Emergent spatial correlations in stochastically evolving populations

We study the spatial pattern formation and emerging long range correlations in a model of three species coevolving in space and time according to stochastic contact rules. Analytical results for the pair correlation functions, based on a truncation approximation and supported by computer simulations, reveal emergent strategies of survival for minority agents based on selection of patterns. Minority agents exhibit defensive clustering and cooperative behavior close to phase transitions.Comment: 11 pages, 4 figures, Adobe PDF forma

A New Crucial Protein Interaction Element That Targets the Adenovirus E4-ORF1 Oncoprotein to Membrane Vesicles

Human adenovirus type 9 exclusively elicits mammary tumors in experimental animals, and the primary oncogenic determinant of this virus is the E4-ORF1 oncogene, as opposed to the well-known E1A and E1Boncogenes. The tumorigenic potential of E4-ORF1, as well as its ability to oncogenically stimulate phosphatidylinositol 3-kinase (PI3K), depends on a carboxyl-terminal PDZ domain-binding motif (PBM) that mediates interactions with several different membrane-associated cellular PDZ proteins, including MUPP1, PATJ, MAGI-1, ZO-2, and Dlg1. Nevertheless, because certain E4-ORF1 mutations that alter neither the sequence nor the function of the PBM abolish E4-ORF1-induced PI3K activation and cellular transformation, we reasoned that E4-ORF1 must possess an additional crucial protein element. In the present study, we identified seven E4-ORF1 amino acid residues that define this new element, designated domain 2, and showed that it mediates binding to a 70-kDa cellular phosphoprotein. We also discovered that domain 2 or the PBM independently promotes E4-ORF1 localization to cytoplasmic membrane vesicles and that this activity of domain 2 depends on E4-ORF1 trimerization. Consistent with the latter observation, molecular-modeling analyses predicted that E4-ORF1 trimerization brings together six out of seven domain 2 residues at each of the three subunit interfaces. These findings importantly demonstrate that PI3K activation and cellular transformation induced by E4-ORF1 require two separate protein interaction elements, domain 2 and the PBM, each of which targets E4-ORF1 to vesicle membranes in cells

Evolution of Yin and Yang isoforms of a chromatin remodeling subunit precedes the creation of two genes

Genes can encode multiple isoforms, broadening their functions and providing a molecular substrate to evolve phenotypic diversity. Evolution of isoform function is a potential route to adapt to new environments. Here we show that de novo, beneficial alleles in the nurf-1 gene became fixed in two laboratory lineages of C. elegans after isolation from the wild in 1951, before methods of cryopreservation were developed. nurf-1 encodes an ortholog of BPTF, a large (>300 kD) multidomain subunit of the NURF chromatin remodeling complex. Using CRISPR-Cas9 genome editing and transgenic rescue, we demonstrate that in C. elegans, nurf-1 has split into two, largely non-overlapping isoforms (NURF-1.D and NURF-1.B, which we call Yin and Yang, respectively) that share only two of 26 exons. Both isoforms are essential for normal gametogenesis but have opposite effects on male/female gamete differentiation. Reproduction in hermaphrodites, which involves production of both sperm and oocytes, requires a balance of these opposing Yin and Yang isoforms. Transgenic rescue and genetic position of the fixed mutations suggest that different isoforms are modified in each laboratory strain. In a related clade of Caenorhabditis nematodes, the shared exons have duplicated, resulting in the split of the Yin and Yang isoforms into separate genes, each containing approximately 200 amino acids of duplicated sequence that has undergone accelerated protein evolution following the duplication. Associated with this duplication event is the loss of two additional nurf-1 transcripts, including the long-form transcript and a newly identified, highly expressed transcript encoded by the duplicated exons. We propose these lost transcripts are non-functional side products necessary to transcribe the Yin and Yang transcripts in the same cells. Our work demonstrates how gene sharing, through the production of multiple isoforms, can precede the creation of new, independent genes.National Institute of General Medical Sciences R01GM114170 Patrick T McGrat National Institute of General Medical Sciences R01GM121688 Ronald E Ellis.The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.S

Functionally distinct monomers and trimers produced by a viral oncoprotein

While the process of homo-oligomer formation and disassembly into subunits represents a common strategy to regulate protein activity, reports of proteins in which the subunit and homo-oligomer perform independent functions are scarce. Tumorigenesis induced by the adenovirus E4-ORF1 oncoprotein depends on its binding to a select group of cellular PDZ proteins, including MUPP1, MAGI-1, ZO-2 and Dlg1. We report here that in cells E4-ORF1 exists as both a monomer and trimer and that monomers specifically bind and sequester MUPP1, MAGI-1 and ZO-2 within insoluble complexes whereas trimers specifically bind Dlg1 and promote its translocation to the plasma membrane. This work exposes a novel strategy wherein the oligomerization state of a protein not only determines the capacity to bind separate related targets but also couples the interactions to different functional consequences

Pneumococcal phosphoglycerate kinase interacts with plasminogen and its tissue activator

