Asymmetrical dose-response shape the evolutionary trade-off between antifungal resistance and nutrient use

Antimicrobial resistance is an emerging threat for public health. The success of resistance mutations depends on the trade-off between the benefits and costs they incur. This trade-off is largely unknown and uncharacterized for antifungals. Here, we systematically catalog the effect of all amino acid substitutions in the yeast cytosine deaminase FCY1, the target of the antifungal 5-FC. We identify over 900 missense mutations granting resistance to 5-FC, a large fraction of which appear to act through destabilisation of the protein. The relationship between 5-FC resistance and growth sustained by cytosine deamination is characterized by a sharp trade-off, such that small gains in resistance universally lead to large losses in canonical enzyme function. We show that this steep relationship can be explained by differences in the dose-response function of 5-FC and cytosine. Our results provide a powerful resource and platform for interpreting drug target variants in fungal pathogens as well as unprecedented insights into resistance-function trade-offs.

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Pleiotropy complicates a trade-off between phage resistance and antibiotic resistance

Proceedings of the National Academy of Sciences ◽

10.1073/pnas.1919888117 ◽

2020 ◽

Vol 117 (21) ◽

pp. 11207-11216 ◽

Cited By ~ 14

Author(s):

Alita R. Burmeister ◽

Abigail Fortier ◽

Carli Roush ◽

Adam J. Lessing ◽

Rose G. Bender ◽

...

Keyword(s):

Antibiotic Resistance ◽

Molecular Mechanisms ◽

Efflux Pump ◽

Resistance Mechanisms ◽

Phage Resistance ◽

Resistance Mutations ◽

Trade Off ◽

Trade Offs ◽

Evolutionary Context ◽

Structural Barrier

Bacteria frequently encounter selection by both antibiotics and lytic bacteriophages. However, the evolutionary interactions between antibiotics and phages remain unclear, in particular, whether and when phages can drive evolutionary trade-offs with antibiotic resistance. Here, we describeEscherichia coliphage U136B, showing it relies on two host factors involved in different antibiotic resistance mechanisms: 1) the efflux pump protein TolC and 2) the structural barrier molecule lipopolysaccharide (LPS). Since TolC and LPS contribute to antibiotic resistance, phage U136B should select for their loss or modification, thereby driving a trade-off between phage resistance and either of the antibiotic resistance mechanisms. To test this hypothesis, we used fluctuation experiments and experimental evolution to obtain phage-resistant mutants. Using these mutants, we compared the accessibility of specific mutations (revealed in the fluctuation experiments) to their actual success during ecological competition and coevolution (revealed in the evolution experiments). BothtolCand LPS-related mutants arise readily during fluctuation assays, withtolCmutations becoming more common during the evolution experiments. In support of the trade-off hypothesis, phage resistance viatolCmutations occurs with a corresponding reduction in antibiotic resistance in many cases. However, contrary to the hypothesis, some phage resistance mutations pleiotropically confer increased antibiotic resistance. We discuss the molecular mechanisms underlying this surprising pleiotropic result, consideration for applied phage biology, and the importance of ecology in evolution of phage resistance. We envision that phages may be useful for the reversal of antibiotic resistance, but such applications will need to account for unexpected pleiotropy and evolutionary context.

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Mutational Analysis of Flucytosine Resistance in Candida glabrata

Antimicrobial Agents and Chemotherapy ◽

10.1128/aac.00605-10 ◽

2010 ◽

Vol 54 (11) ◽

pp. 4733-4738 ◽

Cited By ~ 37

Author(s):

Thomas D. Edlind ◽

Santosh K. Katiyar

Keyword(s):

