Agent-Based Modeling of Intracellular Transport

We develop an agent-based model of the motion and pattern formation of vesicles. These intracellular particles can be found in four different modes of (undirected and directed) motion and can fuse with other vesicles. While the size of vesicles follows a log-normal distribution that changes over time due to fusion processes, their spatial distribution gives rise to distinct patterns. Their occurrence depends on the concentration of proteins which are synthesized based on the transcriptional activities of some genes. Hence, differences in these spatio-temporal vesicle patterns allow indirect conclusions about the (unknown) impact of these genes. By means of agent-based computer simulations we are able to reproduce such patterns on real temporal and spatial scales. Our modeling approach is based on Brownian agents with an internal degree of freedom, $\theta$, that represents the different modes of motion. Conditions inside the cell are modeled by an effective potential that differs for agents dependent on their value $\theta$. Agent's motion in this effective potential is modeled by an overdampted Langevin equation, changes of $\theta$ are modeled as stochastic transitions with values obtained from experiments, and fusion events are modeled as space-dependent stochastic transitions. Our results for the spatio-temporal vesicle patterns can be used for a statistical comparison with experiments. We also derive hypotheses of how the silencing of some genes may affect the intracellular transport, and point to generalizations of the model

Muon capture by 3He nuclei followed by proton and deuteron production

The paper describes an experiment aimed at studying muon capture by ${}^{3}\mathrm{He}$ nuclei in pure ${}^{3}\mathrm{He}$ and $\mathrm{D}_2 + {}^{3}\mathrm{He}$ mixtures at various densities. Energy distributions of protons and deuterons produced via $\mu^-+{}^{3}\mathrm{He}\to p+n+n + \nu_{\mu }$ and $\mu^-+{}^{3} \mathrm{He} \to d+n + \nu_{\mu}$ are measured for the energy intervals $10 - 49$ MeV and $13 - 31$ MeV, respectively. Muon capture rates, $\lambda_\mathrm{cap}^p (\Delta E_p)$ and $\lambda_\mathrm{cap}^d (\Delta E_d)$ are obtained using two different analysis methods. The least--squares methods gives $\lambda_\mathrm{cap}^p = (36.7\pm 1.2) {s}^{- 1}$, $\lambda_\mathrm{cap}^d = (21.3 \pm 1.6) {s}^{- 1}$. The Bayes theorem gives $\lambda_\mathrm{cap}^p = (36.8 \pm 0.8) {s}^{- 1}$, $\lambda_\mathrm{cap}^d = (21.9 \pm 0.6) {s}^{- 1}$. The experimental differential capture rates, $d\lambda_\mathrm{cap}^p (E_p) / dE_p$ and $d\lambda_\mathrm{cap}^d (E_d) / dE_d$, are compared with theoretical calculations performed using the plane--wave impulse approximation (PWIA) with the realistic NN interaction Bonn B potential. Extrapolation to the full energy range yields total proton and deuteron capture rates in good agreement with former results.Comment: 17 pages, 13 figures, accepted for publication in PR

Weak capture of protons by protons

The cross section for the proton weak capture reaction $^1H(p,e^+\nu_e)^2H$ is calculated with wave functions obtained from a number of modern, realistic high-precision interactions. To minimize the uncertainty in the axial two-body current operator, its matrix element has been adjusted to reproduce the measured Gamow-Teller matrix element of tritium $\beta$ decay in model calculations using trinucleon wave functions from these interactions. A thorough analysis of the ambiguities that this procedure introduces in evaluating the two-body current contribution to the pp capture is given. Its inherent model dependence is in fact found to be very weak. The overlap integral $\Lambda^2(E=0)$ for the pp capture is predicted to be in the range 7.05--7.06, including the axial two-body current contribution, for all interactions considered.Comment: 17 pages RevTeX (twocolumn), 5 postscript figure

Induced pseudoscalar coupling of the proton weak interaction

The induced pseudoscalar coupling $g_p$ is the least well known of the weak coupling constants of the proton's charged--current interaction. Its size is dictated by chiral symmetry arguments, and its measurement represents an important test of quantum chromodynamics at low energies. During the past decade a large body of new data relevant to the coupling $g_p$ has been accumulated. This data includes measurements of radiative and non radiative muon capture on targets ranging from hydrogen and few--nucleon systems to complex nuclei. Herein the authors review the theoretical underpinnings of $g_p$, the experimental studies of $g_p$, and the procedures and uncertainties in extracting the coupling from data. Current puzzles are highlighted and future opportunities are discussed.Comment: 58 pages, Latex, Revtex4, prepared for Reviews of Modern Physic

Intracellular Bacteria Encode Inhibitory SNARE-Like Proteins

Pathogens use diverse molecular machines to penetrate host cells and manipulate intracellular vesicular trafficking. Viruses employ glycoproteins, functionally and structurally similar to the SNARE proteins, to induce eukaryotic membrane fusion. Intracellular pathogens, on the other hand, need to block fusion of their infectious phagosomes with various endocytic compartments to escape from the degradative pathway. The molecular details concerning the mechanisms underlying this process are lacking. Using both an in vitro liposome fusion assay and a cellular assay, we showed that SNARE-like bacterial proteins block membrane fusion in eukaryotic cells by directly inhibiting SNARE-mediated membrane fusion. More specifically, we showed that IncA and IcmG/DotF, two SNARE-like proteins respectively expressed by Chlamydia and Legionella, inhibit the endocytic SNARE machinery. Furthermore, we identified that the SNARE-like motif present in these bacterial proteins encodes the inhibitory function. This finding suggests that SNARE-like motifs are capable of specifically manipulating membrane fusion in a wide variety of biological environments. Ultimately, this motif may have been selected during evolution because it is an efficient structural motif for modifying eukaryotic membrane fusion and thus contribute to pathogen survival

