Efficient inference and identifiability analysis for differential equation models with random parameters

Heterogeneity is a dominant factor in the behaviour of many biological processes. Despite this, it is common for mathematical and statistical analyses to ignore biological heterogeneity as a source of variability in experimental data. Therefore, methods for exploring the identifiability of models that explicitly incorporate heterogeneity through variability in model parameters are relatively underdeveloped. We develop a new likelihood-based framework, based on moment matching, for inference and identifiability analysis of differential equation models that capture biological heterogeneity through parameters that vary according to probability distributions. As our novel method is based on an approximate likelihood function, it is highly flexible; we demonstrate identifiability analysis using both a frequentist approach based on profile likelihood, and a Bayesian approach based on Markov-chain Monte Carlo. Through three case studies, we demonstrate our method by providing a didactic guide to inference and identifiability analysis of hyperparameters that relate to the statistical moments of model parameters from independent observed data. Our approach has a computational cost comparable to analysis of models that neglect heterogeneity, a significant improvement over many existing alternatives. We demonstrate how analysis of random parameter models can aid better understanding of the sources of heterogeneity from biological data.Comment: Minor changes to text. Additional results in supplementary material. Additional statistics regarding results given in main and supplementary materia

Eddy current studies from the undulator-based positron source target wheel prototype

The ef­fi­cien­cy of fu­ture positron sources for the next gen­er­a­tion of high-en­er­gy par­ti­cle col­lid­ers (e.g. ILC, CLIC, LHeC) can be im­proved if the positron-pro­duc­tion tar­get is im­mersed in the mag­net­ic field of ad­ja­cent cap­ture op­tics. If the tar­get is also ro­tat­ing due to heat de­po­si­tion con­sid­er­a­tions then eddy cur­rents may be in­duced and lead to ad­di­tion­al heat­ing and stress­es. In this paper we pre­sent data from a ro­tat­ing tar­get wheel pro­to­type for the base­line ILC positron source. The wheel has been op­er­at­ed at rev­o­lu­tion rates up to 1800rpm in fields of the order of 1 Tesla. Com­par­isons are made be­tween torque data ob­tained from a trans­duc­er on the tar­get drive shaft and the re­sults of fi­nite-el­e­ment sim­u­la­tions. Ro­tor­dy­nam­ics is­sues are pre­sent­ed and fu­ture ex­per­i­ments on other as­pects of the positron source tar­get sta­tion are con­sid­ered

Accelerator system for the PRISM based muon to electron conversion experiment

The next generation of lepton flavor violation experiments need high intensity and high quality muon beams. Production of such beams requires sending a short, high intensity proton pulse to the pion production target, capturing pions and collecting the resulting muons in the large acceptance transport system. The substantial increase of beam quality can be obtained by applying the RF phase rotation on the muon beam in the dedicated FFAG ring, which was proposed for the PRISM project.This allows to reduce the momentum spread of the beam and to purify from the unwanted components like pions or secondary protons. A PRISM Task Force is addressing the accelerator and detector issues that need to be solved in order to realize the PRISM experiment. The parameters of the required proton beam, the principles of the PRISM experiment and the baseline FFAG design are introduced. The spectrum of alternative designs for the PRISM FFAG ring are shown. Progress on ring main systems like injection and RF are presented. The current status of the study and its future directions are discussed.Comment: Studies performed within the PRISM Task Force initiativ

High-resolution temporal profiling of transcripts during Arabidopsis leaf senescence reveals a distinct chronology of processes and regulation

Leaf senescence is an essential developmental process that impacts dramatically on crop yields and involves altered regulation of thousands of genes and many metabolic and signaling pathways, resulting in major changes in the leaf. The regulation of senescence is complex, and although senescence regulatory genes have been characterized, there is little information on how these function in the global control of the process. We used microarray analysis to obtain a highresolution time-course profile of gene expression during development of a single leaf over a 3-week period to senescence. A complex experimental design approach and a combination of methods were used to extract high-quality replicated data and to identify differentially expressed genes. The multiple time points enable the use of highly informative clustering to reveal distinct time points at which signaling and metabolic pathways change. Analysis of motif enrichment, as well as comparison of transcription factor (TF) families showing altered expression over the time course, identify clear groups of TFs active at different stages of leaf development and senescence. These data enable connection of metabolic processes, signaling pathways, and specific TF activity, which will underpin the development of network models to elucidate the process of senescence

Kill and cure: genomic phylogeny and bioactivity of Burkholderia gladioli bacteria capable of pathogenic and beneficial lifestyles.

Burkholderia gladioli is a bacterium with a broad ecology spanning disease in humans, animals and plants, but also encompassing multiple beneficial interactions. It is a plant pathogen, a toxin-producing food-poisoning agent, and causes lung infections in people with cystic fibrosis (CF). Contrasting beneficial traits include antifungal production exploited by insects to protect their eggs, plant protective abilities and antibiotic biosynthesis. We explored the genomic diversity and specialized metabolic potential of 206 B. gladioli strains, phylogenomically defining 5 clades. Historical disease pathovars (pv.) B. gladioli pv. allicola and B. gladioli pv. cocovenenans were distinct, while B. gladioli pv. gladioli and B. gladioli pv. agaricicola were indistinguishable; soft-rot disease and CF infection were conserved across all pathovars. Biosynthetic gene clusters (BGCs) for toxoflavin, caryoynencin and enacyloxin were dispersed across B. gladioli, but bongkrekic acid and gladiolin production were clade-specific. Strikingly, 13 % of CF infection strains characterized were bongkrekic acid-positive, uniquely linking this food-poisoning toxin to this aspect of B. gladioli disease. Mapping the population biology and metabolite production of B. gladioli has shed light on its diverse ecology, and by demonstrating that the antibiotic trimethoprim suppresses bongkrekic acid production, a potential therapeutic strategy to minimize poisoning risk in CF has been identified

