Toxoplasma effectors targeting host signaling and transcription

Early electron microscopy studies revealed the elaborate cellular features that define the unique adaptations of apicomplexan parasites. Among these were bulbous rhoptry (ROP) organelles and small, dense granules (GRAs), both of which are secreted during invasion of host cells. These early morphological studies were followed by the exploration of the cellular contents of these secretory organelles, revealing them to be comprised of highly divergent protein families with few conserved domains or predicted functions. In parallel, studies on host-pathogen interactions identified many host signaling pathways that were mysteriously altered by infection. It was only with the advent of forward and reverse genetic strategies that the connections between individual parasite effectors and the specific host pathways that they targeted finally became clear. The current repertoire of parasite effectors includes ROP kinases and pseudokinases that are secreted during invasion and that block host immune pathways. Similarly, many secretory GRA proteins alter host gene expression by activating host transcription factors, through modification of chromatin, or by inducing small noncoding RNAs. These effectors highlight novel mechanisms by whichhas learned to harness host signaling to favor intracellular survival and will guide future studies designed to uncover the additional complexity of this intricate host-pathogen interaction

Sine-Gordon Model - Renormalization Group Solutions and Applications

The sine-Gordon model is discussed and analyzed within the framework of the renormalization group theory. A perturbative renormalization group procedure is carried out through a decomposition of the sine-Gordon field in slow and fast modes. An effective slow modes's theory is derived and re-scaled to obtain the model's flow equations. The resulting Kosterlitz-Thouless phase diagram is obtained and discussed in detail. The theory's gap is estimated in terms of the sine-Gordon model paramaters. The mapping between the sine-Gordon model and models for interacting electrons in one dimension, such as the g-ology model and Hubbard model, is discussed and the previous renormalization group results, obtained for the sine-Gordon model, are thus borrowed to describe different aspects of Luttinger liquid systems, such as the nature of its excitations and phase transitions. The calculations are carried out in a thorough and pedagogical manner, aiming the reader with no previous experience with the sine-Gordon model or the renormalization group approach.Comment: 44 pages, 7 figure

CurlySMILES: a chemical language to customize and annotate encodings of molecular and nanodevice structures

CurlySMILES is a chemical line notation which extends SMILES with annotations for storage, retrieval and modeling of interlinked, coordinated, assembled and adsorbed molecules in supramolecular structures and nanodevices. Annotations are enclosed in curly braces and anchored to an atomic node or at the end of the molecular graph depending on the annotation type. CurlySMILES includes predefined annotations for stereogenicity, electron delocalization charges, extra-molecular interactions and connectivity, surface attachment, solutions, and crystal structures and allows extensions for domain-specific annotations. CurlySMILES provides a shorthand format to encode molecules with repetitive substructural parts or motifs such as monomer units in macromolecules and amino acids in peptide chains. CurlySMILES further accommodates special formats for non-molecular materials that are commonly denoted by composition of atoms or substructures rather than complete atom connectivity

Transport phenomena in electrolyte solutions: Non-equilibrium thermodynamics and statistical mechanics

The theory of transport phenomena in multicomponent electrolyte solutions is presented here through the integration of continuum mechanics, electromagnetism, and non-equilibrium thermodynamics. The governing equations of irreversible thermodynamics, including balance laws, Maxwell's equations, internal entropy production, and linear laws relating the thermodynamic forces and fluxes, are derived. Green-Kubo relations for the transport coefficients connecting electrochemical potential gradients and diffusive fluxes are obtained in terms of the flux-flux time correlations. The relationship between the derived transport coefficients and those of the Stefan-Maxwell and infinitely dilute frameworks are presented, and the connection between the transport matrix and experimentally measurable quantities is described. To exemplify application of the derived Green-Kubo relations in molecular simulations, the matrix of transport coefficients for lithium and chloride ions in dimethyl sulfoxide is computed using classical molecular dynamics and compared with experimental measurements.Comment: fixed typos, added references, addressed comment

Experimental signature of the attractive Coulomb force between positive and negative magnetic monopoles in spin ice

A non-Ohmic current that grows exponentially with the square root of applied electric field is well known from thermionic field emission (the Schottky effect)1, electrolytes (the second Wien effect)2 and semiconductors (the Poole–Frenkel effect)3. It is a universal signature of the attractive Coulomb force between positive and negative electrical charges, which is revealed as the charges are driven in opposite directions by the force of an applied electric field. Here we apply thermal quenches4 to spin ice5,6,7,8,9,10,11 to prepare metastable populations of bound pairs of positive and negative emergent magnetic monopoles12,13,14,15,16 at millikelvin temperatures. We find that the application of a magnetic field results in a universal exponential-root field growth of magnetic current, thus confirming the microscopic Coulomb force between the magnetic monopole quasiparticles and establishing a magnetic analogue of the Poole–Frenkel effect. At temperatures above 300 mK, gradual restoration of kinetic monopole equilibria causes the non-Ohmic current to smoothly evolve into the high-field Wien effect2 for magnetic monopoles, as confirmed by comparison to a recent and rigorous theory of the Wien effect in spin ice17,18. Our results extend the universality of the exponential-root field form into magnetism and illustrate the power of emergent particle kinetics to describe far-from-equilibrium response in complex systems

