bluuebunny/crossref_metadata_2025_split huggingface dataset:
Empirical Complexities in the Genetic Foundations of Lethal Mutagenesis
Authors: Bull James J , Joyce Paul , Gladstone Eric , Molineux Ian J 
Published: August 2013

AbstractFrom population genetics theory, elevating the mutation rate of a large population should progressively reduce average fitness. If the fitness decline is large enough, the population will go extinct in a process known as lethal mutagenesis. Lethal mutagenesis has been endorsed in the virology literature as a promising approach to viral treatment, and several in vitro studies have forced viral extinction with high doses of mutagenic drugs. Yet only one empirical study has tested the genetic models underlying lethal mutagenesis, and the theory failed on even a qualitative level. Here we provide a new level of analysis of lethal mutagenesis by developing and evaluating models specifically tailored to empirical systems that may be used to test the theory. We first quantify a bias in the estimation of a critical parameter and consider whether that bias underlies the previously observed lack of concordance between theory and experiment. We then consider a seemingly ideal protocol that avoids this bias—mutagenesis of virions—but find that it is hampered by other problems. Finally, results that reveal difficulties in the mere interpretation of mutations assayed from double-strand genomes are derived. Our analyses expose unanticipated complexities in testing the theory. Nevertheless, the previous failure of the theory to predict experimental outcomes appears to reside in evolutionary mechanisms neglected by the theory (e.g., beneficial mutations) rather than from a mismatch between the empirical setup and model assumptions. This interpretation raises the specter that naive attempts at lethal mutagenesis may augment adaptation rather than retard it.
Overcompensation in Response to Herbivory in Arabidopsis thaliana: The Role of Glucose-6-Phosphate Dehydrogenase and the Oxidative Pentose-Phosphate Pathway
Authors: Siddappaji Madhura H , Scholes Daniel R , Bohn Martin , Paige Ken N 
Published: August 2013

Abstract
That some plants benefit from being eaten is counterintuitive, yet there is now considerable evidence demonstrating enhanced fitness following herbivory (i.e., plants can overcompensate). Although there is evidence that genetic variation for compensation exists, little is known about the genetic mechanisms leading to enhanced growth and reproduction following herbivory. We took advantage of the compensatory variation in recombinant inbred lines of Arabidopsis thaliana, combined with microarray and QTL analyses to assess the molecular basis of overcompensation. We found three QTL explaining 11.4, 10.1, and 26.7% of the variation in fitness compensation, respectively, and 109 differentially expressed genes between clipped and unclipped plants of the overcompensating ecotype Columbia. From the QTL/microarray screen we uncovered one gene that plays a significant role in overcompensation: glucose-6-phosphate-1-dehydrogenase (G6PDH1). Knockout studies of Transfer-DNA (T-DNA) insertion lines and complementation studies of G6PDH1 verify its role in compensation. G6PDH1 is a key enzyme in the oxidative pentose-phosphate pathway that plays a central role in plant metabolism. We propose that plants capable of overcompensating reprogram their transcriptional activity by up-regulating defensive genes and genes involved in energy metabolism and by increasing DNA content (via endoreduplication) with the increase in DNA content feeding back on pathways involved in defense and metabolism through increased gene expression.
Spargel/dPGC-1 Is a New Downstream Effector in the Insulin–TOR Signaling Pathway in Drosophila
Authors: Mukherjee Subhas , Duttaroy Atanu 
Published: August 2013

Abstract
Insulin and target of rapamycin (TOR) signaling pathways converge to maintain growth so a proportionate body form is attained. Insufficiency in either insulin or TOR results in developmental growth defects due to low ATP level. Spargel is the Drosophila homolog of PGC-1, which is an omnipotent transcriptional coactivator in mammals. Like its mammalian counterpart, Spargel/dPGC-1 is recognized for its role in energy metabolism through mitochondrial biogenesis. An earlier study demonstrated that Spargel/dPGC-1 is involved in the insulin–TOR signaling, but a comprehensive analysis is needed to understand exactly which step of this pathway Spargel/PGC-1 is essential. Using genetic epistasis analysis, we demonstrated that a Spargel gain of function can overcome the TOR and S6K mediated cell size and cell growth defects in a cell autonomous manner. Moreover, the tissue-restricted phenotypes of TOR and S6k mutants are rescued by Spargel overexpression. We have further elucidated that Spargel gain of function sets back the mitochondrial numbers in growth-limited TOR mutant cell clones, which suggests a possible mechanism for Spargel action on cells and tissue to attain normal size. Finally, excess Spargel can ameliorate the negative effect of FoxO overexpression only to a limited extent, which suggests that Spargel does not share all of the FoxO functions and consequently cannot significantly rescue the FoxO phenotypes. Together, our observation established that Spargel/dPGC-1 is indeed a terminal effector in the insulin–TOR pathway operating below TOR, S6K, Tsc, and FoxO. This led us to conclude that Spargel should be incorporated as a new member of this growth-signaling pathway.
TORC1 Signaling Is Governed by Two Negative Regulators in Fission Yeast
Authors: Ma Ning , Liu Qingbin , Zhang Lili , Henske Elizabeth P , Ma Yan 
Published: August 2013

