Implementation of an efficient scheme for calculating nonlinear transfer from wave-wave interactions

Nonlinear transfer from wave-wave interactions is an important term in the action-balance equation governing the evolution of the surface-gravity-wave field. Computation of this term, however, has hitherto been so consuming of computer resources that its full representation has not been feasible in nonparametric two-dimensional computer models of this equation. This paper describes the implementation of a hybrid computational scheme, incorporating a simplification first proposed by Thacker into the EXACT-NL Boltzmann integration scheme of Hasselmann and Hasselmann. This hybrid scheme retains EXACT-NL's symmetry, precision, and two-stage structure, but, by transferring a spectrum-independent preintegration from the second stage to the first, dramatically accelerates the resulting second-stage computation, enabling a relatively efficient and precise determination of nonlinear transfer in two-dimensional wave models. Physically, this preintegration collects together in single hybrid interactions multiple interactions belonging to identical spectral-band quadruplets. Thus all possible interactions are represented, and these interactions are represented in a uniquely efficient manner consistent with the spectral representation. We compute the coefficients in the resulting second-stage hybrid sum by essentially sorting and pre-summing the coefficients generated by a piecewise-constant first-stage EXACT-NL computation, using a variant of EXACT-NL that replaces the gather-scatter operations with a simpler bin-assignment procedure and employs a somewhat simpler set of integration variables. By exploiting the natural scaling of the integrand and partially pre-summing prior to sorting, we are able to further improve the efficiency of this computation for the deep-water case and to refine its integration-grid resolution almost to convergence. In wave-model computations of nonlinear transfer, vectorization on the spatial grid points of the model and selective truncation of the hybrid sum potentially reduce the working computation time for a single model time step to well under one Cray Y-MP single-processor CPU second per hundred grid points, while preserving a remarkably faithful representation of the full transfer

Quantifying the connectivity of a network: The network correlation function method

Networks are useful for describing systems of interacting objects, where the nodes represent the objects and the edges represent the interactions between them. The applications include chemical and metabolic systems, food webs as well as social networks. Lately, it was found that many of these networks display some common topological features, such as high clustering, small average path length (small world networks) and a power-law degree distribution (scale free networks). The topological features of a network are commonly related to the network's functionality. However, the topology alone does not account for the nature of the interactions in the network and their strength. Here we introduce a method for evaluating the correlations between pairs of nodes in the network. These correlations depend both on the topology and on the functionality of the network. A network with high connectivity displays strong correlations between its interacting nodes and thus features small-world functionality. We quantify the correlations between all pairs of nodes in the network, and express them as matrix elements in the correlation matrix. From this information one can plot the correlation function for the network and to extract the correlation length. The connectivity of a network is then defined as the ratio between this correlation length and the average path length of the network. Using this method we distinguish between a topological small world and a functional small world, where the latter is characterized by long range correlations and high connectivity. Clearly, networks which share the same topology, may have different connectivities, based on the nature and strength of their interactions. The method is demonstrated on metabolic networks, but can be readily generalized to other types of networks.Comment: 10 figure

A new modified-rate approach for gas-grain chemical simulations

Understanding grain-surface processes is crucial to interpreting the chemistry of the ISM. However, accurate surface chemistry models are computationally expensive and are difficult to integrate with gas-phase simulations. A new modified-rate method for solving grain-surface chemical systems is presented. Its purpose is accurately to model highly complex systems that can otherwise only be treated using the sometimes inadequate rate-equation approach. In contrast to previous rate-modification techniques, the functional form of the surface production rates was modified, and not simply the rate coefficient. This form is appropriate to the extreme "small-grain" limit, and can be verified using an analytical master-equation approach. Various further modifications were made to this basic form, to account for competition between processes, to improve estimates of surface occupation probabilities, and to allow a switch-over to the normal rate equations where these are applicable. The new method was tested against systems solved previously using exact techniques. Even the simplest method is quite accurate, and a great improvement over rate equations. Further modifications allow the master-equation results to be reproduced exactly for the methanol-producing system, within computational accuracy. Small discrepancies arise when non-zero activation energies are assumed for the methanol system, which result from complex reaction-competition processes that cannot be resolved easily without using exact methods. Inaccuracies in computed abundances are never greater than a few tens of percent, and typically of the order of one percent, in the most complex systems tested. Implementation of the method in simple networks, including hydrogen-only systems, is trivial, whilst the results are highly accurate.Comment: Accepted for publication in Astronomy & Astrophysics. 14 pages, 5 figures, 7 table

Survival Advantage of Both Human Hepatocyte Xenografts and Genome-Edited Hepatocytes for Treatment of α-1 Antitrypsin Deficiency.

Hepatocytes represent an important target for gene therapy and editing of single-gene disorders. In α-1 antitrypsin (AAT) deficiency, one missense mutation results in impaired secretion of AAT. In most patients, lung damage occurs due to a lack of AAT-mediated protection of lung elastin from neutrophil elastase. In some patients, accumulation of misfolded PiZ mutant AAT protein triggers hepatocyte injury, leading to inflammation and cirrhosis. We hypothesized that correcting the Z mutant defect in hepatocytes would confer a selective advantage for repopulation of hepatocytes within an intact liver. A human PiZ allele was crossed onto an immune-deficient (NSG) strain to create a recipient strain (NSG-PiZ) for human hepatocyte xenotransplantation. Results indicate that NSG-PiZ recipients support heightened engraftment of normal human primary hepatocytes as compared with NSG recipients. This model can therefore be used to test hepatocyte cell therapies for AATD, but more broadly it serves as a simple, highly reproducible liver xenograft model. Finally, a promoterless adeno-associated virus (AAV) vector, expressing a wild-type AAT and a synthetic miRNA to silence the endogenous allele, was integrated into the albumin locus. This gene-editing approach leads to a selective advantage of edited hepatocytes, by silencing the mutant protein and augmenting normal AAT production, and improvement of the liver pathology. Mol Ther 2017 Nov 1; 25(11):2477-2489

