@article{22521,
  abstract     = {A fully distributed hydrological analysis at scales significant for water management for present-day, and
projected future climate conditions is presented for a catchment in the Alps. We selected the upper Rhone
basin (Switzerland) as a test case for understanding anthropogenic impacts including climate change on
water resources and flood risk in the Alpine area. The upper Rhone basin contains reservoirs, river diversions and irrigated areas offering the opportunity to study the interaction between climate change effects
and hydraulic infrastructure. Anthropogenic disturbances of the flow regime were implemented in detail
in the hydrological analysis. We downscaled climate model realizations using a methodology that
accounts for the uncertainty in climate change projections related to the stochastic variability of precipitation and air temperature. We showed how climate change effects on streamflow propagate from high
elevation headwater catchments to the river in the main valley by analyzing changes in several hydrological metrics and at various temporal scales across 297 control sections. Changes in the natural hydrological regime imposed by the existing hydraulic infrastructure are likely larger than climate change
signals expected by the middle of the 21st century in most of the river network. Despite a strong uncertainty induced by stochastic climate variability, we identified an elevational dependence of climate
change impacts with a severe reduction in streamflow due to the missing contribution of water from
ice melt at high-elevation and a dampened effect downstream. Reduced ice cover and ice melt are likely
to have significant implications for hydropower production. The impacts can emerge without any additional climate warming. A decrease of August–September discharge and an increase of hourly and daily
maximum flows appear as plausible projected change for the most part of the catchment. However, it is
unlikely that major changes in total runoff for the entire upper Rhone basin will occur in the next four
decades.},
  author       = {Fatichi, Simone and Rimkus, S. and Burlando, P. and Bordoy, R. and Molnar, P.},
  issn         = {1879-2707},
  journal      = {Journal of Hydrology},
  keywords     = {Climate change, Water resources, Stochastic approaches, Ice melt, Alps, Hydrological modeling},
  pages        = {362--382},
  publisher    = {Elsevier},
  title        = {{High-resolution distributed analysis of climate and anthropogenic changes on the hydrology of an Alpine catchment}},
  doi          = {10.1016/j.jhydrol.2015.03.036},
  volume       = {525},
  year         = {2015},
}

@article{22533,
  abstract     = {While the importance of ecosystem functioning is undisputed in the context of climate change and Earth system modeling, the role of short‐scale temporal variability of hydrometeorological forcing (~1 h) on the related ecosystem processes remains to be fully understood. Various impacts of meteorological forcing variability on water and carbon fluxes across a range of scales are explored here using numerical simulations. Synthetic meteorological drivers that highlight dynamic features of the short temporal scale in series of precipitation, temperature, and radiation are constructed. These drivers force a mechanistic ecohydrological model that propagates information content into the dynamics of water and carbon fluxes for an ensemble of representative ecosystems. The focus of the analysis is on a cross‐scale effect of the short‐scale forcing variability on the modeled evapotranspiration and ecosystem carbon assimilation. Interannual variability of water and carbon fluxes is emphasized in the analysis. The main study inferences are summarized as follows: (a) short‐scale variability of meteorological input does affect water and carbon fluxes across a wide range of time scales, spanning from the hourly to the annual and longer scales; (b) different ecosystems respond to the various characteristics of the short‐scale variability of the climate forcing in various ways, depending on dominant factors limiting system productivity; (c) whenever short‐scale variability of meteorological forcing influences primarily fast processes such as photosynthesis, its impact on the slow‐scale variability of water and carbon fluxes is small; and (d) whenever short‐scale variability of the meteorological forcing impacts slow processes such as movement and storage of water in the soil, the effects of the variability can propagate to annual and longer time scales.},
  author       = {Paschalis, Athanasios and Fatichi, Simone and Katul, Gabriel G. and Ivanov, Valeriy Y.},
  issn         = {2169-8961},
  journal      = {Journal of Geophysical Research: Biogeosciences},
  number       = {9},
  pages        = {1716--1740},
  publisher    = {American Geophysical Union},
  title        = {{Cross‐scale impact of climate temporal variability on ecosystem water and carbon fluxes}},
  doi          = {10.1002/2015jg003002},
  volume       = {120},
  year         = {2015},
}

