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Search Results: 1 - 10 of 342436 matches for " Andrew S. Allen "
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Multicellular Tumor Spheroids for Evaluation of Cytotoxicity and Tumor Growth Inhibitory Effects of Nanomedicines In Vitro: A Comparison of Docetaxel-Loaded Block Copolymer Micelles and Taxotere?
Andrew S. Mikhail, Sina Eetezadi, Christine Allen
PLOS ONE , 2013, DOI: 10.1371/journal.pone.0062630
Abstract: While 3-D tissue models have received increasing attention over the past several decades in the development of traditional anti-cancer therapies, their potential application for the evaluation of advanced drug delivery systems such as nanomedicines has been largely overlooked. In particular, new insight into drug resistance associated with the 3-D tumor microenvironment has called into question the validity of 2-D models for prediction of in vivo anti-tumor activity. In this work, a series of complementary assays was established for evaluating the in vitro efficacy of docetaxel (DTX) -loaded block copolymer micelles (BCM+DTX) and Taxotere? in 3-D multicellular tumor spheroid (MCTS) cultures. Spheroids were found to be significantly more resistant to treatment than monolayer cultures in a cell line dependent manner. Limitations in treatment efficacy were attributed to mechanisms of resistance associated with properties of the spheroid microenvironment. DTX-loaded micelles demonstrated greater therapeutic effect in both monolayer and spheroid cultures in comparison to Taxotere?. Overall, this work demonstrates the use of spheroids as a viable platform for the evaluation of nanomedicines in conditions which more closely reflect the in vivo tumor microenvironment relative to traditional monolayer cultures. By adaptation of traditional cell-based assays, spheroids have the potential to serve as intermediaries between traditional in vitro and in vivo models for high-throughput assessment of therapeutic candidates.
Accretion onto the Supermassive Black Hole in M87
Tiziana Di Matteo,Steven W. Allen,Andrew C. Fabian,Andrew S. Wilson,Andrew J. Young
Physics , 2002, DOI: 10.1086/344504
Abstract: Chandra X-ray observations of the giant elliptical galaxy M87 resolve the thermal state of the hot interstellar medium into the accretion (Bondi) radius of its central 3 10^9 Msun black hole. We measure the X-ray gas temperature and density profiles and calculate the Bondi accretion rate, Mdot_Bondi \sim 0.1 Msun/yr. The X-ray luminosity of the active nucleus of M87 observed with Chandra is L_{x, 0.5-7 \keV} \sim 7 \times 10^{40}erg/s. This value is much less than the predicted nuclear luminosity, L_{Bondi} \sim 5 \times 10^{44} erg/s, for accretion at the Bondi rate with a canonical accretion radiative efficiency of 10%. If the black hole in M87 accretes at this rate it must do so at a much lower radiative efficiency than the canonical value. The multiwavelength spectrum of the nucleus is consistent with that predicted by an advection-dominated flow. However, as is likely, the X-ray nucleus is dominated by jet emission then the properties of flow must be modified, possibly by outflows. We show that the overall energetics of the system are just consistent with the predicted Bondi nuclear power. This suggests that either most of the accretion energy is released in the relativistic jet or that the central engine of M87 undergoes on-off activity cycles. We show that, at present, the energy dumped into the ISM by the jet may reduce the accretion rate onto the black hole by a factor \propto (v_j/c_s)^{-2}, where v_j is the jet velocity and c_s the ISM sound speed, and that this is sufficient to account for the low nuclear luminosity.
