Revisiting lagrange relaxation (LR) for processing large-scale mixed integer programming (MIP) problems

Lagrangean Relaxation has been successfully applied to process many well known instances of NP-hard Mixed Integer Programming problems. In this paper we present a Lagrangean Relaxation based generic solver for processing Mixed Integer Programming problems. We choose the constraints, which are relaxed using a constraint classification scheme. The tactical issue of updating the Lagrange multiplier is addressed through sub-gradient optimisation; alternative rules for updating their values are investigated. The Lagrangean relaxation provides a lower bound to the original problem and the upper bound is calculated using a heuristic technique. The bounds obtained by the Lagrangean Relaxation based generic solver were used to warm-start the Branch and Bound algorithm; the performance of the generic solver and the effect of the alternative control settings are reported for a wide class of benchmark models. Finally, we present an alternative technique to calculate the upper bound, using a genetic algorithm that benefits from the mathematical structure of the constraints. The performance of the genetic algorithm is also presented

Predicting protein function with hierarchical phylogenetic profiles: The Gene3D phylo-tuner method applied to eukaryotic Genomes

"Phylogenetic profiling'' is based on the hypothesis that during evolution functionally or physically interacting genes are likely to be inherited or eliminated in a codependent manner. Creating presence-absence profiles of orthologous genes is now a common and powerful way of identifying functionally associated genes. In this approach, correctly determining orthology, as a means of identifying functional equivalence between two genes, is a critical and nontrivial step and largely explains why previous work in this area has mainly focused on using presence-absence profiles in prokaryotic species. Here, we demonstrate that eukaryotic genomes have a high proportion of multigene families whose phylogenetic profile distributions are poor in presence-absence information content. This feature makes them prone to orthology mis-assignment and unsuited to standard profile-based prediction methods. Using CATH structural domain assignments from the Gene3D database for 13 complete eukaryotic genomes, we have developed a novel modification of the phylogenetic profiling method that uses genome copy number of each domain superfamily to predict functional relationships. In our approach, superfamilies are subclustered at ten levels of sequence identity from 30% to 100% - and phylogenetic profiles built at each level. All the profiles are compared using normalised Euclidean distances to identify those with correlated changes in their domain copy number. We demonstrate that two protein families will "auto-tune'' with strong co-evolutionary signals when their profiles are compared at the similarity levels that capture their functional relationship. Our method finds functional relationships that are not detectable by the conventional presence - absence profile comparisons, and it does not require a priori any fixed criteria to define orthologous genes

Prevalence of asymptomatic malaria and bed net ownership and use in Bhutan, 2013: a country earmarked for malaria elimination

BACKGROUND With dwindling malaria cases in Bhutan in recent years, the government of Bhutan has made plans for malaria elimination by 2016. This study aimed to determine coverage, use and ownership of LLINs, as well as the prevalence of asymptomatic malaria at a single time-point, in four sub-districts of Bhutan. METHODS A cross-sectional study was carried out in August 2013. Structured questionnaires were administered to a single respondent in each household (HH) in four sub-districts. Four members from 25 HH, randomly selected from each sub-district, were tested using rapid diagnostic tests (RDT) for asymptomatic Plasmodium falciparum and Plasmodium vivax infection. Multivariable logistic regression models were used to identify factors associated with LLIN use and maintenance. RESULTS All blood samples from 380 participants tested negative for Plasmodium infections. A total of 1,223 HH (92.5% of total HH) were surveyed for LLIN coverage and use. Coverage of LLINs was 99.0% (1,203/1,223 HH). Factors associated with decreased odds of sleeping under a LLIN included: washing LLINs nine months compared to washing LLINs every six months; HH in the least poor compared to the most poor socio-economic quintile; a HH income of Nu 5,001-10,000 (US$1 = Nu 59.55), and Nu >10,000, compared to HH with income of <Nu 1,500; HH located one to three hours walking distance to a health centre compared to being located closer to a health centre; a reported lack of knowledge as to what to do in event of LLINs being torn; and keeping LLINs in a box compared to keeping them hanging in the place of use. Factors associated with use of LLINs for purposes other than the intended use included: income group Nu 1,501-3,000 and HH located one to three hours walking distance from a health centre. CONCLUSIONS There was high coverage of LLINs in the study area with regular use of LLINs throughout the year. LLIN use for purposes other than malaria prevention was low. With high coverage and regular use of LLINs, and a zero prevalence of malaria infection found in historically high-risk communities during the peak malaria season, it appears Bhutan is on course to achieve malaria elimination.We acknowledge Queensland Infectious Disease Unit for providing funds to carry out this study

Agent-based modeling: a systematic assessment of use cases and requirements for enhancing pharmaceutical research and development productivity.