@article{22532,
  abstract     = {The coarse‐grained spatial representation of many terrestrial ecosystem models hampers the importance of local‐scale heterogeneities. To address this issue, we combine a range of observations (forest inventories, eddy flux tower data, and remote sensing products) and modeling approaches with contrasting degrees of abstraction. The following models are selected: (i) Lund‐Potsdam‐Jena (LPJ), a well‐established, area‐based, dynamic global vegetation model (DGVM); (ii) LPJ‐General Ecosystem Simulator, a hybrid, individual‐based approach that additionally considers plant population dynamics in greater detail; and (iii) distributed in space‐LPJ, a spatially explicit version of LPJ, operating at a fine spatial resolution (100 m × 100 m), which uses an enhanced hydrological representation accounting for lateral connectivity of surface and subsurface water fluxes. By comparing model simulations with a multivariate data set available at the catchment scale, we argue that (i) local environmental and topographic attributes that are often ignored or crudely represented in DGVM applications exert a strong control on terrestrial ecosystem response; (ii) the assumption of steady state vegetation and soil carbon pools at the beginning of simulation studies (e.g., under “current conditions”), as embedded in many DGVM applications, is in contradiction with the current state of many forests that are often out of equilibrium; and (iii) model evaluation against vegetation carbon fluxes does not imply an accurate simulation of vegetation carbon stocks. Having gained insights about the magnitude of aggregation‐induced biases due to smoothing of spatial variability at the catchment scale, we discuss the implications of our findings with respect to the global‐scale modeling studies of carbon cycle and we illustrate alternative ways forward.},
  author       = {Pappas, Christoforos and Fatichi, Simone and Rimkus, Stefan and Burlando, Paolo and Huber, Markus O.},
  issn         = {2169-8961},
  journal      = {Journal of Geophysical Research: Biogeosciences},
  number       = {2},
  pages        = {341--360},
  publisher    = {American Geophysical Union},
  title        = {{The role of local‐scale heterogeneities in terrestrial ecosystem modeling}},
  doi          = {10.1002/2014jg002735},
  volume       = {120},
  year         = {2015},
}

@article{22559,
  abstract     = {Extreme precipitation is thought to increase with warming at rates similar to or greater than the water vapour holding capacity of the air at ~ 7% °C−1, the so-called Clausius–Clapeyron (CC) rate. We present an empirical study of the variability in the rates of increase in precipitation intensity with air temperature using 30 years of 10 min and 1 h data from 59 stations in Switzerland. The analysis is conducted on storm events rather than fixed interval data, and divided into storm type subsets based on the presence of lightning which is expected to indicate convection. The average rates of increase in extremes (95th percentile) of mean event intensity computed from 10 min data are 6.5% °C−1 (no-lightning events), 8.9% °C−1 (lightning events) and 10.7% °C−1 (all events combined). For peak 10 min intensities during an event the rates are 6.9% °C−1 (no-lightning events), 9.3% °C−1 (lightning events) and 13.0% °C−1 (all events combined). Mixing of the two storm types exaggerates the relations to air temperature. Doubled CC rates reported by other studies are an exception in our data set, even in convective rain. The large spatial variability in scaling rates across Switzerland suggests that both local (orographic) and regional effects limit moisture supply and availability in Alpine environments, especially in mountain valleys. The estimated number of convective events has increased across Switzerland in the last 30 years, with 30% of the stations showing statistically significant changes. The changes in intense convective storms with higher temperatures may be relevant for hydrological risk connected with those events in the future.},
  author       = {Molnar, P. and Fatichi, Simone and Gaál, L. and Szolgay, J. and Burlando, P.},
  issn         = {1607-7938},
  journal      = {Hydrology and Earth System Sciences},
  number       = {4},
  pages        = {1753--1766},
  publisher    = {Copernicus Publications},
  title        = {{Storm type effects on super Clausius–Clapeyron scaling of intense rainstorm properties with air temperature}},
  doi          = {10.5194/hess-19-1753-2015},
  volume       = {19},
  year         = {2015},
}