Rabies, Still Neglected after 125 Years of Vaccination

International audienceno abstrac

Formulating 'principles of procedure' for the foreign language classroom: A framework for process model language curricula

This article aims to apply Stenhouse's process model of curriculum to foreign language (FL) education, a model which is characterized by enacting principles of procedure which are specific to the discipline which the school subject belongs to. Rather than to replace or dissolve current approaches to FL teaching and curriculum development, this article seeks to improve and enrich communicative and task-based orientations with an additional criterion for assessing the educational worth of the tasks through which these orientations are developed. Unlike the objectives and competences models, principles of procedure provide an intrinsic justification of school curriculum by enacting the epistemological structure of any given area of knowledge in the educational process. Accordingly, the article will first justify the need to come up with a process model of curriculum for FL education which is built around such principles; then, it will formulate a basic framework that reflects the logical structure, concepts and epistemological perspectives of the language studies, as a first step to allowing these to enter the FL classroom and orient the teaching conducted in it; finally, it will present three tasks whose design was inspired by the abovementioned framework, and which were put into practice with Primary education English as a Foreign Language learners during the 2013 2014 and 2014 2015 academic years

Inhibition of Iron Uptake Is Responsible for Differential Sensitivity to V-ATPase Inhibitors in Several Cancer Cell Lines

Many cell lines derived from tumors as well as transformed cell lines are far more sensitive to V-ATPase inhibitors than normal counterparts. The molecular mechanisms underlying these differences in sensitivity are not known. Using global gene expression data, we show that the most sensitive responses to HeLa cells to low doses of V-ATPase inhibitors involve genes responsive to decreasing intracellular iron or decreasing cholesterol and that sensitivity to iron uptake is an important determinant of V-ATPase sensitivity in several cancer cell lines. One of the most sensitive cell lines, melanoma derived SK-Mel-5, over-expresses the iron efflux transporter ferroportin and has decreased expression of proteins involved in iron uptake, suggesting that it actively suppresses cytoplasmic iron. SK-Mel-5 cells have increased production of reactive oxygen species and may be seeking to limit additional production of ROS by iron

Gene fusions and gene duplications: relevance to genomic annotation and functional analysis

BACKGROUND: Escherichia coli a model organism provides information for annotation of other genomes. Our analysis of its genome has shown that proteins encoded by fused genes need special attention. Such composite (multimodular) proteins consist of two or more components (modules) encoding distinct functions. Multimodular proteins have been found to complicate both annotation and generation of sequence similar groups. Previous work overstated the number of multimodular proteins in E. coli. This work corrects the identification of modules by including sequence information from proteins in 50 sequenced microbial genomes. RESULTS: Multimodular E. coli K-12 proteins were identified from sequence similarities between their component modules and non-fused proteins in 50 genomes and from the literature. We found 109 multimodular proteins in E. coli containing either two or three modules. Most modules had standalone sequence relatives in other genomes. The separated modules together with all the single (un-fused) proteins constitute the sum of all unimodular proteins of E. coli. Pairwise sequence relationships among all E. coli unimodular proteins generated 490 sequence similar, paralogous groups. Groups ranged in size from 92 to 2 members and had varying degrees of relatedness among their members. Some E. coli enzyme groups were compared to homologs in other bacterial genomes. CONCLUSION: The deleterious effects of multimodular proteins on annotation and on the formation of groups of paralogs are emphasized. To improve annotation results, all multimodular proteins in an organism should be detected and when known each function should be connected with its location in the sequence of the protein. When transferring functions by sequence similarity, alignment locations must be noted, particularly when alignments cover only part of the sequences, in order to enable transfer of the correct function. Separating multimodular proteins into module units makes it possible to generate protein groups related by both sequence and function, avoiding mixing of unrelated sequences. Organisms differ in sizes of groups of sequence-related proteins. A sample comparison of orthologs to selected E. coli paralogous groups correlates with known physiological and taxonomic relationships between the organisms

SNARE Protein Mimicry by an Intracellular Bacterium

Many intracellular pathogens rely on host cell membrane compartments for their survival. The strategies they have developed to subvert intracellular trafficking are often unknown, and SNARE proteins, which are essential for membrane fusion, are possible targets. The obligate intracellular bacteria Chlamydia replicate within an intracellular vacuole, termed an inclusion. A large family of bacterial proteins is inserted in the inclusion membrane, and the role of these inclusion proteins is mostly unknown. Here we identify SNARE-like motifs in the inclusion protein IncA, which are conserved among most Chlamydia species. We show that IncA can bind directly to several host SNARE proteins. A subset of SNAREs is specifically recruited to the immediate vicinity of the inclusion membrane, and their accumulation is reduced around inclusions that lack IncA, demonstrating that IncA plays a predominant role in SNARE recruitment. However, interaction with the SNARE machinery is probably not restricted to IncA as at least another inclusion protein shows similarities with SNARE motifs and can interact with SNAREs. We modelled IncA's association with host SNAREs. The analysis of intermolecular contacts showed that the IncA SNARE-like motif can make specific interactions with host SNARE motifs similar to those found in a bona fide SNARE complex. Moreover, point mutations in the central layer of IncA SNARE-like motifs resulted in the loss of binding to host SNAREs. Altogether, our data demonstrate for the first time mimicry of the SNARE motif by a bacterium