A crisis continues to brew within the pharmaceutical research and development (R&amp;D) enterprise: productivity continues declining as costs rise, despite ongoing, often dramatic scientific and technical advances. To reverse this trend, we offer various suggestions for both the expansion and broader adoption of modeling and simulation (M&amp;S) methods. We suggest strategies and scenarios intended to enable new M&amp;S use cases that directly engage R&amp;D knowledge generation and build actionable mechanistic insight, thereby opening the door to enhanced productivity. What M&amp;S requirements must be satisfied to access and open the door, and begin reversing the productivity decline? Can current methods and tools fulfill the requirements, or are new methods necessary? We draw on the relevant, recent literature to provide and explore answers. In so doing, we identify essential, key roles for agent-based and other methods. We assemble a list of requirements necessary for M&amp;S to meet the diverse needs distilled from a collection of research, review, and opinion articles. We argue that to realize its full potential, M&amp;S should be actualized within a larger information technology framework--a dynamic knowledge repository--wherein models of various types execute, evolve, and increase in accuracy over time. We offer some details of the issues that must be addressed for such a repository to accrue the capabilities needed to reverse the productivity decline

The Stratigraphic Record of Pre-breakup Geodynamics: Evidence from the Barrow Delta, offshore Northwest Australia

The structural and stratigraphic evolution of rift basins and passive margins has been widely studied, with many analyses demonstrating that delta systems can provide important records of post-rift geodynamic processes. However, the apparent lack of ancient syn-breakup delta systems and the paucity of seismic imaging across continent-ocean boundaries means the transition from continental rifting to oceanic spreading remains poorly understood. The Early Cretaceous Barrow Group of the North Carnarvon Basin, offshore NW Australia was a major deltaic system that formed during the latter stages of continental rifting, and represents a rich sedimentary archive, documenting uplift, subsidence and erosion of the margin. We use a regional database of 2D and 3D seismic and well data to constrain the internal architecture of the Barrow Group. Our results highlight three major depocentres: the Exmouth and Barrow sub-basins, and southern Exmouth Plateau. Over-compaction of pre-Cretaceous sedimentary rocks in the South Carnarvon Basin, and pervasive reworking of Permian and Triassic palynomorphs in the offshore Barrow Group, suggests that the onshore South Carnarvon Basin originally contained a thicker sedimentary succession, which was uplifted and eroded prior to breakup. Backstripping of sedimentary successions encountered in wells in the Exmouth Plateau depocentre indicate anomalously rapid tectonic subsidence (≤0.24 mm yr-1) accommodated Barrow Group deposition, despite evidence for minimal, contemporaneous upper crustal extension. Our results suggest that classic models of uniform extension cannot account for the observations of uplift and subsidence in the North Carnarvon Basin, and may indicate a period of depth-dependent extension or dynamic topography preceding breakup

Cell surface localization of tissue transglutaminase is dependent on a fibronectin-binding site in its N-terminal beta-sandwich domain

Increasing evidence indicates that tissue transglutaminase (tTG) plays a role in the assembly and remodeling of extracellular matrices and promotes cell adhesion. Using an inducible system we have previously shown that tTG associates with the extracellular matrix deposited by stably transfected 3T3 fibroblasts overexpressing the enzyme. We now show by confocal microscopy that tTG colocalizes with pericellular fibronectin in these cells, and by immunogold electron microscopy that the two proteins are found in clusters at the cell surface. Expression vectors encoding the full-length tTG or a N-terminal truncated tTG lacking the proposed fibronectin-binding site (fused to the bacterial reporter enzyme β-galactosidase) were generated to characterize the role of fibronectin in sequestration of tTG in the pericellular matrix. Enzyme-linked immunosorbent assay style procedures using extracts of transiently transfected COS-7 cells and immobilized fibronectin showed that the truncation abolished fibronectin binding. Similarly, the association of tTG with the pericellular matrix of cells in suspension or with the extracellular matrix deposited by cell monolayers was prevented by the truncation. These results demonstrate that tTG binds to the pericellular fibronectin coat of cells via its N-terminal β-sandwich domain and that this interaction is crucial for cell surface association of tTG

Benzotriazole is antiestrogenic in vitro but not in vivo

Copyright © 2007 SETAC. This is the accepted version of the following article: Harris et al (2007), "Benzotriazole is antiestrogenic in vitro but not in vivo", Environmental Toxicology and Chemistry, 26(11), 2367–2372, which has been published in final form at the link below.Benzotriazole (BT) is an anticorrosive agent well known for its use in aircraft deicing and antifreeze fluids but also used in dishwasher detergents. It is highly persistent in the environment; therefore, BT is frequently found in runoff emanating from large airports as well as in the surrounding groundwater. In addition, BT has recently been found to be ubiquitous in Swiss wastewater treatment plant effluents and their receiving waters; however, very little chronic toxicity data is available on which to base a sound ecological risk assessment of this chemical. In vitro assays conducted using a recombinant yeast (anti-) estrogen assay indicated that BT possessed clear antiestrogenic properties. This chemical was approximately 100-fold less potent than Tamoxifen, which was used as a positive control. A subsequent in vivo study, however, involving analysis of vitellogenin induction and somatic indices in adult fathead minnows (Pimephales promelas) exposed to BT at concentrations of 10, 100, and 1,000 μg/L for two weeks showed no evidence of antiestrogenic activity by this compound. The possibility exists that higher concentrations of BT may yet induce the type of activity observed in vitro, although the concentrations used here already far exceed those reported in surface-water samples. Furthermore, adverse effects may be observed in fish or other organisms exposed to BT for a longer period than employed here, although such studies are costly and unlikely to be included in standard risk assessment procedures. A rigorous investigation of the chronic toxicity of BT is imperative