellular signal-regulated kinase (Erk) pathway. When MCF-7 cells were exposed to E2 and BPA in combination with the specific kinase inhibitors pyrazolopyrimidine and 2′-amino-3′-methoxyflavone, reductions in micronucleus frequencies occurred. These findings suggest that the Src/Raf/Erk pathway plays a role in micronucleus formation by estrogenic agents. Enhanced activation of the Src/Raf/Erk cascade disturbs the localization of Aurora B kinase to kinetochores, leading to a defective spindle checkpoint with chromosome malsegregation. Using antikinetochore CREST antibody staining, a high proportion of micronucleus containing kinetochores was observed, indicating that such processes are relevant to the induction of MN by estrogens. Our results suggest that estrogens induce MN by causing improper chromosome segregation, possibly by interfering with kinase signaling that controls the spindle checkpoint, or by inducing centrosome amplification. Our findings may have some relevance in explaining the effects of estrogens in the later stages of breast carcinogenesis.European Commissio

Nanoparticle-mediated targeting of MAPK signaling predisposes tumor to chemotherapy

The MAPK signal transduction cascade is dysregulated in a majority of human tumors. Here we report that a nanoparticle-mediated targeting of this pathway can optimize cancer chemotherapy. We engineered nanoparticles from a unique hexadentate-polyD,L-lactic acid-co-glycolic acid polymer chemically conjugated to PD98059, a selective MAPK inhibitor. The nanoparticles are taken up by cancer cells through endocytosis and demonstrate sustained release of the active agent, resulting in the inhibition of phosphorylation of downstream extracellular signal regulated kinase. We demonstrate that nanoparticle-mediated targeting of MAPK inhibits the proliferation of melanoma and lung carcinoma cells and induces apoptosis in vitro. Administration of the PD98059-nanoparticles in melanoma-bearing mice inhibits tumor growth and enhances the antitumor efficacy of cisplatin chemotherapy. Our study shows the nanoparticle-mediated delivery of signal transduction inhibitors can emerge as a unique paradigm in cancer chemotherapy.Department of Defense Breast Cancer Research Program Era of Hope Award (W81XWH-07–1-0482)Mary Kay Ash Charitable Trus

Salerno's model of DNA reanalysed: could solitons have biological significance?

We investigate the sequence-dependent behaviour of localised excitations in a toy, nonlinear model of DNA base-pair opening originally proposed by Salerno. Specifically we ask whether ``breather'' solitons could play a role in the facilitated location of promoters by RNA polymerase. In an effective potential formalism, we find excellent correlation between potential minima and {\em Escherichia coli} promoter recognition sites in the T7 bacteriophage genome. Evidence for a similar relationship between phage promoters and downstream coding regions is found and alternative reasons for links between AT richness and transcriptionally-significant sites are discussed. Consideration of the soliton energy of translocation provides a novel dynamical picture of sliding: steep potential gradients correspond to deterministic motion, while ``flat'' regions, corresponding to homogeneous AT or GC content, are governed by random, thermal motion. Finally we demonstrate an interesting equivalence between planar, breather solitons and the helical motion of a sliding protein ``particle'' about a bent DNA axis.Comment: Latex file 20 pages, 5 figures. Manuscript of paper to appear in J. Biol. Phys., accepted 02/09/0

Growth Hormone Reprograms Macrophages toward an Anti-Inflammatory and Reparative Profile in an MAFB-Dependent Manner

Growth hormone (GH), a pleiotropic hormone secreted by the pituitary gland, regulates immune and inflammatory responses. In this study, we show that GH regulates the phenotypic and functional plasticity of macrophages both in vitro and in vivo. Specifically, GH treatment of GM-CSF–primed monocyte–derived macrophages promotes a significant enrichment of anti-inflammatory genes and dampens the proinflammatory cytokine profile through PI3K-mediated downregulation of activin A and upregulation of MAFB, a critical transcription factor for anti-inflammatory polarization of human macrophages. These in vitro data correlate with improved remission of inflammation and mucosal repair during recovery in the acute dextran sodium sulfate–induced colitis model in GH-overexpressing mice. In this model, in addition to the GH-mediated effects on other immune cells, we observed that macrophages from inflamed gut acquire an anti-inflammatory/reparative profile. Overall, these data indicate that GH reprograms inflammatory macrophages to an anti-inflammatory phenotype and improves resolution during pathologic inflammatory responses.This work was supported in part by grants from the Spanish Ministry of Science, Innovation and Universities (SAF2017-82940-R Agencia Estatal de Investigación/Fondo Europeo de Desarrollo Regional (AEI/FEDER), Unión Europea [UE] [to M.M.], SAF2017-83785-R AEI/FEDER, UE [to Á.L.C.] and FJCI-2016-29990 AEI/FEDER, UE [to B.S.P.]), from the Redes Temáticas de Investigación Cooperativa en Salud Program of Instituto de Salud Carlos III (RD12/0012/0006 and RD12/0012/0007, Red de Investigación en Inflamación y Enfermedades Reumáticas), and the Regional Government of Madrid (B2017/BMD-3804 [to C.M.-A.])