Abstract
The target of rapamycin (TOR) is a highly conserved protein kinase that regulates cell growth and metabolism. Here we performed a genome-wide screen to identify negative regulators of TOR complex 1 (TORC1) in Schizosaccharomyces pombe by isolating mutants that phenocopy Δtsc2, in which TORC1 signaling is known to be up-regulated. We discovered that Δnpr2 displayed similar phenotypes to Δtsc2 in terms of amino acid uptake defects and mislocalization of the Cat1 permease. However, Δnpr2 and Δtsc2 clearly showed different phenotypes in terms of rapamycin supersensitivity and Isp5 transcription upon various treatments. Furthermore, we showed that Tor2 controls amino acid homeostasis at the transcriptional and post-transcriptional levels. Our data reveal that both Npr2 and Tsc2 negatively regulate TORC1 signaling, and Npr2, but not Tsc2, may be involved in the feedback loop of a nutrient-sensing pathway.
Rare Variants in Hypermutable Genes Underlie Common Morphology and Growth Traits in WildSaccharomyces paradoxus
Authors: Roop Jeremy I , Brem Rachel B 
Published: August 2013

AbstractUnderstanding the molecular basis of common traits is a primary challenge of modern genetics. One model holds that rare mutations in many genetic backgrounds may often phenocopy one another, together explaining the prevalence of the resulting trait in the population. For the vast majority of phenotypes, the role of rare variants and the evolutionary forces that underlie them are unknown. In this work, we use a population of Saccharomyces paradoxus yeast as a model system for the study of common trait variation. We observed an unusual, flocculation and invasive-growth phenotype in one-third of S. paradoxus strains, which were otherwise unrelated. In crosses with each strain in turn, these morphologies segregated as a recessive Mendelian phenotype, mapping either to IRA1 or to IRA2, yeast homologs of the hypermutable human neurofibromatosis gene NF1. The causal IRA1 and IRA2 haplotypes were of distinct evolutionary origin and, in addition to their morphological effects, associated with hundreds of stress-resistance and growth traits, both beneficial and disadvantageous, across S. paradoxus. Single-gene molecular genetic analyses confirmed variant IRA1 and IRA2 haplotypes as causal for these growth characteristics, many of which were independent of morphology. Our data make clear that common growth and morphology traits in yeast result from a suite of variants in master regulators, which function as a mutation-driven switch between phenotypic states.
Predicting Functionally Informative Mutations inEscherichia coliBamA Using Evolutionary Covariance Analysis
Authors: Dwyer Robert S , Ricci Dante P , Colwell Lucy J , Silhavy Thomas J , Wingreen Ned S 
Published: August 2013