@article{1830,
  abstract     = {To prevent epidemics, insect societies have evolved collective disease defences that are highly effective at curing exposed individuals and limiting disease transmission to healthy group members. Grooming is an important sanitary behaviour—either performed towards oneself (self-grooming) or towards others (allogrooming)—to remove infectious agents from the body surface of exposed individuals, but at the risk of disease contraction by the groomer. We use garden ants (Lasius neglectus) and the fungal pathogen Metarhizium as a model system to study how pathogen presence affects self-grooming and allogrooming between exposed and healthy individuals. We develop an epidemiological SIS model to explore how experimentally observed grooming patterns affect disease spread within the colony, thereby providing a direct link between the expression and direction of sanitary behaviours, and their effects on colony-level epidemiology. We find that fungus-exposed ants increase self-grooming, while simultaneously decreasing allogrooming. This behavioural modulation seems universally adaptive and is predicted to contain disease spread in a great variety of host–pathogen systems. In contrast, allogrooming directed towards pathogen-exposed individuals might both increase and decrease disease risk. Our model reveals that the effect of allogrooming depends on the balance between pathogen infectiousness and efficiency of social host defences, which are likely to vary across host–pathogen systems.},
  author       = {Theis, Fabian and Ugelvig, Line V and Marr, Carsten and Cremer, Sylvia},
  issn         = {1471-2970},
  journal      = {Philosophical Transactions of the Royal Society of London. Series B, Biological Sciences},
  number       = {1669},
  publisher    = {Royal Society},
  title        = {{Opposing effects of allogrooming on disease transmission in ant societies}},
  doi          = {10.1098/rstb.2014.0108},
  volume       = {370},
  year         = {2015},
}

@misc{9721,
  abstract     = {To prevent epidemics, insect societies have evolved collective disease defences that are highly effective at curing exposed individuals and limiting disease transmission to healthy group members. Grooming is an important sanitary behaviour—either performed towards oneself (self-grooming) or towards others (allogrooming)—to remove infectious agents from the body surface of exposed individuals, but at the risk of disease contraction by the groomer. We use garden ants (Lasius neglectus) and the fungal pathogen Metarhizium as a model system to study how pathogen presence affects self-grooming and allogrooming between exposed and healthy individuals. We develop an epidemiological SIS model to explore how experimentally observed grooming patterns affect disease spread within the colony, thereby providing a direct link between the expression and direction of sanitary behaviours, and their effects on colony-level epidemiology. We find that fungus-exposed ants increase self-grooming, while simultaneously decreasing allogrooming. This behavioural modulation seems universally adaptive and is predicted to contain disease spread in a great variety of host–pathogen systems. In contrast, allogrooming directed towards pathogen-exposed individuals might both increase and decrease disease risk. Our model reveals that the effect of allogrooming depends on the balance between pathogen infectiousness and efficiency of social host defences, which are likely to vary across host–pathogen systems.},
  author       = {Theis, Fabian and Ugelvig, Line V and Marr, Carsten and Cremer, Sylvia},
  publisher    = {Dryad},
  title        = {{Data from: Opposing effects of allogrooming on disease transmission in ant societies}},
  doi          = {10.5061/dryad.dj2bf},
  year         = {2015},
}

