Endoplasmic Reticulum PI(3)P Lipid Binding Targets Malaria Proteins to the Host Cell

SummaryHundreds of effector proteins of the human malaria parasite Plasmodium falciparum constitute a “secretome” carrying a host-targeting (HT) signal, which predicts their export from the intracellular pathogen into the surrounding erythrocyte. Cleavage of the HT signal by a parasite endoplasmic reticulum (ER) protease, plasmepsin V, is the proposed export mechanism. Here, we show that the HT signal facilitates export by recognition of the lipid phosphatidylinositol-3-phosphate (PI(3)P) in the ER, prior to and independent of protease action. Secretome HT signals, including those of major virulence determinants, bind PI(3)P with nanomolar affinity and amino acid specificities displayed by HT-mediated export. PI(3)P-enriched regions are detected within the parasite's ER and colocalize with endogenous HT signal on ER precursors, which also display high-affinity binding to PI(3)P. A related pathogenic oomycete's HT signal export is dependent on PI(3)P binding, without cleavage by plasmepsin V. Thus, PI(3)P in the ER functions in mechanisms of secretion and pathogenesis

Rigorous mean field model for CPA: Anderson model with free random variables

A model of a randomly disordered system with site-diagonal random energy fluctuations is introduced. It is an extension of Wegner's $n$-orbital model to arbitrary eigenvalue distribution in the electronic level space. The new feature is that the random energy values are not assumed to be independent at different sites but free. Freeness of random variables is an analogue of the concept of independence for non-commuting random operators. A possible realization is the ensemble of at different lattice-sites randomly rotated matrices. The one- and two-particle Green functions of the proposed hamiltonian are calculated exactly. The eigenstates are extended and the conductivity is nonvanishing everywhere inside the band. The long-range behaviour and the zero-frequency limit of the two-particle Green function are universal with respect to the eigenvalue distribution in the electronic level space. The solutions solve the CPA-equation for the one- and two-particle Green function of the corresponding Anderson model. Thus our (multi-site) model is a rigorous mean field model for the (single-site) CPA. We show how the Llyod model is included in our model and treat various kinds of noises.Comment: 24 pages, 2 diagrams, Rev-Tex. Diagrams are available from the authors upon reques

Semigroups of distributions with linear Jacobi parameters

We show that a convolution semigroup of measures has Jacobi parameters polynomial in the convolution parameter $t$ if and only if the measures come from the Meixner class. Moreover, we prove the parallel result, in a more explicit way, for the free convolution and the free Meixner class. We then construct the class of measures satisfying the same property for the two-state free convolution. This class of two-state free convolution semigroups has not been considered explicitly before. We show that it also has Meixner-type properties. Specifically, it contains the analogs of the normal, Poisson, and binomial distributions, has a Laha-Lukacs-type characterization, and is related to the $q=0$ case of quadratic harnesses.Comment: v3: the article is merged back together with arXiv:1003.4025. A significant revision following suggestions by the referee. 2 pdf figure

Applications of Automata and Graphs: Labeling-Operators in Hilbert Space I

We show that certain representations of graphs by operators on Hilbert space have uses in signal processing and in symbolic dynamics. Our main result is that graphs built on automata have fractal characteristics. We make this precise with the use of Representation Theory and of Spectral Theory of a certain family of Hecke operators. Let G be a directed graph. We begin by building the graph groupoid G induced by G, and representations of G. Our main application is to the groupoids defined from automata. By assigning weights to the edges of a fixed graph G, we give conditions for G to acquire fractal-like properties, and hence we can have fractaloids or G-fractals. Our standing assumption on G is that it is locally finite and connected, and our labeling of G is determined by the "out-degrees of vertices". From our labeling, we arrive at a family of Hecke-type operators whose spectrum is computed. As applications, we are able to build representations by operators on Hilbert spaces (including the Hecke operators); and we further show that automata built on a finite alphabet generate fractaloids. Our Hecke-type operators, or labeling operators, come from an amalgamated free probability construction, and we compute the corresponding amalgamated free moments. We show that the free moments are completely determined by certain scalar-valued functions.Comment: 69 page

The Index of (White) Noises and their Product Systems

(See detailed abstract in the article.) We single out the correct class of spatial product systems (and the spatial endomorphism semigroups with which the product systems are associated) that allows the most far reaching analogy in their classifiaction when compared with Arveson systems. The main differences are that mere existence of a unit is not it sufficient: The unit must be CENTRAL. And the tensor product under which the index is additive is not available for product systems of Hilbert modules. It must be replaced by a new product that even for Arveson systems need not coincide with the tensor product

Aggregatibacter Actinomycetemcomitans Leukotoxin is Post-Translationally Modified by Addition of Either Saturated or Hydroxylated Fatty Acyl Chains