Candida Glabrata ◽

Fungal Pathogens ◽

Mutational Analysis ◽

Cytosine Deaminase ◽

Low Frequency ◽

Serum Levels ◽

High Rate ◽

Attractive Alternative ◽

Resistance Mutations ◽

Mucosal Candidiasis

ABSTRACT The antifungal flucytosine (5-fluorocytosine [5FC]) is a prodrug metabolized to its toxic form, 5-fluorouracil (5FU), only by organisms expressing cytosine deaminase. One such organism is Candida glabrata, which has emerged as the second most common agent of bloodstream and mucosal candidiasis. This emergence has been attributed to the high rate at which C. glabrata develops resistance to azole antifungals. As an oral agent, 5FC represents an attractive alternative or complement to azoles; however, the frequency of 5FC resistance mutations and the mechanisms by which these mutations confer resistance have been explored only minimally. On RPMI 1640 medium containing 1 μg/ml 5FC (32-fold above the MIC, but less than 1/10 of typical serum levels), resistant mutants occurred at a relatively low frequency (2 × 10−7). Three of six mutants characterized were 5FU cross-resistant, suggesting a mutation downstream of the Fcy1 gene (cytosine deaminase), which was confirmed by sequence analysis of the Fur1 gene (uracil phosphoribosyl transferase). The remaining three mutants had Fcy1 mutations. To ascertain the effects of 5FC resistance mutations on enzyme function, mutants were isolated in ura3 strains. Three of seven mutants harbored Fcy1 mutations and failed to grow in uridine-free, cytosine-supplemented medium, consistent with inactive Fcy1. The remainder grew in this medium and had wild-type Fcy1; further analysis revealed these to be mutated in the Fcy2L homolog of S. cerevisiae Fcy2 (purine-cytosine transporter). Based on this analysis, we characterized three 5FC-resistant clinical isolates, and mutations were identified in Fur1 and Fcy1. These data provide a framework for understanding 5FC resistance in C. glabrata and potentially in other fungal pathogens.

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Dual Goals for Speed and Accuracy on the Same Performance Task

Journal of Personnel Psychology ◽

10.1027/1866-5888/a000063 ◽

2012 ◽

Vol 11 (3) ◽

pp. 118-126 ◽

Cited By ~ 3

Author(s):

Olive Emil Wetter ◽

Jürgen Wegge ◽

Klaus Jonas ◽

Klaus-Helmut Schmidt

Keyword(s):

Memory Scanning ◽

Performance Task ◽

Performance Tasks ◽

Trade Off ◽

Test Experiment ◽

Trade Offs ◽

New Finding ◽

Sternberg Paradigm ◽

Speed Accuracy ◽

Speed And Accuracy

In most work contexts, several performance goals coexist, and conflicts between them and trade-offs can occur. Our paper is the first to contrast a dual goal for speed and accuracy with a single goal for speed on the same task. The Sternberg paradigm (Experiment 1, n = 57) and the d2 test (Experiment 2, n = 19) were used as performance tasks. Speed measures and errors revealed in both experiments that dual as well as single goals increase performance by enhancing memory scanning. However, the single speed goal triggered a speed-accuracy trade-off, favoring speed over accuracy, whereas this was not the case with the dual goal. In difficult trials, dual goals slowed down scanning processes again so that errors could be prevented. This new finding is particularly relevant for security domains, where both aspects have to be managed simultaneously.

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The Effects of Decision Time on Perceptions of Decisions and Decision Makers in (Moral) Trade-Off Scenarios

10.31234/osf.io/37t2r ◽

2019 ◽

Author(s):

Anna Katharina Spälti ◽

Mark John Brandt ◽

Marcel Zeelenberg

Keyword(s):

Decision Process ◽

Decision Time ◽

Decision Makers ◽

Process Information ◽

Total N ◽

Trade Off ◽

Financial Gain ◽

Trade Offs ◽

Sacred Values ◽

Moral Context

People often have to make trade-offs. We study three types of trade-offs: 1) "secular trade-offs" where no moral or sacred values are at stake, 2) "taboo trade-offs" where sacred values are pitted against financial gain, and 3) "tragic trade-offs" where sacred values are pitted against other sacred values. Previous research (Critcher et al., 2011; Tetlock et al., 2000) demonstrated that tragic and taboo trade-offs are not only evaluated by their outcomes, but are also evaluated based on the time it took to make the choice. We investigate two outstanding questions: 1) whether the effect of decision time differs for evaluations of decisions compared to decision makers and 2) whether moral contexts are unique in their ability to influence character evaluations through decision process information. In two experiments (total N = 1434) we find that decision time affects character evaluations, but not evaluations of the decision itself. There were no significant differences between tragic trade-offs and secular trade-offs, suggesting that the decisions structure may be more important in evaluations than moral context. Additionally, the magnitude of the effect of decision time shows us that decision time, may be of less practical use than expected. We thus urge, to take a closer examination of the processes underlying decision time and its perception.