@article{22585,
  abstract     = {Most of the currently experienced global environmental changes (rising atmospheric CO2 concentrations, warming, altered amount and pattern of precipitation, and increased nutrient load) directly or indirectly affect ecosystem surface energy balance and plant transpiration. As a consequence, the relative humidity of the air surrounding the vegetation changes, thus creating a feedback loop whose net effect on transpiration and finally productivity is not trivial to quantify. Forcedly, in any global change experiment with the above drivers, we can only treat small plots, or ‘islands’, of vegetation. This means that the treated plots will likely experience the ambient humidity conditions influenced by the surrounding, non-treated vegetation. Experimental assessments of global change effects will thus systematically lack modifications originating from these potentially important feedback mechanisms, introducing a bias of unknown magnitude in all measurements of processes directly or indirectly depending on plant transpiration. We call this potential bias the ‘island effect’. Here, we discuss its implications in various global change experiments with plants. We also suggest ways to complement experiments using modelling approaches and observational studies. Ultimately, there is no obvious solution to deal with the island effect in field experiments and only models can provide an estimate of modification of responses by these feedbacks. However, we suggest that increasing the awareness of the island effect among both experimental researchers and modellers will greatly improve the interpretation of vegetation responses to global change.},
  author       = {Leuzinger, Sebastian and Fatichi, Simone and Cusens, Jarrod and Körner, Christian and Niklaus, Pascal A.},
  issn         = {2041-2851},
  journal      = {AoB Plants},
  keywords     = {DGVM, Elevated CO2, FACE, Hydrology, Land–atmosphere coupling, Vegetation feedback effects, Warming},
  publisher    = {Oxford University Press},
  title        = {{The ‘island effect’ in terrestrial global change experiments: a problem with no solution?}},
  doi          = {10.1093/aobpla/plv092},
  volume       = {7},
  year         = {2015},
}

@article{22471,
  abstract     = {Extreme climate conditions can dramatically alter ecosystems and are expected to become more common in thefuture; however, our understanding of species and ecosystem responses to extreme conditions is limited. Wemust meet this challenge by designing experiments that cover broad ranges of environmental stress, extendingto levels well beyond those observed currently. Such experiments are important because they can identify phys-iological, community, and biogeochemical thresholds, and improve our understanding of mechanistic ecologi-cal responses to climate extremes. Although natural environmental gradients can be used to observe a range ofecological responses, manipulation experiments – including those that impose drought and heat gradients – arenecessary to induce variation beyond common limits. Importantly, manipulation experiments allow for deter-mination of the cause and effect of species and ecosystem threshold responses. We present a rationale and rec-ommendations for conducting extreme experiments that extend beyond the historical and even the predictedranges of environmental conditions.},
  author       = {Kayler, Zachary E and De Boeck, Hans J and Fatichi, Simone and Grünzweig, José M and Merbold, Lutz and Beier, Claus and McDowell, Nathan and Dukes, Jeffrey S},
  issn         = {1540-9309},
  journal      = {Frontiers in Ecology and the Environment},
  number       = {4},
  pages        = {219--225},
  publisher    = {Wiley},
  title        = {{Experiments to confront the environmental extremes of climate change}},
  doi          = {10.1890/140174},
  volume       = {13},
  year         = {2015},
}