AbstractThe essential outer membrane β-barrel protein BamA forms a complex with four lipoprotein partners BamBCDE that assembles β-barrel proteins into the outer membrane of Escherichia coli. Detailed genetic studies have shown that BamA cycles through multiple conformations during substrate assembly, suggesting that a complex network of residues may be involved in coordinating conformational changes and lipoprotein partner function. While genetic analysis of BamA has been informative, it has also been slow in the absence of a straightforward selection for mutants. Here we take a bioinformatic approach to identify candidate residues for mutagenesis using direct coupling analysis. Starting with the BamA paralog FhaC, we show that direct coupling analysis works well for large β-barrel proteins, identifying pairs of residues in close proximity in tertiary structure with a true positive rate of 0.64 over the top 50 predictions. To reduce the effects of noise, we designed and incorporated a novel structured prior into the empirical correlation matrix, dramatically increasing the FhaC true positive rate from 0.64 to 0.88 over the top 50 predictions. Our direct coupling analysis of BamA implicates residues R661 and D740 in a functional interaction. We find that the substitutions R661G and D740G each confer OM permeability defects and destabilize the BamA β-barrel. We also identify synthetic phenotypes and cross-suppressors that suggest R661 and D740 function in a similar process and may interact directly. We expect that the direct coupling analysis approach to informed mutagenesis will be particularly useful in systems lacking adequate selections and for dynamic proteins with multiple conformations.
Unexpected Relationship Between Tympanometry and Mortality in Children With Nontraumatic Coma
Authors: Gwer Samson , Chengo Eddie , Newton Charles R.J.C. , Kirkham Fenella J. 
Published: August 2013

OBJECTIVE:
We sought to further examine the relationship between tympanometry and mortality after noting an unexpected association on assessment of baseline data of a study whose primary aim was to investigate the utility of noninvasive tympanic membrane displacement measurement for monitoring intracranial pressure in childhood coma.

METHODS:
We recruited children who presented with acute nontraumatic coma to the high-dependency unit of Kilifi District Hospital on the rural coast of Kenya. We excluded children with sickle cell disease, epilepsy, and neurodevelopmental delay. We performed tympanometry on the right ear before tympanic membrane displacement analyzer measurements. All children were managed according to standard World Health Organization guidelines.

RESULTS:
We recruited 72 children with a median age of 3.2 years (interquartile range [IQR]: 2.0–4.3 years); 31 (43%) were female. Thirty-eight (53%) had cerebral malaria, 8 (11%) acute bacterial meningitis, 4 (6%) sepsis, and 22 (30%) encephalopathy of unknown etiology. Twenty (28%) children died. Tympanometry was normal in 25 (35%) children. Adjusting for diagnosis and clinical features of increased intracranial pressure, both associated with death on univariable analysis, children with abnormal tympanometry had greater odds of dying than did those with normal tympanometry (adjusted odds ratio: 17.0; 95% confidence interval: 1.9–152.4; P = .01). Children who died had a lower compliance (0.29 mL; IQR: 0.09–0.33 mL) compared with those who survived (0.48 mL; IQR: 0.29–0.70 mL) (P &lt; .01).

CONCLUSIONS:
Abnormal tympanometry appears to be significantly associated with death in children with acute nontraumatic coma. This finding needs to be explored further through a prospective study that incorporates imaging and intensive physiologic monitoring.
Vedic Science and Modern Science
Authors: King Anna 
Published: August 2013

This article raises questions about how non-Christian theologies, especially literalist or ‘fundamentalist’ types, respond to, and join in, the debate over modern science and religion. It focuses attention on the response of Indian religious traditions to one particular theme in the Western discourse on modernity and religion; namely, the notion of rational science as seemingly opposed to irrational religions, and ef?cacious technology as seemingly opposed to ineffective rituals. It presents the case study of ISKCON, a branch of Gaudiya Vaishnavism, which makes use of these oppositions by classifying its own teachings as scienti?c, and by asserting that science and religion are ultimately reconcilable because true scienti?c knowledge can only come from religion. This strategy sustains its position as a universalist religion within a modern environment that appears to be hostile towards religion. This article explores why ISKCON in its public documents adopts largely confrontational attitudes to science and historical and archaeological scholarship, and why, while some of these texts claim to lay out the evidence fully and fairly, they are in general characterised by religious apologetic rather than reason and argument. It examines Prabhupada’s ‘scienti?c legacy’ in the form of ISKCON’s public and semi-of?cial pronouncements on history, culture and science, and considers the notion that any ethical or theological principle must be consistent with the natural world as we experience it.
Methodologically this article goes beyond what might be seen as the natural boundaries of religious studies by engaging vigorously with ISKCON’s public stance towards science. It might therefore seem that the author attempts to be theologically normative. However, the aim is not to press a particular (liberal) theological approach, but to clarify ISKCON’s position and to offer a critique. The article argues that ISKCON often con?ates science with scientism and that its representation of ‘Western science’ is ideologically motivated. ISKCON compares the restrictive and reductive effects of modern scienti?c paradigms with the harmony brought about by revealed Vedic science. However, this article asks whether ISKCON’s own literalist understanding of Vedic literature and culture is compatible with a positive evaluation of modern scienti?c achievements. The twenty-?rst century may need scienti?c solutions to a whole range of issues, from global warming to food security, and from ?ghting crime to developing new medicines. While ISKCON seeks to resacralise the world, it may do so at the cognitive cost of demoting reason and modern science.
An Emergent Trans-Asian Energy Nexus: Likely Costs and Possible Benefits
Authors: Piggott Leanne 
Published: August 2013