Survival Advantage of Both Human Hepatocyte Xenografts and Genome-Edited Hepatocytes for Treatment of alpha-1 Antitrypsin Deficiency

Hepatocytes represent an important target for gene therapy and editing of single-gene disorders. In alpha-1 antitrypsin (AAT) deficiency, one missense mutation results in impaired secretion of AAT. In most patients, lung damage occurs due to a lack of AAT-mediated protection of lung elastin from neutrophil elastase. In some patients, accumulation of misfolded PiZ mutant AAT protein triggers hepatocyte injury, leading to inflammation and cirrhosis. We hypothesized that correcting the Z mutant defect in hepatocytes would confer a selective advantage for repopulation of hepatocytes within an intact liver. A human PiZ allele was crossed onto an immune-deficient (NSG) strain to create a recipient strain (NSG-PiZ) for human hepatocyte xenotransplantation. Results indicate that NSG-PiZ recipients support heightened engraftment of normal human primary hepatocytes as compared with NSG recipients. This model can therefore be used to test hepatocyte cell therapies for AATD, but more broadly it serves as a simple, highly reproducible liver xenograft model. Finally, a promoterless adeno-associated virus (AAV) vector, expressing a wild-type AAT and a synthetic miRNA to silence the endogenous allele, was integrated into the albumin locus. This gene-editing approach leads to a selective advantage of edited hepatocytes, by silencing the mutant protein and augmenting normal AAT production, and improvement of the liver pathology

Optimal allocation without transfer payments

Author's draft dated February 2010 issued as discussion paper by University of Exeter Business School. Final version published by Elsevier; available online at http://www.sciencedirect.com/Often an organization or government must allocate goods without collecting payment in return. This may pose a difficult problem either when agents receiving those goods have private information in regards to their values or needs. In this paper, we find an optimal mechanism to allocate goods when the designer is benevolent. While the designer cannot charge agents, he can receive a costly but wasteful signal from them. We find conditions for cases in which ignoring these costly signals by giving agents equal share (or using lotteries if the goods are indivisible) is optimal. In other cases, those that send the highest signal should receive the goods; however, we then show that there exist cases where more complicated mechanisms are superior. Also, we show that the optimal mechanism is independent of the scarcity of the goods being allocated

Mathematics education and technology

Recent international surveys such as the Organisation for Economic Co-operation and Development (OECD) report Students, Computers and Learning ( 2015) highlight the wide gap in students’ access to, and use of, technology in secondary mathematics in participating countries. The OECD “snapshot” methodology in which 15-year-old students were asked if they (or their teachers) had performed a range of mathematical tasks using computers in the month preceding their completion of the Programme for International Student Assessment (PISA) survey revealed low levels of technology use (see Fig. 1)

Insertion Sequence Inversions Mediated by Ectopic Recombination between Terminal Inverted Repeats

Transposable elements are widely distributed and diverse in both eukaryotes and prokaryotes, as exemplified by DNA transposons. As a result, they represent a considerable source of genomic variation, for example through ectopic (i.e. non-allelic homologous) recombination events between transposable element copies, resulting in genomic rearrangements. Ectopic recombination may also take place between homologous sequences located within transposable element sequences. DNA transposons are typically bounded by terminal inverted repeats (TIRs). Ectopic recombination between TIRs is expected to result in DNA transposon inversions. However, such inversions have barely been documented. In this study, we report natural inversions of the most common prokaryotic DNA transposons: insertion sequences (IS). We identified natural TIR-TIR recombination-mediated inversions in 9% of IS insertion loci investigated in Wolbachia bacteria, which suggests that recombination between IS TIRs may be a quite common, albeit largely overlooked, source of genomic diversity in bacteria. We suggest that inversions may impede IS survival and proliferation in the host genome by altering transpositional activity. They may also alter genomic instability by modulating the outcome of ectopic recombination events between IS copies in various orientations. This study represents the first report of TIR-TIR recombination within bacterial IS elements and it thereby uncovers a novel mechanism of structural variation for this class of prokaryotic transposable elements

In Vivo Characterization of the Homing Endonuclease within the polB Gene in the Halophilic Archaeon Haloferax volcanii

Inteins are parasitic genetic elements, analogous to introns that excise themselves at the protein level by self-splicing, allowing the formation of functional non-disrupted proteins. Many inteins contain a homing endonuclease (HEN) gene, and rely on its activity for horizontal propagation. In the halophilic archaeon, Haloferax volcanii, the gene encoding DNA polymerase B (polB) contains an intein with an annotated but uncharacterized HEN. Here we examine the activity of the polB HEN in vivo, within its natural archaeal host. We show that this HEN is highly active, and able to insert the intein into both a chromosomal target and an extra-chromosomal plasmid target, by gene conversion. We also demonstrate that the frequency of its incorporation depends on the length of the flanking homologous sequences around the target site, reflecting its dependence on the homologous recombination machinery. Although several evolutionary models predict that the presence of an intein involves a change in the fitness of the host organism, our results show that a strain deleted for the intein sequence shows no significant changes in growth rate compared to the wild type