Interactions and emergent processes are essential for research on complex systems involving many components. Most studies focus solely on pairwise interactions and ignore higher-order interactions among three or more components. To gain deeper insights into higher-order interactions and complex environments, we study antibiotic combinations applied to pathogenic Escherichia coli and obtain unprecedented amounts of detailed data (251 two-drug combinations, 1512 three-drug combinations, 5670 four-drug combinations, and 13608 five-drug combinations). Directly opposite to previous assumptions and reports, we find higher-order interactions increase in frequency with the number of drugs in the bacteria’s environment. Specifically, as more drugs are added, we observe an elevated frequency of net synergy (effect greater than expected based on independent individual effects) and also increased instances of emergent antagonism (effect less than expected based on lower-order interaction effects). These findings have implications for the potential efficacy of drug combinations and are crucial for better navigating problems associated with the combinatorial complexity of multi-component systems.

No abstract

Antibiotic effectiveness often changes when two or more such drugs are administered simultaneously, and unearthing antibiotic combinations with enhanced efficacy (synergy) has been a longstanding clinical goal. However, antibiotic resistance, which undermines individual drugs, threatens such combined treatments. Remarkably, it has emerged that antibiotic combinations whose combined effect is lower than that of at least one of the individual drugs can slow or even reverse the evolution of resistance. We synthesize and review studies of such so-called “suppressive interactions” in the literature. We examine why these interactions have been largely disregarded in the past, the strategies used to identify them, their mechanistic basis, demonstrations of their potential to reverse the evolution of resistance, and arguments for and against using them in clinical treatment. We suggest future directions for research on these interactions, aiming to expand the basic body of knowledge on suppression and to determine their applicability in the clinic.

Understanding how stressors combine to affect population abundances and trajectories is a fundamental ecological problem with increasingly important implications worldwide. Generalisations about interactions among stressors are challenging due to different categorisation methods and how stressors vary across species and systems. Here, we propose using a newly introduced framework to analyse data from the last 25 years on ecological stressor interactions, for example combined effects of temperature, salinity and nutrients on population survival and growth. We contrast our results with the most commonly used existing methodanalysis of variance (ANOVA)and show that ANOVA assumptions are often violated and have inherent limitations for detecting interactions. Moreover, we argue that rescalingexamining relative rather than absolute responsesis critical for ensuring that any interaction measure is independent of the strength of single-stressor effects. In contrast, non-rescaled measureslike ANOVAfind fewer interactions when single-stressor effects are weak. After reexamining 840 two-stressor combinations, we conclude that antagonism and additivity are the most frequent interaction types, in strong contrast to previous reports that synergy dominates yet supportive of more recent studies that find more antagonism. Consequently, measuring and reassessing the frequency of stressor interaction types is imperative for a better understanding of how stressors affect populations.

Context In rodents, cold exposure induces the activation of brown adipose tissue (BAT) and the induction of intracellular triacylglycerol (TAG) lipolysis. However, in humans, the kinetics of supraclavicular (SCV) BAT activation and the potential importance of TAG stores remain poorly defined. Objective To determine the time course of BAT activation and changes in intracellular TAG using MRI assessment of the SCV (i.e., BAT depot) and fat in the posterior neck region (i.e., non-BAT). Design Cross-sectional. Setting Clinical research center. Patients or Other Participants Twelve healthy male volunteers aged 18 to 29 years [body mass index = 24.7 ± 2.8 kg/m2 and body fat percentage = 25.0% ± 7.4% (both, mean ± SD)]. Intervention(s) Standardized whole-body cold exposure (180 minutes at 18°C) and immediate rewarming (30 minutes at 32°C). Main Outcome Measure(s) Proton density fat fraction (PDFF) and T2* of the SCV and posterior neck fat pads. Acquisitions occurred at 5- to 15-minute intervals during cooling and subsequent warming. Results SCV PDFF declined significantly after only 10 minutes of cold exposure [−1.6% (SE: 0.44%; P = 0.007)] and continued to decline until 35 minutes, after which time it remained stable until 180 minutes. A similar time course was also observed for SCV T2*. In the posterior neck fat (non-BAT), there were no cold-induced changes in PDFF or T2*. Rewarming did not result in a change in SCV PDFF or T2*. Conclusions The rapid cold-induced decline in SCV PDFF suggests that in humans BAT is activated quickly in response to cold and that TAG is a primary substrate.