Noise-driven oscillations in microbial population dynamics
Bhavin S. Khatri,Andrew Free,Rosalind J. Allen
Quantitative Biology , 2011, DOI: 10.1016/j.jtbi.2012.08.013
Abstract: Microbial populations in the natural environment are likely to experience growth conditions very different from those of a typical laboratory xperiment. In particular, removal rates of biomass and substrate are unlikely to be balanced under realistic environmental conditions. Here, we consider a single population growing on a substrate under conditions where the removal rates of substrate and biomass are not necessarily equal. For a large population, with deterministic growth dynamics, our model predicts that this system can show transient (damped) oscillations. For a small population, demographic noise causes these oscillations to be sustained indefinitely. These oscillations arise when the dynamics of changes in biomass are faster than the dynamics of the substrate, for example, due to a high microbial death rate and/or low substrate flow rates. We show that the same mechanism can produce sustained stochastic oscillations in a two-species, nutrient-cycling microbial ecosystem. Our results suggest that oscillatory population dynamics may be a common feature of small microbial populations in the natural environment, even in the absence of complex interspecies interactions.
Modeling Urban Hydrology: A Comparison of New Urbanist and Traditional Neighborhood Design Surface Runoff  [PDF]
Christopher Andrew Day, Keith Allen Bremer
International Journal of Geosciences (IJG) , 2013, DOI: 10.4236/ijg.2013.45083
Abstract:

Urban development generally leads to an increase in impervious cover resulting in a greater volume of surface runoff following storm activity. However, the type of urban development in place strongly controls the degree of impervious cover generated. Traditional neighborhood designs focus on a medium-to-low urban density spread over larger areas, while new urbanist neighborhood designs incorporate more diversity by increasing urban density across smaller areas. The purpose of this study is to model and compare the potential surface runoff for two urban neighborhoods in Austin, Texas-Circle C Ranch, a traditional neighborhood design, and Mueller, a new urbanist development for a 10-year 24-hour storm scenario. Potential surface runoff was calculated by layering various geospatial datasets representing the physical characteristics of both study sites within the Watershed Modeling System (WMS) to configure the HEC-HMS runoff model. Results initially imply that the higher density new urbanist neighborhood significantly increases total and peak storm runoff compared to the traditional neighborhood. However, a greater number of residential units are available at Mueller over the same area as Circle C Ranch. When taking this into account the increased potential surface runoff is negated at the new urbanist site. Although new urbanist neighborhoods will usually contain more residential units than traditional developments when compared at the same scale, the higher urban density associated with these neighborhoods demand the development of more effective stormwater retention systems to cope with a potential increase in surface runoff.

Evaluating the Potential Efficacy of Invasive Lionfish (Pterois volitans) Removals
Andrew B. Barbour,Michael S. Allen,Thomas K. Frazer,Krista D. Sherman
PLOS ONE , 2012, DOI: 10.1371/journal.pone.0019666
Abstract: The lionfish, Pterois volitans (Linnaeus) and Pterois miles (Bennett), invasion of the Western Atlantic Ocean, Caribbean Sea and Gulf of Mexico has the potential to alter aquatic communities and represents a legitimate ecological concern. Several local removal programs have been initiated to control this invasion, but it is not known whether removal efforts can substantially reduce lionfish numbers to ameliorate these concerns. We used an age-structured population model to evaluate the potential efficacy of lionfish removal programs and identified critical data gaps for future studies. We used high and low estimates for uncertain parameters including: length at 50% vulnerability to harvest (Lvul), instantaneous natural mortality (M), and the Goodyear compensation ratio (CR). The model predicted an annual exploitation rate between 35 and 65% would be required to cause recruitment overfishing on lionfish populations for our baseline parameter estimates for M and CR (0.5 and 15). Lionfish quickly recovered from high removal rates, reaching 90% of unfished biomass six years after a 50-year simulated removal program. Quantifying lionfish natural mortality and the size-selective vulnerability to harvest are the most important knowledge gaps for future research. We suggest complete eradication of lionfish through fishing is unlikely, and substantial reduction of adult abundance will require a long-term commitment and may be feasible only in small, localized areas where annual exploitation can be intense over multiple consecutive years.