In this article, I state that the IEA predicts that global energy usage will continue to increase over the next twenty years by as much as 45%, driven largely by the emerging economies of North and South Asia. This assessment is most pertinent in relation to oil, which currently accounts for the largest share of global energy use due to the oil dependence of the transport sector. I point out that the major supplier of oil to the global market, West Asia’s Arabian/Persian Gulf, is also experiencing relatively high energy consumption growth, and the Gulf states have thus found themselves confronted with the paradox of needing to develop alternative energy sources for their own domestic use while requiring the world’s traditional dependence on oil to continue so that they can maintain their export revenues. To the extent that alternative energy sources are developed, the commerciality of the oil reserves of supplier states is made less secure. The article explains how the growth in oil consumption has also raised questions about the medium to long-term security of supply for Asian oil-importing states which have invested substantially in supply contracts and in acquiring equity in upstream production in the Gulf. I examine both the potential threats and benefits that might arise from this emerging trans-Asian oil nexus including the increasing dependence by Asian oil importers on supplies from an inherently unstable region, and the pursuit of alternate technologies by
suppliers and consumers.
Social justice through multilingual education. Tove Skutnabb-Kangas, Robert Phillipson, Ajit K. Mohanty and Minati Panda (eds) (2009)
Authors: Vorstman Emmanuelle Le Pichon 
Published: August 2013

Bristol: Multilingual Matters. Pp. vii + 389. ISBN-13 9781847691903 (hbk) ISBN-13 9781847691897 (pbk)
Dose-Dense FEC Followed by Dose-Dense Ixabepilone as Neoadjuvant Treatment for Breast Cancer Patients: A Feasibility Study
Authors: Clavarezza Matteo , Bordonaro Roberto , Daniele Bruno , Ferrandina Gabriella , Barni Sandro , Turazza Monica , Coati Francesca , De Matteis Andrea , De Placido Sabino , Cognetti Francesco , Olmeo Nina Antonina , Carrozza Francesco , Bruzzi Paolo , Del Mastrol Lucia ,   for the Gruppo Italiano Mammella.
Published: August 2013

Abstract

Background.
Ixabepilone is an effective chemotherapy in metastatic breast cancer that has been pretreated with anthracyclines and is resistant or refractory to taxanes. Adjuvant dose-dense (DD) chemotherapy is more effective than regimens administered every 3 weeks, especially in hormonal receptor (HR)-negative tumors.

Methods.
A feasibility study of neoadjuvant DD ixabepilone was conducted in breast cancer patients with tumors measuring at least 2 cm. Patients received 5-fluorouracil 600 mg/m2, epirubicin 90 mg/m2, and cyclophosphamide 600 mg/m2 (“FEC” in combination) administered intravenously on day 1 every 14 days with granulocyte-colony stimulating factor (filgrastim) followed by ixabepilone 40 mg/m2 administered intravenously on day 1 every 14 days with granulocyte-colony stimulating factor. The study's primary endpoint was feasibility, and the secondary endpoint was pathologic complete response. A two-stage Simon's design was adopted.

Results.
Forty-seven patients were enrolled, and 42 were evaluable. For 10 of 42 patients, DD ixabepilone was not feasible. Six (14%) required ixabepilone interruption, and four (9.5%) required ixabepilone dose reduction of 25%. One toxic death occurred. Hematologic grade 3–4 toxicities included anemia (9.5%), grade 4 neutropenia (2.4%), febrile neutropenia (4.8%), and thrombocytopenia (2.4%). Nonhematologic grade 3–4 toxicities consisted of fatigue (14.3%), mucositis (14.3%), sensory neuropathy (7.1%), onychopathy (7.1%), and liver toxicity (4.8%). Grade 2 sensory neuropathy lasting longer than 7 days was recorded in 11.9% of patients. Pathologic complete response was observed in 16 of 42 patients (38.1%), including 11 of 23 (47.8%) with HR-negative tumors and 5 of 19 (26.3%) with HR-positive tumors.

