Search algorithms as a framework for the optimization of drug combinations

Combination therapies are often needed for effective clinical outcomes in the management of complex diseases, but presently they are generally based on empirical clinical experience. Here we suggest a novel application of search algorithms, originally developed for digital communication, modified to optimize combinations of therapeutic interventions. In biological experiments measuring the restoration of the decline with age in heart function and exercise capacity in Drosophila melanogaster, we found that search algorithms correctly identified optimal combinations of four drugs with only one third of the tests performed in a fully factorial search. In experiments identifying combinations of three doses of up to six drugs for selective killing of human cancer cells, search algorithms resulted in a highly significant enrichment of selective combinations compared with random searches. In simulations using a network model of cell death, we found that the search algorithms identified the optimal combinations of 6-9 interventions in 80-90% of tests, compared with 15-30% for an equivalent random search. These findings suggest that modified search algorithms from information theory have the potential to enhance the discovery of novel therapeutic drug combinations. This report also helps to frame a biomedical problem that will benefit from an interdisciplinary effort and suggests a general strategy for its solution.Comment: 36 pages, 10 figures, revised versio

Functional Inequality in Latin America: News from the Twentieth Century

We report on a novel approach for the measurement of gas adsorption in microporous solids using X-ray computed tomography (CT) that we refer to as digital adsorption. Similar to conventional macroscopic methods, the proposed protocol combines observations with an inert and an adsorbing gas to produce equilibrium isotherms in terms of the truly measurable quantity in an adsorption experiment, namely the surface excess. Most significantly, X-ray CT allows probing the adsorption process in three dimensions, so as to build spatially-resolved adsorption isotherms with a resolution of approximately 10 mm3 within a fixed-bed column. Experiments have been carried out at 25 C and in the pressure range 1-30bar using CO2 on activated carbon, zeolite 13X and glass beads (as control material), and results are validated against literature data. A scaling approach was applied to analyze the whole population of measured adsorption isotherms (~7600), leading to single universal adsorption isotherm curves that are descriptive of all voxels for a given adsorbate-adsorbent system. By analyzing the adsorption heterogeneity at multiple length scales (1 mm3 to 1 cm3), packing heterogeneity was identified as the main contributor for the larger spatial variability in the adsorbed amount observed for the activated carbon rods as compared to zeolite pellets. We also show that this technique is readily applicable to a large spectrum of commercial porous solids, and that it can be further extended to weakly adsorbing materials with appropriate protocols that reduce measurement uncertainties. As such, the obtained results prove the feasibility of digital adsorption and highlight substantial opportunities for its wider use in the field of adsorptive characterization of porous solids

Balancing the dilution and oddity effects: Decisions depend on body size

Background Grouping behaviour, common across the animal kingdom, is known to reduce an individual's risk of predation; particularly through dilution of individual risk and predator confusion (predator inability to single out an individual for attack). Theory predicts greater risk of predation to individuals more conspicuous to predators by difference in appearance from the group (the ‘oddity’ effect). Thus, animals should choose group mates close in appearance to themselves (eg. similar size), whilst also choosing a large group. Methodology and Principal Findings We used the Trinidadian guppy (Poecilia reticulata), a well known model species of group-living freshwater fish, in a series of binary choice trials investigating the outcome of conflict between preferences for large and phenotypically matched groups along a predation risk gradient. We found body-size dependent differences in the resultant social decisions. Large fish preferred shoaling with size-matched individuals, while small fish demonstrated no preference. There was a trend towards reduced preferences for the matched shoal under increased predation risk. Small fish were more active than large fish, moving between shoals more frequently. Activity levels increased as predation risk decreased. We found no effect of unmatched shoal size on preferences or activity. Conclusions and Significance Our results suggest that predation risk and individual body size act together to influence shoaling decisions. Oddity was more important for large than small fish, reducing in importance at higher predation risks. Dilution was potentially of limited importance at these shoal sizes. Activity levels may relate to how much sampling of each shoal was needed by the test fish during decision making. Predation pressure may select for better decision makers to survive to larger size, or that older, larger fish have learned to make shoaling decisions more efficiently, and this, combined with their size relative to shoal-mates, and attractiveness as prey items influences shoaling decisions

Genome Sequencing and Analysis of a Type A Clostridium perfringens Isolate from a Case of Bovine Clostridial Abomasitis

Clostridium perfringens is a common inhabitant of the avian and mammalian gastrointestinal tracts and can behave commensally or pathogenically. Some enteric diseases caused by type A C. perfringens, including bovine clostridial abomasitis, remain poorly understood. To investigate the potential basis of virulence in strains causing this disease, we sequenced the genome of a type A C. perfringens isolate (strain F262) from a case of bovine clostridial abomasitis. The ∼3.34 Mbp chromosome of C. perfringens F262 is predicted to contain 3163 protein-coding genes, 76 tRNA genes, and an integrated plasmid sequence, Cfrag (∼18 kb). In addition, sequences of two complete circular plasmids, pF262C (4.8 kb) and pF262D (9.1 kb), and two incomplete plasmid fragments, pF262A (48.5 kb) and pF262B (50.0 kb), were identified. Comparison of the chromosome sequence of C. perfringens F262 to complete C. perfringens chromosomes, plasmids and phages revealed 261 unique genes. No novel toxin genes related to previously described clostridial toxins were identified: 60% of the 261 unique genes were hypothetical proteins. There was a two base pair deletion in virS, a gene reported to encode the main sensor kinase involved in virulence gene activation. Despite this frameshift mutation, C. perfringens F262 expressed perfringolysin O, alpha-toxin and the beta2-toxin, suggesting that another regulation system might contribute to the pathogenicity of this strain. Two complete plasmids, pF262C (4.8 kb) and pF262D (9.1 kb), unique to this strain of C. perfringens were identified

