A Relaxation of Üresin and Dubois’ Asynchronous Fixed-Point Theory in Agda

Abstract: Üresin and Dubois’ paper “Parallel Asynchronous Algorithms for Discrete Data” shows how a class of synchronous iterative algorithms may be transformed into asynchronous iterative algorithms. They then prove that the correctness of the resulting asynchronous algorithm can be guaranteed by reasoning about the synchronous algorithm alone. These results have been used to prove the correctness of various distributed algorithms, including in the fields of routing, numerical analysis and peer-to-peer protocols. In this paper we demonstrate several ways in which the assumptions that underlie this theory may be relaxed. Amongst others, we (i) expand the set of schedules for which the asynchronous iterative algorithm is known to converge and (ii) weaken the conditions that users must prove to hold to guarantee convergence. Furthermore, we demonstrate that two of the auxiliary results in the original paper are incorrect, and explicitly construct a counter-example. Finally, we also relax the alternative convergence conditions proposed by Gurney based on ultrametrics. Many of these relaxations and errors were uncovered after formalising the work in the proof assistant Agda. This paper describes the Agda code and the library that has resulted from this work. It is hoped that the library will be of use to others wishing to formally verify the correctness of asynchronous iterative algorithms

Gut reactions: breaking down xenobiotic–microbiome interactions

The microbiome plays a key role in health and disease, and there has been considerable interest in therapeutic targeting of the microbiome as well as mining this rich resource in drug discovery efforts. However, a growing body of evidence suggests that the gut microbiota can itself influence the actions of a range of xenobiotics, in both beneficial and potentially harmful ways. Traditionally, clinical studies evaluating the pharmacokinetics of new drugs have mostly ignored the important direct and indirect effects of the gut microbiome on drug metabolism and efficacy. Despite some important observations from xenobiotic metabolism in general, there is only an incomplete understanding of the scope of influence of the microbiome specifically on drug metabolism and absorption, and how this might influence systemic concentrations of parent compounds and toxic metabolites. The significance of both microbial metabolism of xenobiotics and the impact of the gut microbiome on host hepatic enzyme systems is nonetheless gaining traction and presents a further challenge in drug discovery efforts, with implications for improving treatment outcomes or counteracting adverse drug reactions. Microbial factors must now be considered when determining drug pharmacokinetics and the impact that an evolving and dynamic microbiome could have in this regard. In this review, we aim to integrate the contribution of the gut microbiome in health and disease to xenobiotic metabolism focusing on therapeutic interventions, pharmacological drug action, and chemical biotransformations that collectively will have implications for the future practice of precision medicine

The Most Metal-Poor Stars. II. Chemical Abundances of 190 Metal-Poor Stars Including 10 New Stars With [Fe/H] < -3.5

We present a homogeneous chemical abundance analysis of 16 elements in 190 metal-poor Galactic halo stars (38 program and 152 literature objects). The sample includes 171 stars with [Fe/H] < -2.5, of which 86 are extremely metal poor, [Fe/H] < -3.0. Our program stars include ten new objects with [Fe/H] < -3.5. We identify a sample of "normal" metal-poor stars and measure the trends between [X/Fe] and [Fe/H], as well as the dispersion about the mean trend for this sample. Using this mean trend, we identify objects that are chemically peculiar relative to "normal" stars at the same metallicity. These chemically unusual stars include CEMP-no objects, one star with high [Si/Fe], another with high [Ba/Sr], and one with unusually low [X/Fe] for all elements heavier than Na. The Sr and Ba abundances indicate that there may be two nucleosynthetic processes at lowest metallicity that are distinct from the main r-process. Finally, for many elements, we find a significant trend between [X/Fe] versus Teff which likely reflects non-LTE and/or 3D effects. Such trends demonstrate that care must be exercised when using abundance measurements in metal-poor stars to constrain chemical evolution and/or nucleosynthesis predictions.Comment: Accepted for publication in Ap

DNA methylation among firefighters

Firefighters are exposed to carcinogens and have elevated cancer rates. We hypothesized that occupational exposures in firefighters would lead to DNA methylation changes associated with activation of cancer pathways and increased cancer risk. To address this hypothesis, we collected peripheral blood samples from 45 incumbent and 41 new recruit nonsmoking male firefighters and analyzed the samples for DNA methylation using an Illumina Methylation EPIC 850k chip. Adjusting for age and ethnicity, we performed: 1) genome-wide differential methylation analysis; 2) genome-wide prediction for firefighter status (incumbent or new recruit) and years of service; and 3) Ingenuity Pathway Analysis (IPA). Four CpGs, including three in the YIPF6, MPST, and PCED1B genes, demonstrated above 1.5-fold statistically significant differential methylation after Bonferroni correction. Genome-wide methylation predicted with high accuracy incumbent and new recruit status as well as years of service among incumbent firefighters. Using IPA, the top pathways with more than 5 gene members annotated from differentially methylated probes included Sirtuin signaling pathway, p53 signaling, and 5' AMP-activated protein kinase (AMPK) signaling. These DNA methylation findings suggest potential cellular mechanisms associated with increased cancer risk in firefighters.US Federal Emergency Management Agency Assistance to Firefighters Grant program [EMW-2014-FP-00200]Open access journalThis item from the UA Faculty Publications collection is made available by the University of Arizona with support from the University of Arizona Libraries. If you have questions, please contact us at [email protected]