Genetic variants alter T-bet binding and gene expression in mucosal inflammatory disease

The polarization of CD4+ T cells into distinct T helper cell lineages is essential for protective immunity against infection, but aberrant T cell polarization can cause autoimmunity. The transcription factor T-bet (TBX21) specifies the Th1 lineage and represses alternative T cell fates. Genome-wide association studies have identified single nucleotide polymorphisms (SNPs) that may be causative for autoimmune diseases. The majority of these polymorphisms are located within non-coding distal regulatory elements. It is considered that these genetic variants contribute to disease by altering the binding of regulatory proteins and thus gene expression, but whether these variants alter the binding of lineage-specifying transcription factors has not been determined. Here, we show that SNPs associated with the mucosal inflammatory diseases Crohn’s disease, ulcerative colitis (UC) and celiac disease, but not rheumatoid arthritis or psoriasis, are enriched at T-bet binding sites. Furthermore, we identify disease-associated variants that alter T-bet binding in vitro and in vivo. ChIP-seq for T-bet in individuals heterozygous for the celiac disease-associated SNPs rs1465321 and rs2058622 and the IBD-associated SNPs rs1551398 and rs1551399, reveals decreased binding to the minor disease-associated alleles. Furthermore, we show that rs1465321 is an expression quantitative trait locus (eQTL) for the neighboring gene IL18RAP, with decreased T-bet binding associated with decreased expression of this gene. These results suggest that genetic polymorphisms may predispose individuals to mucosal autoimmune disease through alterations in T-bet binding. Other disease-associated variants may similarly act by modulating the binding of lineage-specifying transcription factors in a tissue-selective and disease-specific manner

Ascorbic acid supplementation does not lower plasma lipoprotein(a) concentrations

Abstract Elevated plasma concentrations of lipoprotein(a) (Lp[a]) are associated with premature coronary heart disease (CHD). Lp(a) is a lipoprotein particle consisting of low-density lipoprotein (LDL) with apolipoprotein (apo) (a) attached to the apo B-100 component of LDL. It has been hypothesized that ascorbic acid supplementation may reduce plasma levels of Lp(a). The purpose of this study was to determine whether ascorbic acid supplementation at a dose of 1 g/day would lower plasma concentrations of Lp(a) when studied in a randomized, placebo-controlled, blinded fashion. One hundred and one healthy men and women ranging in age from 20 to 69 years were studied for 8 months. Lp(a) values at baseline for the placebo group (n= 52) and the ascorbic acid supplemented group (n= 49) were 0.026 and 0.033 g/l, respectively. The 8-month concentrations were 0.027 g/l (placebo) and 0.038 g/l (supplemented group). None of these values were significantly different from each other. In addition, no difference in plasma Lp(a) concentration was seen between the placebo and supplemented groups when only subjects with an initial Lp(a) value of ]0.050 g/l were analyzed. Our data indicate that plasma Lp(a) concentrations are not significantly affected by ascorbic acid supplementation in healthy human subjects

Study of 2b-decay of Mo-100 and Se-82 using the NEMO3 detector

After analysis of 5797 h of data from the detector NEMO3, new limits on neutrinoless double beta decay of Mo-100 (T_{1/2} > 3.1 10^{23} y, 90% CL) and Se-82 (T_{1/2} > 1.4 10^{23} y, 90% CL) have been obtained. The corresponding limits on the effective majorana neutrino mass are: m < (0.8-1.2) eV and m < (1.5-3.1) eV, respectively. Also the limits on double-beta decay with Majoron emission are: T_{1/2} > 1.4 10^{22} y (90% CL) for Mo-100 and T_{1/2}> 1.2 10^{22} y (90%CL) for Se-82. Corresponding bounds on the Majoron-neutrino coupling constant are g < (0.5-0.9) 10^{-4} and < (0.7-1.6) 10^{-4}. Two-neutrino 2b-decay half-lives have been measured with a high accuracy, T_{1/2} Mo-100 = [7.68 +- 0.02(stat) +- 0.54(syst) ] 10^{18} y and T_{1/2} Se-82 = [10.3 +- 0.3(stat) +- 0.7(syst) ] 10^{19} y.Comment: 5 pages, 4 figure

Study of 2 beta-decay of Mo-100 and Se-82 using the NEMO3 detector

After analysis of 5797 h of data from the detector NEMO3, new limits on neutrinoless double beta decay of Mo-100 (T-1/2 > 3.1 x 10(23) y, 90% CL) and Se-82 (T-1/2 > 1.4 x 10(23) y, 90% CL) have been obtained. The corresponding limits on the effective majorana neutrino mass are: 1.4 x 10(22) y (90% CL) for Mo-100 and T-1/2 > 1.2 x 10(22) y (90% CL) for Se-82. Corresponding bounds on the Majoron-neutrino coupling constant are < (0.5-0.9) x 10(- 4) and <(0.7-1.6) x 10(- 4). Two-neutrino 2beta-decay half-lives have been measured with a high accuracy, (T1/2Mo)-Mo-100 = [7.68 +/- 0.02(stat) +/- 0.54(syst)] x 10(18) y and (T1/2Se)-Se-82 = [10.3 +/- 0.3(stat) +/- 0.7(syst)] x 10(19) y. (C) 2004 MAIK "Nauka/Interperiodica"