Trade-offs between drug toxicity and benefit in the multi-antibiotic resistance system underlie optimal growth of E. coli

Background: Efflux is a widespread mechanism of reversible drug resistance in bacteria that can be triggered by environmental stressors, including many classes of drugs. While such chemicals when used alone are typically toxic to the cell, they can also induce the efflux of a broad range of agents and may therefore prove beneficial to cells in the presence of multiple stressors. The cellular response to a combination of such chemical stressors may be governed by a trade-off between the fitness costs due to drug toxicity and benefits mediated by inducible systems. Unfortunately, disentangling the cost-benefit interplay using measurements of bacterial growth in response to the competing effects of the drugs is not possible without the support of a theoretical framework. Results: Here, we use the well-studied multiple antibiotic resistance (MAR) system in E. coli to experimentally characterize the trade-off between drug toxicity (“cost”) and drug-induced resistance (“benefit”) mediated by efflux pumps. Specifically, we show that the combined effects of a MAR-inducing drug and an antibiotic are governed by a superposition of cost and benefit functions that govern these trade-offs. We find that this superposition holds for all drug concentrations, and it therefore allows us to describe the full dose–response diagram for a drug pair using simpler cost and benefit functions. Moreover, this framework predicts the existence of optimal growth at a non-trivial concentration of inducer. We demonstrate that optimal growth does not coincide with maximum induction of the mar promoter, but instead results from the interplay between drug toxicity and mar induction. Finally, we derived and experimentally validated a general phase diagram highlighting the role of these opposing effects in shaping the interaction between two drugs. Conclusions: Our analysis provides a quantitative description of the MAR system and highlights the trade-off between inducible resistance and the toxicity of the inducing agent in a multi-component environment. The results provide a predictive framework for the combined effects of drug toxicity and induction of the MAR system that are usually masked by bulk measurements of bacterial growth. The framework may also be useful for identifying optimal growth conditions in more general systems where combinations of environmental cues contribute to both transient resistance and toxicity.Engineering and Applied SciencesMolecular and Cellular Biolog

Uncovering Scaling Laws to Infer Multi-drug Response of Resistant Microbes and Cancer Cells

Drug resistance in bacterial infections and cancers constitutes a major threat to human health. Treatments often include several interacting drugs, but even potent therapies can become ineffective in resistant mutants. Here we simplify the picture of drug resistance by identifying scaling laws that unify the multi-drug responses of drug sensitive and drug resistant cells. Based on these scaling relationships, we are able to infer the two-drug response of resistant mutants in previously unsampled regions of dosage space in clinically relevant microbes such as E. coli, E. faecalis, S. aureus and S. cerevisiae, as well as in human non-small cell lung cancer, melanoma, and breast cancer stem cells. Importantly, we find that scaling relations also apply across evolutionarily close strains. Finally, scaling allows one to rapidly identify new drug combinations and predict potent dosage regimes for targeting resistant mutants without any prior mechanistic knowledge of the specific resistance mechanism.Molecular and Cellular Biolog

Invasive crayfish impacts on native fish diet and growth vary with fish life stage

Assessing the impacts of invasive organisms is a major challenge in ecology. Some widespread invasive species such as crayfish are potential competitors and reciprocal predators of ecologically and recreationally important native fish species. Here, we examine the effects of signal crayfish (Pacifastacus leniusculus) on the growth, diet, and trophic position of the chub (Squalius cephalus) in four rivers in Britain. Growth rates of 0+ chub were typically lower in sympatric populations with signal crayfish compared with allopatric populations, and this effect could be traced through to 2+ chub in one river. However, growth rates of older chub (5+ to 6+) were typically higher in the presence of crayfish. Sympatry with crayfish resulted in lower chub length-at-age and mass-at-age in half of the rivers sampled, with no change detected in the other rivers. Stable isotope analyses (δ13C and δ15N) revealed that both chub and crayfish were omnivorous, feeding at multiple trophic levels and occupying similar trophic positions. We found some evidence that chub trophic position was greater at invaded sites on one river, with no difference detected on a second river. Mixing models suggested crayfish were important food items for both small and large chub at invaded sites. This study provides evidence that invasive species can have both positive and negative effects on different life stages of a native species, with the net impact likely to depend on responses at the population level

Kentucky Probationers\u27 and Parolees\u27 Perceptions of the Severity of Prison versus County Jail and Probation

This study extends a growing body of research on offenders\u27 perceptions of the punitiveness of criminal sanctions. Specifically, we examine punishment equivalency ratings by Kentucky probationers and parolees (N-588) meant to gauge their perceptions of the severity of prison compared to both probation and county jail. Ratings are analyzed by several demographic characteristics. We find that, in general, survey respondents pereceived county jail as more severe than prison but that probation was rated as less severe

A Microfabricated Segmented-Involute-Foil Regenerator for Enhancing Reliability and Performance of Stirling Engines: Phase II Final Report for the Radioisotope Power Conversion Technology NRA Contract NAS3-03124