Mercury flux to sediments of Lake Tahoe, California-Nevada

Author Posting. © The Author(s), 2009. This is the author's version of the work. It is posted here by permission of Springer for personal use, not for redistribution. The definitive version was published in Water, Air, & Soil Pollution 210 (2010): 399-407, doi:10.1007/s11270-009-0262-y.We report estimates of mercury (Hg) flux to the sediments of Lake Tahoe, California-Nevada: 2 and 15-20 µg/m2/yr in preindustrial and modern sediments, respectively. These values result in a modern to preindustrial flux ratio of 7.5-10, which is similar to flux ratios recently reported for other alpine lakes in California, and greater than the value of 3 typically seen worldwide. We offer plausible hypotheses to explain the high flux ratios, including (1) proportionally less photoreduction and evasion of Hg with the onset of cultural eutrophication and (2) a combination of enhanced regional oxidation of gaseous elemental Hg and transport of the resulting reactive gaseous Hg to the surface with nightly downslope flows of air. If either of these mechanisms is correct, it could lead to local/regional solutions to lessen the impact of globally increasing anthropogenic emissions of Hg on Lake Tahoe and other alpine ecosystems.Funding was provided by Miami University, EPA-STAR, the Postdoctoral Scholar Program at Woods Hole Oceanographic Institution, and the USGS

Chromosomal copy number heterogeneity predicts survival rates across cancers.

Survival rates of cancer patients vary widely within and between malignancies. While genetic aberrations are at the root of all cancers, individual genomic features cannot explain these distinct disease outcomes. In contrast, intra-tumour heterogeneity (ITH) has the potential to elucidate pan-cancer survival rates and the biology that drives cancer prognosis. Unfortunately, a comprehensive and effective framework to measure ITH across cancers is missing. Here, we introduce a scalable measure of chromosomal copy number heterogeneity (CNH) that predicts patient survival across cancers. We show that the level of ITH can be derived from a single-sample copy number profile. Using gene-expression data and live cell imaging we demonstrate that ongoing chromosomal instability underlies the observed heterogeneity. Analysing 11,534 primary cancer samples from 37 different malignancies, we find that copy number heterogeneity can be accurately deduced and predicts cancer survival across tissues of origin and stages of disease. Our results provide a unifying molecular explanation for the different survival rates observed between cancer types

Mercury sources to Lake Ozette and Lake Dickey : highly contaminated remote coastal lakes, Washington State, USA

Author Posting. © The Author(s), 2009. This is the author's version of the work. It is posted here by permission of Springer for personal use, not for redistribution. The definitive version was published in Water, Air, & Soil Pollution 208 (2009): 275-286, doi:10.1007/s11270-009-0165-y.Mercury concentrations in largemouth bass and mercury accumulation rates in age-dated sediment cores were examined at Lake Ozette and Lake Dickey in Washington State. Goals of the study were to compare concentrations in fish tissues at the two lakes with lakes in a larger statewide dataset and evaluate factors influencing lake loading at Ozette and Dickey, which may include: catchment disturbances, coastal mercury cycling, and the role of trans-Pacific Asian mercury. Mercury fish tissue concentrations at the lakes were among the highest recorded in Washington State. Wet deposition and historical atmospheric monitoring from the area show no indication of enhanced deposition from Asian sources or coastal atmospheric processes. Sediment core records from the lakes displayed rapidly increasing sedimentation rates coinciding with commercial logging. The unusually high mercury flux rates and mercury tissue concentrations recorded at Lake Ozette and Lake Dickey appear to be associated with logging within the catchments

A qualitative study on the acceptability and preference of three types of long-lasting insecticide-treated bed nets in Solomon Islands: implications for malaria elimination

Background. In March 2008, the Solomon Islands and Vanuatu governments raised the goal of their National Malaria Programmes from control to elimination. Vector control measures, such as indoor residual spraying (IRS) and long-lasting insecticidal bed nets (LLINs) are key integral components of this programme. Compliance with these interventions is dependent on their acceptability and on the socio-cultural context of the local population. These factors need to be investigated locally prior to programme implementation. Method. Twelve focus group discussions (FGDs) were carried out in Malaita and Temotu Provinces, Solomon Islands in 2008. These discussions explored user perceptions of acceptability and preference for three brands of long-lasting insecticide-treated bed nets (LLINs) and identified a number of barriers to their proper and consistent use. Results. Mosquito nuisance and perceived threat of malaria were the main determinants of bed net use. Knowledge of malaria and the means to prevent it were not sufficient to guarantee compliance with LLIN use. Factors such as climate, work and evening social activities impact on the use of bed nets, particularly in men. LLIN acceptability plays a varying role in compliance with their use in villages involved in this study. Participants in areas of reported high and year round mosquito nuisance and perceived threat of malaria reported LLIN use regardless of any reported unfavourable characteristics. Those in areas of low or seasonal mosquito nuisance were more likely to describe the unfavourable characteristics of LLINs as reasons for their intermittent or non-compliance. The main criterion for LLIN brand acceptability was effectiveness in preventing mosquito bites and malaria. Discussions highlighted considerable confusion around LLIN care and washing which may be impacting on their effectiveness and reducing their acceptability in Solomon Islands. Conclusion. Providing LLINs that are acceptable will be more important for improving compliance in areas of low or seasonal mosquito nuisance and malaria transmission. The implications of these findings on malaria elimination in Solomon Islands are discussed