@article{22493,
  abstract     = {Predictions of a warmer climate over the Great Lakes region due to global change generally agree on the magnitude of temperature changes, but precipitation projections exhibit dependence on which General Circulation Models and emission scenarios are chosen. To minimize model- and scenario-specific biases, we combined information provided by the 3rd phase of the Coupled Model Intercomparison Project database. Specifically, the results of 12 GCMs for three emission scenarios B1, A1B, and A2 were analyzed for mid- (2046–2065) and end-century (2081–2100) intervals, for six locations of a hydroclimatic transect of Michigan. As a result of Bayesian Weighted Averaging, total annual precipitation averaged over all locations and the three emission scenarios increases by 7 % (mid-)–10 % (end-century), as compared to the control period (1961–1990). The projected changes across seasons are non-uniform and precipitation decreases by 3 % (mid-)–5 % (end-) for the months of August and September are likely. Further, average temperature is very likely to increase by 2.02–2.85 °C by the mid-century and 2.58–4.73 °C by the end-century. Three types of non-additive uncertainty sources due to climate models, anthropogenic forcings, and climate internal variability are addressed. When compared to the emission uncertainty, the relative magnitudes of the uncertainty types for climate model ensemble and internal variability are 149 and 225 % for mean monthly precipitation, and they are respectively 127 and 123 % for mean monthly temperature. A decreasing trend of the frost days and an increasing trend of the growing season length are identified. Also, a significant increase in the magnitude and frequency of heavy rainfall events is projected, with relatively more pronounced changes for heavy hourly rainfall as compared to daily events. Quantifying the inherent natural uncertainty and projecting hourly-based extremes, the study results deliver useful information for water resource stakeholders interested in impacts of climate change on hydro-morphological processes.},
  author       = {Kim, Jongho and Ivanov, Valeriy Y. and Fatichi, Simone},
  issn         = {1436-3259},
  journal      = {Stochastic Environmental Research and Risk Assessment},
  keywords     = {Climate change, Weather generator, Stochastic downscaling, Uncertainty, CMIP3, Internal variability, Emission scenarios, Extreme indicators, The Great Lakes region},
  number       = {3},
  pages        = {923--944},
  publisher    = {Springer Nature},
  title        = {{Climate change and uncertainty assessment over a hydroclimatic transect of Michigan}},
  doi          = {10.1007/s00477-015-1097-2},
  volume       = {30},
  year         = {2015},
}

@article{1811,
  abstract     = {Atomic form factors are widely used for the characterization of targets and specimens, from crystallography to biology. By using recent mathematical results, here we derive an analytical expression for the atomic form factor within the independent particle model constructed from nonrelativistic screened hydrogenic wave functions. The range of validity of this analytical expression is checked by comparing the analytically obtained form factors with the ones obtained within the Hartee-Fock method. As an example, we apply our analytical expression for the atomic form factor to evaluate the differential cross section for Rayleigh scattering off neutral atoms.},
  author       = {Safari, Laleh and Santos, José and Amaro, Pedro and Jänkälä, Kari and Fratini, Filippo},
  journal      = {Journal of Mathematical Physics},
  number       = {5},
  publisher    = {AIP Publishing},
  title        = {{Analytical evaluation of atomic form factors: Application to Rayleigh scattering}},
  doi          = {10.1063/1.4921227},
  volume       = {56},
  year         = {2015},
}

@article{1677,
  abstract     = {We consider real symmetric and complex Hermitian random matrices with the additional symmetry hxy = hN-y,N-x. The matrix elements are independent (up to the fourfold symmetry) and not necessarily identically distributed. This ensemble naturally arises as the Fourier transform of a Gaussian orthogonal ensemble. Italso occurs as the flip matrix model - an approximation of the two-dimensional Anderson model at small disorder. We show that the density of states converges to the Wigner semicircle law despite the new symmetry type. We also prove the local version of the semicircle law on the optimal scale.},
  author       = {Alt, Johannes},
  journal      = {Journal of Mathematical Physics},
  number       = {10},
  publisher    = {AIP Publishing},
  title        = {{The local semicircle law for random matrices with a fourfold symmetry}},
  doi          = {10.1063/1.4932606},
  volume       = {56},
  year         = {2015},
}