Conclusion.
Despite high activity, DD ixabepilone after DD FEC is poorly tolerated.
Three-Phase Compositional Modeling With Capillarity in Heterogeneous and Fractured Media
Authors: Moortgat Joachim , Firoozabadi Abbas 
Published: August 2013

SummaryWe model for the first time capillarity in fully compositional three-phase flow, with higher-order finite-element (FE) methods. Capillary pressure gradients may be an important driving force, particularly in layered or fractured porous media, which exhibit sharp discontinuities in permeability. We introduce a simple local computation of the capillary pressure gradients, propose a fractional-flow formulation in terms of the total flux, and resolve complications arising from gravity and capillarity in the upwinding of phase fluxes. Fractures are modeled with the crossflow equilibrium concept, which allows large timesteps and includes all physical interactions between fractures and matrix blocks. The pressure and flux fields are discretized by the mixed hybrid finite-element method, and mass transport is approximated by a higher-order local discontinuous Galerkin (DG) method. Numerical-dispersion and grid-orientation effects are significantly reduced, which allows computations on coarser grids and with larger timesteps. The main advantages in the context of this work are the accurate pressure gradients and fluxes at the interface between regions of different permeabilities. The phase compositions are computed with state-of-the-art phase-splitting algorithms and stability analyses to guarantee the global minimum of Gibbs free energy. Accurate compositional simulation motivates the use of an implicit-pressure/explicit-composition (IMPEC) scheme, and we discuss the associated Courant-Friedrichs-Lewy (CFL) condition on the time-steps. We present various numerical examples on both core- and large-scale, illustrating the capillary end effect, capillary-driven crossflow in layered media, and the importance of capillarity in fractured media for three-phase flow.
Analytical Solutions for Multiple Matrix in Fractured Reservoirs: Application to Conventional and Unconventional Reservoirs
Authors: Torcuk Mehmet A. , Kurtoglu Basak , Alharthy Najeeb , Kazemi Hossein 
Published: August 2013

Summary
In this paper, we present a new method to model heterogeneity and flow channeling in petroleum reservoirs—especially reservoirs containing interconnected microfractures. The method is applicable to both conventional and unconventional reservoirs where the interconnected microfractures form the major flow path. The flow equations, which could include flow contributions from matrix blocks of various size, permeability, and porosities, are solved by the Laplace-transform analytical solutions and finite-difference numerical solutions. The accuracy of flow from and into nanodarcy matrix blocks is of great interest to those dealing with unconventional reservoirs; thus, matrix flow equations are solved by use of both pseudosteady-state (PSS) and unsteady state (USS) formulations and the results are compared.
The matrix blocks can be of different size and properties within the representative elementary volume (REV) in the analytical solutions, and within each control volume (CV) in the numerical solutions. Although the analytical solutions were developed for slightly compressible rock/fluid linear systems, the numerical solutions are general and can be used for nonlinear, multiphase, multicomponent flow problems.
The mathematical solutions were used to analyze the longterm and short-term performances of two separate wells in an unconventional reservoir. It is concluded that matrix contribution to flow is very slow in a typical low-permeability unconventional reservoir and much of the enhanced production is from the fluids contained in the microfractures rather than in the matrix.
In addition to field applications, the mathematical formulations and solution methods are presented in a transparent fashion to allow easy usage of the techniques for reservoir and engineering applications.
Tie-Line-Based K-Value Method for Compositional Simulation
Authors: Rannou Guillaume , Voskov Denis , Tchelepi Hamdi 
Published: August 2013

Summary
The thermodynamic behavior of multicomponent multiphase systems is highly nonlinear, and the coupling to the flow equations is quite complex; as a result, equation-of-state (EOS) -based simulations can be computationally prohibitive. We describe a new K-value method that captures the compositional dependence of the phase behavior. Specifically, we propose a method for selecting compositions used in the tabulation of K-values and define an operator that interpolates the K-values as a function of pressure and composition. The method employs the minimal critical pressure (MCP) to detect supercritical compositions, which allows for effective modeling of multicontact miscible displacements. We compare our K-value approach with standard EOS compositional simulation for several isothermal problems, and we demonstrate the efficiency and accuracy of the proposed method.