A major cellular substrate for protein kinases, annexin II, is a DNA-binding protein

AbstractWe have screened a human cDNA expression library in λgt11 for clones encoding Alu-binding proteins using direct binding of labeled Alu DNA to recombinant phage lysates fixed on a membrane, and isolated a clone 98% identical in sequence to the well-known substrate of protein kinases, annexin II, which was suggested earlier to play a role in transduction of mitogenic signals and DNA replication. A diagnostic property of annexins is their binding to phospholipids in the presence of calcium ions, and we have found that the interaction of proteins of human nuclear extracts with Alu subsequences is suppressed by Ca/phosphatidylserine liposomes, suggesting overlapping of Ca/phospholipid- and DNA-binding domains in annexin II

Prednisone and azathioprine in patients with inflammatory cardiomyopathy: systematic review and meta-analysis

Aims: Chronic non-viral myocarditis, also called inflammatory cardiomyopathy, can be treated with immune suppression on tops of optimal medical therapy (OMT) for heart failure, using a combination of prednisolone and azathioprine (IPA). However, there has been inconsistency in the effects of immunosuppression treatment. This meta-analysis is the first to evaluate all available data of the effect of this treatment on left ventricular ejection fraction (LVEF) and the combined clinical endpoint of cardiovascular mortality and/or heart transplantation-free survival. Methods and results: All trials with using IPA vs. OMT in this syndrome were searched using OVID Medline and ClinicalTrials. gov, following the PRISMA guidelines. Missing data were retrieved after contacting the corresponding authors. All data was reviewed and analysed using and standard meta-analysis methods. A random effect model was used to pool the effect sizes. A total of four trials (three randomised controlled trials and one propensity-matched retrospective registry) including 369 patients were identified. IPA on top of OMT did not improve LVEF [mean difference 9.9% (95% confidence interval -1.8, 21.7)] with significant heterogeneity. When we limited our pooled estimate to the published studies only, significant LVEF improvement by IPA was observed [14% (1.4, 26.6)]. No cardiovascular mortality benefit was observed with the intervention [risk ratio 0.34 (0.08, 1.51)]. Conclusions: At the moment, there is insufficient evidence supporting functional and prognostic benefits of IPA added to OMT in virus negative inflammatory positive cardiomyopathy. Further adequate-powered well-designed prospective RCTs should be warranted to explore the potential effects of adding immunosuppressive therapy to OMT

Asexual and sexual replication in sporulating organisms

This paper develops models describing asexual and sexual replication in sporulating organisms. Replication via sporulation is the replication strategy for all multicellular life, and may even be observed in unicellular life (such as with budding yeast). We consider diploid populations replicating via one of two possible sporulation mechanisms: (1) Asexual sporulation, whereby adult organisms produce single-celled diploid spores that grow into adults themselves. (2) Sexual sporulation, whereby adult organisms produce single-celled diploid spores that divide into haploid gametes. The haploid gametes enter a haploid "pool", where they may recombine with other haploids to form a diploid spore that then grows into an adult. We consider a haploid fusion rate given by second-order reaction kinetics. We work with a simplified model where the diploid genome consists of only two chromosomes, each of which may be rendered defective with a single point mutation of the wild-type. We find that the asexual strategy is favored when the rate of spore production is high compared to the characteristic growth rate from a spore to a reproducing adult. Conversely, the sexual strategy is favored when the rate of spore production is low compared to the characteristic growth rate from a spore to a reproducing adult. As the characteristic growth time increases, or as the population density increases, the critical ratio of spore production rate to organism growth rate at which the asexual strategy overtakes the sexual one is pushed to higher values. Therefore, the results of this model suggest that, for complex multicellular organisms, sexual replication is favored at high population densities, and low growth and sporulation rates.Comment: 8 pages, 5 figures, to be submitted to Journal of Theoretical Biology, figures not included in this submissio

The Error and Repair Catastrophes: A Two-Dimensional Phase Diagram in the Quasispecies Model