Leveraging Prior Information to Detect Causal Variants via Multi-Variant Regression
Nanye Long ,Samuel P. Dickson,Jessica M. Maia,Hee Shin Kim,Qianqian Zhu,Andrew S. Allen
PLOS Computational Biology , 2013, DOI: 10.1371/journal.pcbi.1003093
Abstract: Although many methods are available to test sequence variants for association with complex diseases and traits, methods that specifically seek to identify causal variants are less developed. Here we develop and evaluate a Bayesian hierarchical regression method that incorporates prior information on the likelihood of variant causality through weighting of variant effects. By simulation studies using both simulated and real sequence variants, we compared a standard single variant test for analyzing variant-disease association with the proposed method using different weighting schemes. We found that by leveraging linkage disequilibrium of variants with known GWAS signals and sequence conservation (phastCons), the proposed method provides a powerful approach for detecting causal variants while controlling false positives.
Genic Intolerance to Functional Variation and the Interpretation of Personal Genomes
Slavé Petrovski ,Quanli Wang,Erin L. Heinzen,Andrew S. Allen,David B. Goldstein
PLOS Genetics , 2013, DOI: 10.1371/journal.pgen.1003709
Abstract: A central challenge in interpreting personal genomes is determining which mutations most likely influence disease. Although progress has been made in scoring the functional impact of individual mutations, the characteristics of the genes in which those mutations are found remain largely unexplored. For example, genes known to carry few common functional variants in healthy individuals may be judged more likely to cause certain kinds of disease than genes known to carry many such variants. Until now, however, it has not been possible to develop a quantitative assessment of how well genes tolerate functional genetic variation on a genome-wide scale. Here we describe an effort that uses sequence data from 6503 whole exome sequences made available by the NHLBI Exome Sequencing Project (ESP). Specifically, we develop an intolerance scoring system that assesses whether genes have relatively more or less functional genetic variation than expected based on the apparently neutral variation found in the gene. To illustrate the utility of this intolerance score, we show that genes responsible for Mendelian diseases are significantly more intolerant to functional genetic variation than genes that do not cause any known disease, but with striking variation in intolerance among genes causing different classes of genetic disease. We conclude by showing that use of an intolerance ranking system can aid in interpreting personal genomes and identifying pathogenic mutations.
Robust Regression Analysis of Copy Number Variation Data based on a Univariate Score
Glen A. Satten, Andrew S. Allen, Morna Ikeda, Jennifer G. Mulle, Stephen T. Warren
PLOS ONE , 2014, DOI: 10.1371/journal.pone.0086272
Abstract: Motivation The discovery that copy number variants (CNVs) are widespread in the human genome has motivated development of numerous algorithms that attempt to detect CNVs from intensity data. However, all approaches are plagued by high false discovery rates. Further, because CNVs are characterized by two dimensions (length and intensity) it is unclear how to order called CNVs to prioritize experimental validation. Results We developed a univariate score that correlates with the likelihood that a CNV is true. This score can be used to order CNV calls in such a way that calls having larger scores are more likely to overlap a true CNV. We developed cnv.beast, a computationally efficient algorithm for calling CNVs that uses robust backward elimination regression to keep CNV calls with scores that exceed a user-defined threshold. Using an independent dataset that was measured using a different platform, we validated our score and showed that our approach performed better than six other currently-available methods. Availability cnv.beast is available at http://www.duke.edu/~asallen/Software.ht?ml.
Is Sustained Virological Response a Marker of Treatment Efficacy in Patients with Chronic Hepatitis C Viral Infection with No Response or Relapse to Previous Antiviral Intervention?
