Metastability for reversible probabilistic cellular automata with self--interaction

The problem of metastability for a stochastic dynamics with a parallel updating rule is addressed in the Freidlin--Wentzel regime, namely, finite volume, small magnetic field, and small temperature. The model is characterized by the existence of many fixed points and cyclic pairs of the zero temperature dynamics, in which the system can be trapped in its way to the stable phase. %The characterization of the metastable behavior %of a system in the context of parallel dynamics is a very difficult task, %since all the jumps in the configuration space are allowed. Our strategy is based on recent powerful approaches, not needing a complete description of the fixed points of the dynamics, but relying on few model dependent results. We compute the exit time, in the sense of logarithmic equivalence, and characterize the critical droplet that is necessarily visited by the system during its excursion from the metastable to the stable state. We need to supply two model dependent inputs: (1) the communication energy, that is the minimal energy barrier that the system must overcome to reach the stable state starting from the metastable one; (2) a recurrence property stating that for any configuration different from the metastable state there exists a path, starting from such a configuration and reaching a lower energy state, such that its maximal energy is lower than the communication energy

Identification of inhibitors of Plasmodium falciparum phosphoethanolamine methyltransferase using an enzyme-coupled transmethylation assay

<p>Abstract</p> <p>Background</p> <p>The phosphoethanolamine methyltransferase, PfPMT, of the human malaria parasite <it>Plasmodium falciparum</it>, a member of a newly identified family of phosphoethanolamine methyltransferases (PMT) found solely in some protozoa, nematodes, frogs, and plants, is involved in the synthesis of the major membrane phospholipid, phosphatidylcholine. PMT enzymes catalyze a three-step S-adenosylmethionine-dependent methylation of the nitrogen atom of phosphoethanolamine to form phosphocholine. In <it>P. falciparum</it>, this activity is a limiting step in the pathway of synthesis of phosphatidylcholine from serine and plays an important role in the development, replication and survival of the parasite within human red blood cells.</p> <p>Results</p> <p>We have employed an enzyme-coupled methylation assay to screen for potential inhibitors of PfPMT. In addition to hexadecyltrimethylammonium, previously known to inhibit PfPMT, two compounds dodecyltrimethylammonium and amodiaquine were also found to inhibit PfPMT activity <it>in vitro</it>. Interestingly, PfPMT activity was not inhibited by the amodiaquine analog, chloroquine, or other aminoquinolines, amino alcohols, or histamine methyltransferase inhibitors. Using yeast as a surrogate system we found that unlike wild-type cells, yeast mutants that rely on PfPMT for survival were sensitive to amodiaquine, and their phosphatidylcholine biosynthesis was inhibited by this compound. Furthermore NMR titration studies to characterize the interaction between amoidaquine and PfPMT demonstrated a specific and concentration dependent binding of the compound to the enzyme.</p> <p>Conclusion</p> <p>The identification of amodiaquine as an inhibitor of PfPMT <it>in vitro </it>and in yeast, and the biophysical evidence for the specific interaction of the compound with the enzyme will set the stage for the development of analogs of this drug that specifically inhibit this enzyme and possibly other PMTs.</p

Magnetic order in the Ising model with parallel dynamics

It is discussed how the equilibrium properties of the Ising model are described by an Hamiltonian with an antiferromagnetic low temperature behavior if only an heat bath dynamics, with the characteristics of a Probabilistic Cellular Automaton, is assumed to determine the temporal evolution of the system.Comment: 9 pages, 3 figure

Critical droplets in Metastable States of Probabilistic Cellular Automata

We consider the problem of metastability in a probabilistic cellular automaton (PCA) with a parallel updating rule which is reversible with respect to a Gibbs measure. The dynamical rules contain two parameters $\beta$ and $h$ which resemble, but are not identical to, the inverse temperature and external magnetic field in a ferromagnetic Ising model; in particular, the phase diagram of the system has two stable phases when $\beta$ is large enough and $h$ is zero, and a unique phase when $h$ is nonzero. When the system evolves, at small positive values of $h$, from an initial state with all spins down, the PCA dynamics give rise to a transition from a metastable to a stable phase when a droplet of the favored $+$ phase inside the metastable $-$ phase reaches a critical size. We give heuristic arguments to estimate the critical size in the limit of zero ``temperature'' ($\beta\to\infty$), as well as estimates of the time required for the formation of such a droplet in a finite system. Monte Carlo simulations give results in good agreement with the theoretical predictions.Comment: 5 LaTeX picture

An Exactly Solvable Anisotropic Directed Percolation Model in Three Dimensions

We solve exactly a special case of the anisotropic directed bond percolation problem in three dimensions, in which the occupation probability is 1 along two spatial directions, by mapping it to a five-vertex model. We determine the asymptotic shape of the ininite cluster and hence the direction dependent critical probability. The exponents characterising the fluctuations of the boundary of the wetted cluster in d-dimensions are related to those of the (d-2)-dimensional KPZ equation.Comment: 4 pages, RevTex, 4 figures. 1 reference added, minor change

The Statistical Physics of Regular Low-Density Parity-Check Error-Correcting Codes