This paper develops a two gene, single fitness peak model for determining the equilibrium distribution of genotypes in a unicellular population which is capable of genetic damage repair. The first gene, denoted by $\sigma_{via}$, yields a viable organism with first order growth rate constant $k > 1$ if it is equal to some target ``master'' sequence $\sigma_{via, 0}$. The second gene, denoted by $\sigma_{rep}$, yields an organism capable of genetic repair if it is equal to some target ``master'' sequence $\sigma_{rep, 0}$. This model is analytically solvable in the limit of infinite sequence length, and gives an equilibrium distribution which depends on \mu \equiv L\eps , the product of sequence length and per base pair replication error probability, and \eps_r , the probability of repair failure per base pair. The equilibrium distribution is shown to exist in one of three possible ``phases.'' In the first phase, the population is localized about the viability and repairing master sequences. As \eps_r exceeds the fraction of deleterious mutations, the population undergoes a ``repair'' catastrophe, in which the equilibrium distribution is still localized about the viability master sequence, but is spread ergodically over the sequence subspace defined by the repair gene. Below the repair catastrophe, the distribution undergoes the error catastrophe when $\mu$ exceeds \ln k/\eps_r , while above the repair catastrophe, the distribution undergoes the error catastrophe when $\mu$ exceeds $\ln k/f_{del}$, where $f_{del}$ denotes the fraction of deleterious mutations.Comment: 14 pages, 3 figures. Submitted to Physical Review

Tissue Microenvironments Define and Get Reinforced by Macrophage Phenotypes in Homeostasis or during Inflammation, Repair and Fibrosis

Current macrophage phenotype classifications are based on distinct in vitro culture conditions that do not adequately mirror complex tissue environments. In vivo monocyte progenitors populate all tissues for immune surveillance which supports the maintenance of homeostasis as well as regaining homeostasis after injury. Here we propose to classify macrophage phenotypes according to prototypical tissue environments, e.g. as they occur during homeostasis as well as during the different phases of (dermal) wound healing. In tissue necrosis and/or infection, damage- and/or pathogen-associated molecular patterns induce proinflammatory macrophages by Toll-like receptors or inflammasomes. Such classically activated macrophages contribute to further tissue inflammation and damage. Apoptotic cells and antiinflammatory cytokines dominate in postinflammatory tissues which induce macrophages to produce more antiinflammatory mediators. Similarly, tumor-associated macrophages also confer immunosuppression in tumor stroma. Insufficient parenchymal healing despite abundant growth factors pushes macrophages to gain a profibrotic phenotype and promote fibrocyte recruitment which both enforce tissue scarring. Ischemic scars are largely devoid of cytokines and growth factors so that fibrolytic macrophages that predominantly secrete proteases digest the excess extracellular matrix. Together, macrophages stabilize their surrounding tissue microenvironments by adapting different phenotypes as feed-forward mechanisms to maintain tissue homeostasis or regain it following injury. Furthermore, macrophage heterogeneity in healthy or injured tissues mirrors spatial and temporal differences in microenvironments during the various stages of tissue injury and repair. Copyright (C) 2012 S. Karger AG, Base

Search for a massive invisible particle X0X^0 in B+→e+X0B^{+}\to e^{+}X^{0} and B+→μ+X0B^{+}\to \mu^{+}X^{0} decays

We present a search for a non-Standard-Model invisible particle $X^0$ in the mass range $0.1\textrm{-}1.8 \,{\rm GeV}/{c^2}$ in $B^{+}\to e^{+} X^{0}$ and $B^{+}\to \mu^{+} X^{0}$ decays. The results are obtained from a $711~{\rm fb}^{-1}$ data sample that corresponds to $772 \times 10^{6} B\bar{B}$ pairs, collected at the $\Upsilon(4S)$ resonance with the Belle detector at the KEKB $e^+ e^-$ collider. One $B$ meson is fully reconstructed in a hadronic mode to determine the momentum of the lepton of the signal decay in the rest frame of the recoiling partner $B$ meson. We find no evidence of a signal and set upper limits on the order of $10^{-6}$.Comment: 8 pages, 4 figures, 3 table