@article{22494,
  abstract     = {Changes in near-surface humidity are evaluated in relation to changes in other meteorological variables such as air temperature, precipitation, and sunshine duration for a 31 year period (1981–2011) using hourly time series recorded in Switzerland. Trends in meteorological variables are analyzed at the seasonal and subdaily scale, and changes in water vapor are tested for Clausius-Clapeyron scaling. Results show a marked seasonality of climatic changes with a trend toward warmer, clearer, and drier near-surface atmosphere strengthening from January to June. During this period considerable negative trends in relative humidity are detected. An abrupt shift in climatic trends occurs during the month of July, after which warming trends are considerably smaller and relative humidity remains constant or increases. An evaluation of reanalysis products demonstrates strong consistency with station observations and when combined with teleconnection indices supports the hypothesis that shifts in the general circulation patterns rather than local feedbacks are the principal drivers of observed seasonality of climate change. However, local feedbacks can play a role in enhancing summer humidity and convective activity (lightning and evening precipitation). Subdaily changes are significant with more pronounced daytime trends of temperature and humidity during spring and the opposite during summer. The strong seasonality and diurnal variability of changes in near-surface meteorology over the last three decades in Switzerland warns against climate change impact assessments at local scale that consider uniform changes in air temperature and assume Clausius-Clapeyron scaling for near-surface humidity.},
  author       = {Fatichi, Simone and Molnar, Peter and Mastrotheodoros, Theodoros and Burlando, Paolo},
  issn         = {2169-8996},
  journal      = {Journal of Geophysical Research: Atmospheres},
  number       = {6},
  pages        = {2358--2374},
  publisher    = {American Geophysical Union},
  title        = {{Diurnal and seasonal changes in near‐surface humidity in a complex orography}},
  doi          = {10.1002/2014jd022537},
  volume       = {120},
  year         = {2015},
}

@article{1587,
  abstract     = {We investigate the quantum interference shifts between energetically close states, where the state structure is observed by laser spectroscopy. We report a compact and analytical expression that models the quantum interference induced shift for any admixture of circular polarization of the incident laser and angle of observation. An experimental scenario free of quantum interference can thus be predicted with this formula. Although this study is exemplified here for muonic deuterium, it can be applied to any other laser spectroscopy measurement of ns-n′p frequencies of a nonrelativistic atomic system, via an ns→n′p→n′′s scheme.},
  author       = {Amaro, Pedro and Fratini, Filippo and Safari, Laleh and Antognini, Aldo and Indelicato, Paul and Pohl, Randolf and Santos, José},
  journal      = {Physical Review A},
  number       = {6},
  publisher    = {American Physical Society},
  title        = {{Quantum interference shifts in laser spectroscopy with elliptical polarization}},
  doi          = {10.1103/PhysRevA.92.062506},
  volume       = {92},
  year         = {2015},
}

@article{1940,
  abstract     = {We typically think of cells as responding to external signals independently by regulating their gene expression levels, yet they often locally exchange information and coordinate. Can such spatial coupling be of benefit for conveying signals subject to gene regulatory noise? Here we extend our information-theoretic framework for gene regulation to spatially extended systems. As an example, we consider a lattice of nuclei responding to a concentration field of a transcriptional regulator (the "input") by expressing a single diffusible target gene. When input concentrations are low, diffusive coupling markedly improves information transmission; optimal gene activation functions also systematically change. A qualitatively new regulatory strategy emerges where individual cells respond to the input in a nearly step-like fashion that is subsequently averaged out by strong diffusion. While motivated by early patterning events in the Drosophila embryo, our framework is generically applicable to spatially coupled stochastic gene expression models.},
  author       = {Sokolowski, Thomas R and Tkacik, Gasper},
  journal      = {Physical Review E},
  number       = {6},
  publisher    = {American Physical Society},
  title        = {{Optimizing information flow in small genetic networks. IV. Spatial coupling}},
  doi          = {10.1103/PhysRevE.91.062710},
  volume       = {91},
  year         = {2015},
}

@article{1883,
  abstract     = {We introduce a one-parametric family of tree growth models, in which branching probabilities decrease with branch age τ as τ-α. Depending on the exponent α, the scaling of tree depth with tree size n displays a transition between the logarithmic scaling of random trees and an algebraic growth. At the transition (α=1) tree depth grows as (logn)2. This anomalous scaling is in good agreement with the trend observed in evolution of biological species, thus providing a theoretical support for age-dependent speciation and associating it to the occurrence of a critical point.
},
  author       = {Keller-Schmidt, Stephanie and Tugrul, Murat and Eguíluz, Víctor and Hernandez Garcia, Emilio and Klemm, Konstantin},
  journal      = {Physical Review E},
  number       = {2},
  publisher    = {American Physical Society},
  title        = {{Anomalous scaling in an age-dependent branching model}},
  doi          = {10.1103/PhysRevE.91.022803},
  volume       = {91},
  year         = {2015},
}