Aggregatibacter actinomycetemcomitans, a common inhabitant of the human upper aerodigestive tract, produces a repeat in toxin (RTX), leukotoxin (LtxA). The LtxA is transcribed as a 114-kDa inactive protoxin with activation being achieved by attachment of short chain fatty acyl groups to internal lysine residues. Methyl esters of LtxA that were isolated from A. actinomycetemcomitans strains JP2 and HK1651 and subjected to gas chromatography/mass spectrometry contained palmitoyl (C16:0, 27-29%) and palmitolyl (C16:1 cis Δ9, 43-44%) fatty acyl groups with smaller quantities of myristic (C14:0, 14%) and stearic (C18:0, 12-14%) fatty acids. Liquid chromatography/mass spectrometry of tryptic peptides from acylated and unacylated recombinant LtxA confirmed that Lys562 and Lys687 are the sites of acyl group attachment. During analysis of recombinant LtxA peptides, we observed peptide spectra that were not observed as part of the RTX acylation schemes of either Escherichia coliα-hemolysin or Bordetella pertussis cyclolysin. Mass calculations of these spectra suggested that LtxA was also modified by the addition of monohydroxylated forms of C14 and C16 acyl groups. Multiple reaction monitoring mass spectrometry identified hydroxymyristic and hydroxypalmitic acids in wild-type LtxA methyl esters. Single or tandem replacement of Lys562 and Lys687 with Arg blocks acylation, resulting in a \u3e75% decrease in cytotoxicity when compared with wild-type toxin, suggesting that these post-translational modifications are playing a critical role in LtxA-mediated target cell cytotoxicity. © 2011 John Wiley & Sons A/S

Aggregatibacter Actinomycetemcomitans Leukotoxin is Post-Translationally Modified by Addition of Either Saturated or Hydroxylated Fatty Acyl Chains

Aggregatibacter actinomycetemcomitans, a common inhabitant of the human upper aerodigestive tract, produces a repeat in toxin (RTX), leukotoxin (LtxA). The LtxA is transcribed as a 114-kDa inactive protoxin with activation being achieved by attachment of short chain fatty acyl groups to internal lysine residues. Methyl esters of LtxA that were isolated from A. actinomycetemcomitans strains JP2 and HK1651 and subjected to gas chromatography/mass spectrometry contained palmitoyl (C16:0, 27–29%) and palmitolyl (C16:1 cis Δ9, 43–44%) fatty acyl groups with smaller quantities of myristic (C14:0, 14%) and stearic (C18:0, 12–14%) fatty acids. Liquid chromatography/mass spectrometry of tryptic peptides from acylated and unacylated recombinant LtxA confirmed that Lys562 and Lys687 are the sites of acyl group attachment. During analysis of recombinant LtxA peptides, we observed peptide spectra that were not observed as part of the RTX acylation schemes of either Escherichia coli α-hemolysin or Bordetella pertussis cyclolysin. Mass calculations of these spectra suggested that LtxA was also modified by the addition of monohydroxylated forms of C14 and C16 acyl groups. Multiple reaction monitoring mass spectrometry identified hydroxymyristic and hydroxypalmitic acids in wild-type LtxA methyl esters. Single or tandem replacement of Lys562 and Lys687 with Arg blocks acylation, resulting in a \u3e75% decrease in cytotoxicity when compared with wild-type toxin, suggesting that these posttranslational modifications are playing a critical role in LtxA-mediated target cell cytotoxicity

Inferring hidden states in Langevin dynamics on large networks: Average case performance

We present average performance results for dynamical inference problems in large networks, where a set of nodes is hidden while the time trajectories of the others are observed. Examples of this scenario can occur in signal transduction and gene regulation networks. We focus on the linear stochastic dynamics of continuous variables interacting via random Gaussian couplings of generic symmetry. We analyze the inference error, given by the variance of the posterior distribution over hidden paths, in the thermodynamic limit and as a function of the system parameters and the ratio {\alpha} between the number of hidden and observed nodes. By applying Kalman filter recursions we find that the posterior dynamics is governed by an "effective" drift that incorporates the effect of the observations. We present two approaches for characterizing the posterior variance that allow us to tackle, respectively, equilibrium and nonequilibrium dynamics. The first appeals to Random Matrix Theory and reveals average spectral properties of the inference error and typical posterior relaxation times, the second is based on dynamical functionals and yields the inference error as the solution of an algebraic equation.Comment: 20 pages, 5 figure

Exosomal αvβ6 integrin is required for monocyte M2 polarization in prostate cancer

Therapeutic approaches aimed at curing prostate cancer are only partially successful given the occurrence of highly metastatic resistant phenotypes that frequently develop in response to therapies. Recently, we have described αvβ6, a surface receptor of the integrin family as a novel therapeutic target for prostate cancer; this epithelial-specific molecule is an ideal target since, unlike other integrins, it is found in different types of cancer but not in normal tissues. We describe a novel αvβ6-mediated signaling pathway that has profound effects on the microenvironment. We show that αvβ6 is transferred from cancer cells to monocytes, including β6-null monocytes, by exosomes and that monocytes from prostate cancer patients, but not from healthy volunteers, express αvβ6. Cancer cell exosomes, purified via density gradients, promote M2 polarization, whereas αvβ6 down-regulation in exosomes inhibits M2 polarization in recipient monocytes. Also, as evaluated by our proteomic analysis, αvβ6 down-regulation causes a significant increase in donor cancer cells, and their exosomes, of two molecules that have a tumor suppressive role, STAT1 and MX1/2. Finally, using the Ptenpc−/− prostate cancer mouse model, which carries a prostate epithelial-specific Pten deletion, we demonstrate that αvβ6 inhibition in vivo causes up-regulation of STAT1 in cancer cells. Our results provide evidence of a novel mechanism that regulates M2 polarization and prostate cancer progression through transfer of αvβ6 from cancer cells to monocytes through exosomes