A variation of Gallager error-correcting codes is investigated using statistical mechanics. In codes of this type, a given message is encoded into a codeword which comprises Boolean sums of message bits selected by two randomly constructed sparse matrices. The similarity of these codes to Ising spin systems with random interaction makes it possible to assess their typical performance by analytical methods developed in the study of disordered systems. The typical case solutions obtained via the replica method are consistent with those obtained in simulations using belief propagation (BP) decoding. We discuss the practical implications of the results obtained and suggest a computationally efficient construction for one of the more practical configurations.Comment: 35 pages, 4 figure

Universal Short-Time Dynamics in the Kosterlitz-Thouless Phase

We study the short-time dynamics of systems that develop ``quasi long-range order'' after a quench to the Kosterlitz-Thouless phase. With the working hypothesis that the ``universal short-time behavior'', previously found in Ising-like systems, also occurs in the Kosterlitz-Thouless phase, we explore the scaling behavior of thermodynamic variables during the relaxational process following the quench. As a concrete example, we investigate the two-dimensional $6$-state clock model by Monte Carlo simulation. The exponents governing the magnetization, the second moment, and the autocorrelation function are calculated. From them, by means of scaling relations, estimates for the equilibrium exponents $z$ and $\eta$ are derived. In particular, our estimates for the temperature-dependent anomalous dimension $\eta$ that governs the static correlation function are consistent with existing analytical and numerical results and, thus, confirm our working hypothesis.Comment: 16 pages, 9 postscript figures, REVTEX 3.0, submitted to Phys. Rev.

GWAS of random glucose in 476,326 individuals provide insights into diabetes pathophysiology, complications and treatment stratification

This is the final version. Available on open access from Nature Research via the DOI in this recordData availability: Meta-analysis summary statistics for the GWAS presented in this manuscript are available on the MAGIC website (magicinvestigators.org) and through the NHGRI-EBI GWAS Catalog (https://www.ebi.ac.uk/gwas/downloads/summary-statistics, GCP ID: GCP000666; with study accession codes for Europeans-only meta-analysis: GCST90271557; cross-ancestry meta-analysis: GCST90271558; and sex-dimorphic meta-analysis: GCST90271559). UK Biobank individual-level data can be obtained through a data access application available at https://www.ukbiobank.ac.uk/. In this study, we made use of data made available by: 1000 Genomes project (https://www.genome.gov/27528684/1000-genomes-project); SNPsnap (https://data.broadinstitute.org/mpg/snpsnap/index.html); Tabula Muris (https://www.czbiohub.org/tabula-muris/); GTEx Consortium (https://gtexportal.org/home/); microbiome GWAS (https://mibiogen.gcc.rug.nl/); Human Gut Microbiome Atlas (https://www.microbiomeatlas.org); eQTLGen Consortium (https://www.eqtlgen.org/); TIGER expression data (http://tiger.bsc.es/) and LDHub database (http://ldsc.broadinstitute.org/ldhub/).Conventional measurements of fasting and postprandial blood glucose levels investigated in genome-wide association studies (GWAS) cannot capture the effects of DNA variability on ‘around the clock’ glucoregulatory processes. Here we show that GWAS meta-analysis of glucose measurements under nonstandardized conditions (random glucose (RG)) in 476,326 individuals of diverse ancestries and without diabetes enables locus discovery and innovative pathophysiological observations. We discovered 120 RG loci represented by 150 distinct signals, including 13 with sex-dimorphic effects, two cross-ancestry and seven rare frequency signals. Of these, 44 loci are new for glycemic traits. Regulatory, glycosylation and metagenomic annotations highlight ileum and colon tissues, indicating an underappreciated role of the gastrointestinal tract in controlling blood glucose. Functional follow-up and molecular dynamics simulations of lower frequency coding variants in glucagon-like peptide-1 receptor (GLP1R), a type 2 diabetes treatment target, reveal that optimal selection of GLP-1R agonist therapy will benefit from tailored genetic stratification. We also provide evidence from Mendelian randomization that lung function is modulated by blood glucose and that pulmonary dysfunction is a diabetes complication. Our investigation yields new insights into the biology of glucose regulation, diabetes complications and pathways for treatment stratification

GWAS of random glucose in 476,326 individuals provide insights into diabetes pathophysiology, complications and treatment stratification

Conventional measurements of fasting and postprandial blood glucose levels investigated in genome-wide association studies (GWAS) cannot capture the effects of DNA variability on ‘around the clock’ glucoregulatory processes. Here we show that GWAS meta-analysis of glucose measurements under nonstandardized conditions (random glucose (RG)) in 476,326 individuals of diverse ancestries and without diabetes enables locus discovery and innovative pathophysiological observations. We discovered 120 RG loci represented by 150 distinct signals, including 13 with sex-dimorphic effects, two cross-ancestry and seven rare frequency signals. Of these, 44 loci are new for glycemic traits. Regulatory, glycosylation and metagenomic annotations highlight ileum and colon tissues, indicating an underappreciated role of the gastrointestinal tract in controlling blood glucose. Functional follow-up and molecular dynamics simulations of lower frequency coding variants in glucagon-like peptide-1 receptor (GLP1R), a type 2 diabetes treatment target, reveal that optimal selection of GLP-1R agonist therapy will benefit from tailored genetic stratification. We also provide evidence from Mendelian randomization that lung function is modulated by blood glucose and that pulmonary dysfunction is a diabetes complication. Our investigation yields new insights into the biology of glucose regulation, diabetes complications and pathways for treatment stratification