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Predicting Undesired Treatment Outcome in Mental Healthcare: Machine Learning Study (Preprint)

10.2196/preprints.17235 ◽

2019 ◽

Author(s):

Kasper Van Mens ◽

Joran Lokkerbol ◽

Richard Janssen ◽

Robert de Lange ◽

Bea Tiemens

Keyword(s):

Machine Learning ◽

Treatment Outcome ◽

Mental Health Treatment ◽

Mental Healthcare ◽

Machine Learning Algorithms ◽

Gradient Boosting ◽

Trade Off ◽

Trade Offs ◽

Outcome Monitoring ◽

Extreme Gradient Boosting

BACKGROUND It remains a challenge to predict which treatment will work for which patient in mental healthcare. OBJECTIVE In this study we compare machine algorithms to predict during treatment which patients will not benefit from brief mental health treatment and present trade-offs that must be considered before an algorithm can be used in clinical practice. METHODS Using an anonymized dataset containing routine outcome monitoring data from a mental healthcare organization in the Netherlands (n = 2,655), we applied three machine learning algorithms to predict treatment outcome. The algorithms were internally validated with cross-validation on a training sample (n = 1,860) and externally validated on an unseen test sample (n = 795). RESULTS The performance of the three algorithms did not significantly differ on the test set. With a default classification cut-off at 0.5 predicted probability, the extreme gradient boosting algorithm showed the highest positive predictive value (ppv) of 0.71(0.61 – 0.77) with a sensitivity of 0.35 (0.29 – 0.41) and area under the curve of 0.78. A trade-off can be made between ppv and sensitivity by choosing different cut-off probabilities. With a cut-off at 0.63, the ppv increased to 0.87 and the sensitivity dropped to 0.17. With a cut-off of at 0.38, the ppv decreased to 0.61 and the sensitivity increased to 0.57. CONCLUSIONS Machine learning can be used to predict treatment outcomes based on routine monitoring data.This allows practitioners to choose their own trade-off between being selective and more certain versus inclusive and less certain.

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Challenges in the Empirical Study of Global Governance Legitimacy

10.1093/oso/9780198826873.003.0011 ◽

2018 ◽

Cited By ~ 1

Author(s):

Steven Bernstein

Keyword(s):

Empirical Study ◽

Global Governance ◽

Research Agenda ◽

Cultural Factors ◽

Theory Building ◽

Trade Off ◽

Trade Offs ◽

Different Types ◽

Political Communities

This commentary discusses three challenges for the promising and ambitious research agenda outlined in the volume. First, it interrogates the volume’s attempts to differentiate political communities of legitimation, which may vary widely in composition, power, and relevance across institutions and geographies, with important implications not only for who matters, but also for what gets legitimated, and with what consequences. Second, it examines avenues to overcome possible trade-offs from gains in empirical tractability achieved through the volume’s focus on actor beliefs and strategies. One such trade-off is less attention to evolving norms and cultural factors that may underpin actors’ expectations about what legitimacy requires. Third, it addresses the challenge of theory building that can link legitimacy sources, (de)legitimation practices, audiences, and consequences of legitimacy across different types of institutions.

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Toward Inclusive Landscape Governance in Contested Landscapes: Exploring the Contribution of Participatory Tools in the Upper Suriname River Basin

Environmental Management ◽

10.1007/s00267-021-01504-8 ◽

2021 ◽

Author(s):

Lisa Best ◽

Kimberley Fung-Loy ◽

Nafiesa Ilahibaks ◽

Sara O. I. Ramirez-Gomez ◽

Erika N. Speelman

Keyword(s):

Land Use ◽

River Basin ◽

Scenario Planning ◽

Community Members ◽

Trade Off ◽

3 Dimensional ◽

Landscape Governance ◽

Information Tools ◽

Tribal Communities ◽

Trade Offs

AbstractNowadays, tropical forest landscapes are commonly characterized by a multitude of interacting institutions and actors with competing land-use interests. In these settings, indigenous and tribal communities are often marginalized in landscape-level decision making. Inclusive landscape governance inherently integrates diverse knowledge systems, including those of indigenous and tribal communities. Increasingly, geo-information tools are recognized as appropriate tools to integrate diverse interests and legitimize the voices, values, and knowledge of indigenous and tribal communities in landscape governance. In this paper, we present the contribution of the integrated application of three participatory geo-information tools to inclusive landscape governance in the Upper Suriname River Basin in Suriname: (i) Participatory 3-Dimensional Modelling, (ii) the Trade-off! game, and (iii) participatory scenario planning. The participatory 3-dimensional modelling enabled easy participation of community members, documentation of traditional, tacit knowledge and social learning. The Trade-off! game stimulated capacity building and understanding of land-use trade-offs. The participatory scenario planning exercise helped landscape actors to reflect on their own and others’ desired futures while building consensus. Our results emphasize the importance of systematically considering tool attributes and key factors, such as facilitation, for participatory geo-information tools to be optimally used and fit with local contexts. The results also show how combining the tools helped to build momentum and led to diverse yet complementary insights, thereby demonstrating the benefits of integrating multiple tools to address inclusive landscape governance issues.