Geographic mobility and social inequality among Peruvian university students

The purpose of this study was to explore geographic mobility among university students in Peru and to understand how mobility patterns differ by region and by demographic indicators of inequality. The ways that students may be able to move geographically in order to access quality higher education within the educational system can be a driver of equality or inequality, depending on who is able to take advantage. Using data from a university census, we examine how demographic indicators of inequality are related to geographic mobility for university attendance, how prior geographic mobility predicts later mobility for university attendance, and how these relationships differ based on the number and quality of universities in a region. Results show that sociodemographic variables related to social inequality explain a substantial amount of students\u27 postsecondary mobility. However, some of these relationships do not operate in the same way in all of the regions. Depending on the availability of universities and their quality, patterns of association between inequality and geographic mobility change. Implications for higher education policy as well as further research examining geographic mobility and inequality in education are discussed

Island method for estimating the statistical significance of profile-profile alignment scores

<p>Abstract</p> <p>Background</p> <p>In the last decade, a significant improvement in detecting remote similarity between protein sequences has been made by utilizing alignment profiles in place of amino-acid strings. Unfortunately, no analytical theory is available for estimating the significance of a gapped alignment of two profiles. Many experiments suggest that the distribution of local profile-profile alignment scores is of the Gumbel form. However, estimating distribution parameters by random simulations turns out to be computationally very expensive.</p> <p>Results</p> <p>We demonstrate that the background distribution of profile-profile alignment scores heavily depends on profiles' composition and thus the distribution parameters must be estimated independently, for each pair of profiles of interest. We also show that accurate estimates of statistical parameters can be obtained using the "island statistics" for profile-profile alignments.</p> <p>Conclusion</p> <p>The island statistics can be generalized to profile-profile alignments to provide an efficient method for the alignment score normalization. Since multiple island scores can be extracted from a single comparison of two profiles, the island method has a clear speed advantage over the direct shuffling method for comparable accuracy in parameter estimates.</p

Evidence for Regulated Interleukin-4 Expression in Chondrocyte-Scaffolds under In Vitro Inflammatory Conditions

OBJECTIVE: To elucidate the anti-inflammatory and anabolic effects of regulated expression of IL-4 in chondrocyte-scaffolds under in vitro inflammatory conditions. METHODS: Mature articular chondrocytes from dogs (n = 3) were conditioned through transient transfection using pcDNA3.1.cIL-4 (constitutive) or pCOX-2.cIL-4 (cytokine-responsive) plasmids. Conditioned cells were seeded in alginate microspheres and rat-tail collagen type I matrix (CaReS®) to generate two types of tissue-engineered 3-dimensional scaffolds. Inflammatory arthritis was simulated in the packed chondrocytes through exogenous addition of recombinant canine (rc) IL-1β (100 ng/ml) plus rcTNFα (50 ng/ml) in culture media for 96 hours. Harvested cells and culture media were analyzed by various assays to monitor the anti-inflammatory and regenerative (anabolic) properties of cIL-4. RESULTS: cIL-4 was expressed from COX-2 promoter exclusively on the addition of rcIL-1β and rcTNFα while its expression from CMV promoter was constitutive. The expressed cIL-4 downregulated the mRNA expression of IL-1β, TNFα, IL-6, iNOS and COX-2 in the cells and inhibited the production of NO and PGE(2) in culture media. At the same time, it up-regulated the expression of IGF-1, IL-1ra, COL2a1 and aggrecan in conditioned chondrocytes in both scaffolds along with a diminished release of total collagen and sGAG into the culture media. An increased amount of cIL-4 protein was detected both in chondrocyte cell lysate and in concentrated culture media. Neutralizing anti-cIL-4 antibody assay confirmed that the anti-inflammatory and regenerative effects seen are exclusively driven by cIL-4. There was a restricted expression of IL-4 under COX-2 promoter possibly due to negative feedback loop while it was over-expressed under CMV promoter (undesirable). Furthermore, the anti-inflammatory /anabolic outcomes from both scaffolds were reproducible and the therapeutic effects of cIL-4 were both scaffold- and promoter-independent. CONCLUSIONS: Regulated expression of therapeutic candidate gene(s) coupled with suitable scaffold(s) could potentially serve as a useful tissue-engineering tool to devise future treatment strategies for osteoarthritis