An actual-size microfabricated regenerator comprised of a stack of 42 disks, 19 mm diameter and 0.25 mm thick, with layers of microscopic, segmented, involute-shaped flow channels was fabricated and tested. The geometry resembles layers of uniformly-spaced segmented-parallel-plates, except the plates are curved. Each disk was made from electro-plated nickel using the LiGA process. This regenerator had feature sizes close to those required for an actual Stirling engine but the overall regenerator dimensions were sized for the NASA/Sunpower oscillating-flow regenerator test rig. Testing in the oscillating-flow test rig showed the regenerator performed extremely well, significantly better than currently used random-fiber material, producing the highest figures of merit ever recorded for any regenerator tested in that rig over its ~20 years of use

Changes in toxin content, biomass and pigments of the dinoflagellate Alexandrium minutum during nitrogen refeeding and growth into nitrogen or phosphorus stress

Two strains oi the paralytic shellfish toxin (PST) producing dinoflagellate Alexandrium minutum Halim (highly toxic ALl V and weakly toxic AL2V) were grown in batch culture with either nitrate or phosphate as the limiting nutrient. In comparison with cells of the strain AL1V, cells of AL2V grew at a similar C-specific Tale, had a higher C/N ratio, and lower ratios of chl a/chl C2and chl a/peridinin. Neither chlorophylls flor carotenoids could be used to estimate C-biomass, N-biomass or toxin content for this organismo The toxin profile for both strains was dominated (up to 95 %) by the gonyautoxin GTX4, with smaller proportions of GTX1, GTX2 and GTX3. The Tale of toxin synthesis for both strains was greatest 1 to 2 d after the N-refeeding of N-deprived cells, with the net Tale of toxin syn- .thesis exceeding that of C-biomass and cell division by a factor of up to 4. Toxin synthesis was not enhanced by short-term P-stress. N-stress alone led to a decrease in toxin cell-I, but P-stress followed by N-stress did not result in such a decline, implicating phosphorus in the regulation of toxin metabolism. Although arginine is a majar precursor for PST synthesis, taurine, glycine, glutamine, and cell N showed similar relations to that observed for arginine with respect to toxin contento Furthermore, the mole ratio of arginine/toxin could vary by a factor of up to 5 between AL1V and AL2V at peak values of toxin cell-1, and by more than 5 within a strain when growing under different conditions. These observations suggest that the relationship between free arginine content and toxin content is complex. No explanation for the higher toxin content of AL1V is apparent, except that AL1V has a higher N-content per cell and this may be conducive to a higher Tale of synthesis of the N-rich toxins.Publicado

Do the photometric colors of Type II-P Supernovae allow accurate determination of host galaxy extinction?

We present infrared photometry of SN 1999em, plus optical photometry, infrared photometry, and optical spectroscopy of SN 2003hn. Both objects were Type II-P supernovae. The V-[RIJHK] color curves of these supernovae evolved in a very similar fashion until the end of plateau phase. This allows us to determine how much more extinction the light of SN 2003hn suffered compared to SN 1999em. Since we have an estimate of the total extinction suffered by SN 1999em from model fits of ground-based and space-based spectra as well as photometry of SN 1999em, we can estimate the total extinction and absolute magnitudes of SN 2003hn with reasonable accuracy. Since the host galaxy of SN 2003hn also produced the Type Ia SN 2001el, we can directly compare the absolute magnitudes of these two SNe of different types.Comment: 24 pages, 6 figure

Hubble Space Telescope Observations of Nine High-Redshift ESSENCE Supernovae

We present broad-band light curves of nine supernovae ranging in redshift from 0.5 to 0.8. The supernovae were discovered as part of the ESSENCE project, and the light curves are a combination of Cerro Tololo 4-m and Hubble Space Telescope (HST) photometry. On the basis of spectra and/or light-curve fitting, eight of these objects are definitely Type Ia supernovae, while the classification of one is problematic. The ESSENCE project is a five-year endeavor to discover about 200 high-redshift Type Ia supernovae, with the goal of tightly constraining the time average of the equation-of-state parameter [w = p/(rho c^2)] of the "dark energy." To help minimize our systematic errors, all of our ground-based photometry is obtained with the same telescope and instrument. In 2003 the highest-redshift subset of ESSENCE supernovae was selected for detailed study with HST. Here we present the first photometric results of the survey. We find that all but one of the ESSENCE SNe have slowly declining light curves, and the sample is not representative of the low-redshift set of ESSENCE Type Ia supernovae. This is unlikely to be a sign of evolution in the population. We attribute the decline-rate distribution of HST events to a selection bias at the high-redshift edge of our sample and find that such a bias will infect other magnitude-limited SN Ia searches unless appropriate precautions are taken.Comment: 62 pages, 18 numbered figures, accepted for publication in the Astronomical Journa

Supernova Cosmology and the ESSENCE project

The proper usage of Type Ia supernovae (SNe Ia) as distance indicators has revolutionized cosmology, and added a new dominant component to the energy density of the Universe, dark energy. Following the discovery and confirmation era, the currently ongoing SNe Ia surveys aim to determine the properties of the dark energy. ESSENCE is a five year ground-based supernova survey aimed at finding and characterizing 200 SNe Ia in the redshift domain z=[0.2-0.8]. The goal of the project is to put constraints on the equation of state parameter, w, of the dark energy with an accuracy of <10%. This paper presents these ongoing efforts in the context of the current developments in observational cosmology.Comment: Submitted to EPS1