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On the effectiveness of tracking and testing in SEIR models for improving health vs. economy trade-offs

Scientific Reports ◽

10.1038/s41598-021-95415-7 ◽

2021 ◽

Vol 11 (1) ◽

Author(s):

Yoav Kolumbus ◽

Noam Nisan

Keyword(s):

Additional Parameter ◽

Patient Privacy ◽

Economic Costs ◽

Trade Off ◽

Seir Model ◽

Social Question ◽

Social Distancing ◽

Trade Offs ◽

Asymptomatic Individuals ◽

Testing Policies

AbstractWe study the effectiveness of tracking and testing policies for suppressing epidemic outbreaks. We evaluate the performance of tracking-based intervention methods on a network SEIR model, which we augment with an additional parameter to model pre-symptomatic and asymptomatic individuals, and study the effectiveness of these methods in combination with or as an alternative to quarantine and global lockdown policies. Our focus is on the basic trade-off between human-lives lost and economic costs, and on how this trade-off changes under different quarantine, lockdown, tracking, and testing policies. Our main findings are as follows: (1) Tests combined with patient quarantines reduce both economic costs and mortality, however, an extensive-scale testing capacity is required to achieve a significant improvement. (2) Tracking significantly reduces both economic costs and mortality. (3) Tracking combined with a moderate testing capacity can achieve containment without lockdowns. (4) In the presence of a flow of new incoming infections, dynamic “On–Off” lockdowns are more efficient than fixed lockdowns. In this setting as well, tracking strictly improves efficiency. The results show the extreme usefulness of policies that combine tracking and testing for reducing mortality and economic costs, and their potential to contain outbreaks without imposing any social distancing restrictions. This highlights the difficult social question of trading-off these gains against patient privacy, which is inevitably infringed by tracking.

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AND-OR-XOR NETWORK SYNTHESIS WITH AREA-POWER TRADE-OFF

Journal of Circuits System and Computers ◽

10.1142/s0218126611007736 ◽

2011 ◽

Vol 20 (06) ◽

pp. 1019-1035 ◽

Cited By ~ 1

Author(s):

SAMBHU NATH PRADHAN ◽

M. TILAK KUMAR ◽

SANTANU CHATTOPDHYAY

Keyword(s):

Boolean Function ◽

Solution Space ◽

Leakage Power ◽

Total Power ◽

Synthesis Process ◽

Network Synthesis ◽

Trade Off ◽

Delay Performance ◽

Trade Offs ◽

Power Trade

In this paper, a heuristic based on genetic algorithm to realize multi-output Boolean function as three-level AND-OR-XOR network performing area power trade-off is presented. All the previous works dealt with the minimization of number of product terms only in the two sum-of-product-expressions representing a Boolean function during AND-OR-XOR network synthesis. To the best of knowledge this is the first ever effort to incorporate total power, that is, dynamic and leakage power along with the area (in terms of number of product terms) during three-level AND-OR-XOR networks synthesis. The synthesis process, without changing the delay performance results in lesser number of product terms compared to those reported in the literature. It also enumerates the trade-offs present in the solution space for different weights associated with area, dynamic power, and leakage power of the resulting circuit.

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Trade-Off Analysis for the Design of a High Performance Hydrostatic Actuation System

10.1115/imece2000-1981 ◽

2000 ◽

Author(s):

S. R. Habibi

Keyword(s):

Mathematical Modeling ◽

Quadratic Programming ◽

High Performance ◽

Design Parameters ◽

Mathematical Functions ◽

Trade Off ◽

Actuation System ◽

Trade Offs ◽

Expected Performance ◽

Dominant Design

Abstract This paper considers the design of a high performance hydrostatic actuation system referred to as the ElectroHydraulic Actuator (EHA). The expected performance of EHA and its dominant design parameters are identified by using mathematical modeling. The design parameters are classified into Direct and Indirect categories based on the measure of their accessibility to the designer. The Direct parameters are directly quantifiable and, can be linked to the performance of EHA through a set of mathematical functions. A prototype of EHA has been produced and described. The mathematical functions linking performance to design parameters are used to investigate design trade-offs. Design improvements to the prototype are suggested by using constrained quadratic programming.

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