18 pags, 8 figs, 1 tabStreptococcus pneumoniae is not only a commensal of the nasopharyngeal epithelium, but may also cause life-threatening diseases. Immune- electron microscopy studies revealed that the bacterial glycolytic enzyme, phosphoglycerate kinase (PGK), is localised on the pneumococcal surface of both capsulated and non-capsulated strains and colocalises with plasminogen. Since pneumococci may concentrate host plasminogen (PLG) together with its activators on the bacterial cell surface to facilitate the formation of plasmin, the involvement of PGK in this process was studied. Specific binding of human or murine PLG to strain-independent PGK was documented, and surface plasmon resonance analyses indicated a high affinity interaction with the kringle domains 1-4 of PLG. Crystal structure determination of pneumococcal PGK together with peptide array analysis revealed localisation of PLG-binding site in the N-terminal region and provided structural motifs for the interaction with PLG. Based on structural analysis data, a potential interaction of PGK with tissue plasminogen activator (tPA) was proposed and experimentally confirmed by binding studies, plasmin activity assays and thrombus degradation analyses. © Schattauer 2014.The research leading to these results has received funding from the European Community’s Seventh Framework Program under Grant Agreement no. HEALTH-F3–2009–223111. This work was also supported by grants from the Spanish Ministry of Economy and Competitiveness (BFU2011–25326) and Comunidad Autónoma de Madrid (CAM) S2010-BMD-2457 (BIPEDD2). J.K. is funded by a grant from Ministerio de Economía y Competitividad (BFU2011–24595). A.M. also acknowledges CAM for financial support to the Fundación Severo Ochoa through the AMAROUTO progra

High Throughput Method to Quantify Anterior-Posterior Polarity of T-Cells and Epithelial Cells

The virologic synapse (VS), which is formed between a virus-infected and uninfected cell, plays a central role in the transmission of certain viruses, such as HIV and HTLV-1. During VS formation, HTLV-1-infected T-cells polarize cellular and viral proteins toward the uninfected T-cell. This polarization resembles anterior-posterior cell polarity induced by immunological synapse (IS) formation, which is more extensively characterized than VS formation and occurs when a T-cell interacts with an antigen-presenting cell. One measure of cell polarity induced by both IS or VS formation is the repositioning of the microtubule organizing center (MTOC) relative to the contact point with the interacting cell. Here we describe an automated, high throughput system to score repositioning of the MTOC and thereby cell polarity establishment. The method rapidly and accurately calculates the angle between the MTOC and the IS for thousands of cells. We also show that the system can be adapted to score anterior-posterior polarity establishment of epithelial cells. This general approach represents a significant advancement over manual cell polarity scoring, which is subject to experimenter bias and requires more time and effort to evaluate large numbers of cells

Reflection Spectroscopy of the Black Hole Binary XTE J1752-223 in its Long-Stable Hard State

We present a detailed spectral analysis of the Black Hole Binary XTE J1752-223 in the hard state of its 2009 outburst. Regular monitoring of this source by RXTE provided high signal-to-noise spectra along the outburst rise and decay. During one full month this source stalled at $\sim$30\% of its peak count rate at a constant hardness and intensity. By combining all the data in this exceptionally-stable hard state, we obtained an aggregate PCA spectrum (3-45 keV) with 100 million counts, and a corresponding HEXTE spectrum (20-140 keV) with 5.8 million counts. Implementing a version of our reflection code with a physical model for Comptonization, we obtain tight constraints on important physical parameters for this system. In particular, the inner accretion disk is measured very close in, at $R_\mathrm{in}=1.7\pm0.4$ $R_g$. Assuming $R_\mathrm{in}=R_\mathrm{ISCO}$, we find a relatively high black hole spin ($a_*=0.92\pm0.06$). Imposing a lamppost geometry, we obtain a low inclination ($i=35\pm4$ deg), which agrees with the upper limit found in the radio ($i<49$ deg). However, we note that this model cannot be statistically distinguished from a non-lamppost model with free emissivity index, for which the inclination is markedly higher. Additionally, we find a relatively cool corona ($57-70$ keV), and large iron abundance ($3.3-3.7$ solar). We further find that properly accounting for Comptonization of the reflection emission improves the fit significantly and causes an otherwise low reflection fraction ($\sim 0.2-0.3$) to increase by an order of magnitude, in line with geometrical expectations for a lamppost corona. We compare these results with similar investigations reported for GX 339-4 in its bright hard state.Comment: Accepted for publication in ApJ. 11 pages, 7 figure

Reflection Spectroscopy of the Black Hole Binary XTE J1752−223 in Its Long-stable Hard State

We present a detailed spectral analysis of the black hole binary XTE J1752−223 in the hard state of its 2009 outburst. Regular monitoring of this source by the Rossi X-ray Timing Explorer mission provided high signal-to-noise spectra along the outburst rise and decay. During one full month this source stalled at ~30% of its peak count rate at a constant hardness and intensity. By combining all the data in this exceptionally stable hard state, we obtained an aggregate proportional counter array spectrum (3–45 keV) with 100 million counts, and a corresponding high energy X-ray timing experiment spectrum (20–140 keV) with 5.8 million counts. Implementing a version of our reflection code with a physical model for Comptonization, we obtain tight constraints on important physical parameters for this system. In particular, the inner accretion disk is measured very close in, at R_(in) = 1.7 ± 0.4 R_g . Assuming R_(in_ = R_(ISCO), we find a relatively high black hole spin (a_* = 0.92 ± 0.06). Imposing a lamppost geometry, we obtain a low inclination (i = 35° ± 4°), which agrees with the upper limit found in the radio (i < 49°). However, we note that this model cannot be statistically distinguished from a non-lamppost model with a free emissivity index, for which the inclination is markedly higher. Additionally, we find a relatively cool corona (57–70 keV) and large iron abundance (3.3–3.7 solar). We further find that properly accounting for Comptonization of the reflection emission improves the fit significantly and causes an otherwise low reflection fraction (~0.2–0.3) to increase by an order of magnitude, in line with geometrical expectations for a lamppost corona. We compare these results with similar investigations reported for GX 339−4 in its bright hard state