An Integrated Approach to Testing Dynamic, Multilevel Theory: Using Computational Models to Connect Theory, Model, and Data

Some of the most influential theories in organizational sciences explicitly describe a dynamic, multilevel process. Yet the inherent complexity of such theories makes them difficult to test. These theories often describe multiple subprocesses that interact reciprocally over time at different levels of analysis and over different time scales. Computational (i.e., mathematical) modeling is increasingly advocated as a method for developing and testing theories of this type. In organizational sciences, however, efforts that have been made to test models empirically are often indirect. We argue that the full potential of computational modeling as a tool for testing dynamic, multilevel theory is yet to be realized. In this article, we demonstrate an approach to testing dynamic, multilevel theory using computational modeling. The approach uses simulations to generate model predictions and Bayesian parameter estimation to fit models to empirical data and facilitate model comparisons. This approach enables a direct integration between theory, model, and data that we believe enables a more rigorous test of theory

Nonperturbative Light-Front QCD

In this work the determination of low-energy bound states in Quantum Chromodynamics is recast so that it is linked to a weak-coupling problem. This allows one to approach the solution with the same techniques which solve Quantum Electrodynamics: namely, a combination of weak-coupling diagrams and many-body quantum mechanics. The key to eliminating necessarily nonperturbative effects is the use of a bare Hamiltonian in which quarks and gluons have nonzero constituent masses rather than the zero masses of the current picture. The use of constituent masses cuts off the growth of the running coupling constant and makes it possible that the running coupling never leaves the perturbative domain. For stabilization purposes an artificial potential is added to the Hamiltonian, but with a coefficient that vanishes at the physical value of the coupling constant. The weak-coupling approach potentially reconciles the simplicity of the Constituent Quark Model with the complexities of Quantum Chromodynamics. The penalty for achieving this perturbative picture is the necessity of formulating the dynamics of QCD in light-front coordinates and of dealing with the complexities of renormalization which such a formulation entails. We describe the renormalization process first using a qualitative phase space cell analysis, and we then set up a precise similarity renormalization scheme with cutoffs on constituent momenta and exhibit calculations to second order. We outline further computations that remain to be carried out. There is an initial nonperturbative but nonrelativistic calculation of the hadronic masses that determines the artificial potential, with binding energies required to be fourth order in the coupling as in QED. Next there is a calculation of the leading radiative corrections to these masses, which requires our renormalization program. Then the real struggle of finding the right extensions to perturbation theory to study the strong-coupling behavior of bound states can begin.Comment: 56 pages (REVTEX), Report OSU-NT-94-28. (figures not included, available via anaonymous ftp from pacific.mps.ohio-state.edu in subdirectory pub/infolight/qcd

Impact of host and environmental factors on β-glucuronidase enzymatic activity: implications for gastrointestinal serotonin

The gastrointestinal tract houses a reservoir of bacterial-derived enzymes which can directly catalyze the metabolism of drugs, dietary elements, and endogenous molecules. Both host and environmental factors may influence this enzymatic activity, with the potential to dictate the availability of the biologically-active form of endogenous molecules in the gut and influence inter-individual variation in drug metabolism. We aimed to investigate the influence of the microbiota, and the modulation of its composition, on fecal enzymatic activity. Intrinsic factors related to the host, including age, sex, and genetic background, were explored. Fecalase, a cell-free extract of feces, was prepared and used in a colorimetric-based assay to quantify enzymatic activity. To demonstrate the functional effects of fecal enzymatic activity, we examined β-glucuronidase-mediated cleavage of serotonin β-D-glucuronide (5-HT-GLU) and the resultant production of free 5-HT by HPLC. As expected, β-glucuronidase and β-glucosidase activity were absent in germ-free mice. Enzymatic activity was significantly influenced by mouse strain and animal species. Sex and age significantly altered metabolic activity with implications for free 5-HT. β-glucuronidase and β-glucosidase activity remained at reduced levels for nearly two weeks after cessation of antibiotic administration. This effect on fecalase corresponded to significantly lower 5-HT levels as compared to incubation with pre-antibiotic fecalase from the same mice. Dietary targeting of the microbiota using prebiotics did not alter β-glucuronidase or β-glucosidase activity. Our data demonstrate that multiple factors influence the activity of bacterial-derived enzymes which may have potential clinical implications for drug metabolism and the deconjugation of host-produced glucuronides in the gut