@inproceedings{1820,
  abstract     = {We consider partially observable Markov decision processes (POMDPs) with a set of target states and every transition is associated with an integer cost. The optimization objec- tive we study asks to minimize the expected total cost till the target set is reached, while ensuring that the target set is reached almost-surely (with probability 1). We show that for integer costs approximating the optimal cost is undecidable. For positive costs, our results are as follows: (i) we establish matching lower and upper bounds for the optimal cost and the bound is double exponential; (ii) we show that the problem of approximating the optimal cost is decidable and present ap- proximation algorithms developing on the existing algorithms for POMDPs with finite-horizon objectives. While the worst- case running time of our algorithm is double exponential, we present efficient stopping criteria for the algorithm and show experimentally that it performs well in many examples.},
  author       = {Chatterjee, Krishnendu and Chmelik, Martin and Gupta, Raghav and Kanodia, Ayush},
  booktitle    = {Proceedings of the Twenty-Ninth AAAI Conference on Artificial Intelligence },
  location     = {Austin, TX, USA},
  pages        = {3496--3502},
  publisher    = {AAAI Press},
  title        = {{Optimal cost almost-sure reachability in POMDPs}},
  doi          = {10.1609/aaai.v29i1.9683},
  volume       = {5},
  year         = {2015},
}

@article{1619,
  abstract     = {The emergence of drug resistant pathogens is a serious public health problem. It is a long-standing goal to predict rates of resistance evolution and design optimal treatment strategies accordingly. To this end, it is crucial to reveal the underlying causes of drug-specific differences in the evolutionary dynamics leading to resistance. However, it remains largely unknown why the rates of resistance evolution via spontaneous mutations and the diversity of mutational paths vary substantially between drugs. Here we comprehensively quantify the distribution of fitness effects (DFE) of mutations, a key determinant of evolutionary dynamics, in the presence of eight antibiotics representing the main modes of action. Using precise high-throughput fitness measurements for genome-wide Escherichia coli gene deletion strains, we find that the width of the DFE varies dramatically between antibiotics and, contrary to conventional wisdom, for some drugs the DFE width is lower than in the absence of stress. We show that this previously underappreciated divergence in DFE width among antibiotics is largely caused by their distinct drug-specific dose-response characteristics. Unlike the DFE, the magnitude of the changes in tolerated drug concentration resulting from genome-wide mutations is similar for most drugs but exceptionally small for the antibiotic nitrofurantoin, i.e., mutations generally have considerably smaller resistance effects for nitrofurantoin than for other drugs. A population genetics model predicts that resistance evolution for drugs with this property is severely limited and confined to reproducible mutational paths. We tested this prediction in laboratory evolution experiments using the “morbidostat”, a device for evolving bacteria in well-controlled drug environments. Nitrofurantoin resistance indeed evolved extremely slowly via reproducible mutations—an almost paradoxical behavior since this drug causes DNA damage and increases the mutation rate. Overall, we identified novel quantitative characteristics of the evolutionary landscape that provide the conceptual foundation for predicting the dynamics of drug resistance evolution.},
  author       = {Chevereau, Guillaume and Dravecka, Marta and Batur, Tugce and Guvenek, Aysegul and Ayhan, Dilay and Toprak, Erdal and Bollenbach, Mark Tobias},
  journal      = {PLoS Biology},
  number       = {11},
  publisher    = {Public Library of Science},
  title        = {{Quantifying the determinants of evolutionary dynamics leading to drug resistance}},
  doi          = {10.1371/journal.pbio.1002299},
  volume       = {13},
  year         = {2015},
}