Kurinchi S. Gurusamy, Edward Wilson, Ronald L. Koretz, Victoria B. Allen, Brian R. Davidson, Andrew K. Burroughs, Christian Gluud
PLOS ONE , 2013, DOI: 10.1371/journal.pone.0083313
Abstract: Background Randomised clinical trials (RCTs) of antiviral interventions in patients with chronic hepatitis C virus (HCV) infection use sustained virological response (SVR) as the main outcome. There is sparse information on long-term mortality from RCTs. Methods We created a decision tree model based on a Cochrane systematic review on interferon retreatment for patients who did not respond to initial therapy or who relapsed following SVR. Extrapolating data to 20 years, we modelled the outcome from three scenarios: (1) observed medium-term (5 year) annual mortality rates continue to the long term (20 years); (2) long-term annual mortality in retreatment responders falls to that of the general population while retreatment non-responders continue at the medium-term mortality; (3) long-term annual mortality in retreatment non-responders is the same as control group non-responders (i.e., the increased treatment-related medium mortality “wears off”). Results The mean differences in life expectancy over 20 years with interferon versus control in the first, second, and third scenarios were -0.34 years (95% confidence interval (CI) -0.71 to 0.03), -0.23 years (95% CI -0.69 to 0.24), and -0.01 (95% CI -0.3 to 0.27), respectively. The life expectancy was always lower in the interferon group than in the control group in scenario 1. In scenario 3, the interferon group had a longer life expectancy than the control group only when more than 7% in the interferon group achieved SVR. Conclusions SVR may be a good prognostic marker but does not seem to be a valid surrogate marker for assessing HCV treatment efficacy of interferon retreatment. The SVR threshold at which retreatment increases life expectancy may be different for different drugs depending upon the adverse event profile and treatment efficacy. This has to be determined for each drug by RCTs and appropriate modelling before SVR can be accepted as a surrogate marker.
The Intolerance of Regulatory Sequence to Genetic Variation Predicts Gene Dosage Sensitivity
Slavé Petrovski?,Ayal B. Gussow?,Quanli Wang?,Matt Halvorsen?,Yujun Han?,William H. Weir?,Andrew S. Allen,David B. Goldstein
PLOS Genetics , 2015, DOI: 10.1371/journal.pgen.1005492
Abstract: Noncoding sequence contains pathogenic mutations. Yet, compared with mutations in protein-coding sequence, pathogenic regulatory mutations are notoriously difficult to recognize. Most fundamentally, we are not yet adept at recognizing the sequence stretches in the human genome that are most important in regulating the expression of genes. For this reason, it is difficult to apply to the regulatory regions the same kinds of analytical paradigms that are being successfully applied to identify mutations among protein-coding regions that influence risk. To determine whether dosage sensitive genes have distinct patterns among their noncoding sequence, we present two primary approaches that focus solely on a gene’s proximal noncoding regulatory sequence. The first approach is a regulatory sequence analogue of the recently introduced residual variation intolerance score (RVIS), termed noncoding RVIS, or ncRVIS. The ncRVIS compares observed and predicted levels of standing variation in the regulatory sequence of human genes. The second approach, termed ncGERP, reflects the phylogenetic conservation of a gene’s regulatory sequence using GERP++. We assess how well these two approaches correlate with four gene lists that use different ways to identify genes known or likely to cause disease through changes in expression: 1) genes that are known to cause disease through haploinsufficiency, 2) genes curated as dosage sensitive in ClinGen’s Genome Dosage Map, 3) genes judged likely to be under purifying selection for mutations that change expression levels because they are statistically depleted of loss-of-function variants in the general population, and 4) genes judged unlikely to cause disease based on the presence of copy number variants in the general population. We find that both noncoding scores are highly predictive of dosage sensitivity using any of these criteria. In a similar way to ncGERP, we assess two ensemble-based predictors of regional noncoding importance, ncCADD and ncGWAVA, and find both scores are significantly predictive of human dosage sensitive genes and appear to carry information beyond conservation, as assessed by ncGERP. These results highlight that the intolerance of noncoding sequence stretches in the human genome can provide a critical complementary tool to other genome annotation approaches to help identify the parts of the human genome increasingly likely to harbor mutations that influence risk of disease.
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