Prevalence and patterns of higher-order drug interactions in Escherichia coli.

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

Exposure to Kynurenic Acid during Adolescence Increases Sign-Tracking and Impairs Long-Term Potentiation in Adulthood

Changes in brain reward systems are thought to contribute significantly to the cognitive and behavioral impairments of schizophrenia, as well as the propensity to develop co-occurring substance abuse disorders. Presently, there are few treatments for persons with a dual diagnosis and little is known about the neural substrates that underlie co-occurring schizophrenia and substance abuse. One goal of the present study was to determine if a change in the concentration of kynurenic acid (KYNA), a tryptophan metabolite that is increased in the brains of people with schizophrenia, affects reward-related behavior. KYNA is an endogenous antagonist of NMDA glutamate receptors and α7 nicotinic acetylcholine receptors, both of which are critically involved in neurodevelopment, plasticity, and behavior. In Experiment 1, rats were treated throughout adolescence with L-kynurenine (L-KYN), the precursor of KYNA. As adults, the rats were tested drug-free in an autoshaping procedure in which a lever was paired with food. Rats treated with L-KYN during adolescence exhibited increased sign-tracking behavior (lever pressing) when they were tested as adults. Sign-tracking is thought to reflect the lever acquiring incentive salience (motivational value) as a result of its pairing with reward. Thus, KYNA exposure may increase the incentive salience of cues associated with reward, perhaps contributing to an increase in sensitivity to drug-related cues in persons with schizophrenia. In Experiment 2, we tested the effects of exposure to KYNA during adolescence on hippocampal long-term potentiation (LTP). Rats treated with L-KYN exhibited no LTP after a burst of high-frequency stimulation that was sufficient to produce robust LTP in vehicle-treated rats. This finding represents the first demonstrated consequence of elevated KYNA concentration during development and provides insight into the basis for cognitive and behavioral deficits that result from exposure to KYNA during adolescence

How Often Are Antibiotic-Resistant Bacteria Said to “Evolve” in the News?

Media plays an important role in informing the general public about scientific ideas.We examine whether the word “evolve,” sometimes considered controversial by the general public, is frequently used in the popular press. Specifically, we ask how often articles discussing antibiotic resistance use the word “evolve” (or its lexemes) as opposed to alternative terms such as “emerge” or “develop.” We chose the topic of antibiotic resistance because it is a medically important issue; bacterial evolution is a central player in human morbidity and mortality. We focused on the most widely-distributed newspapers written in English in the United States, United Kingdom, Canada, India, and Australia. We examined all articles that focused primarily on the evolution of antibiotic resistance, were published in 2014 or earlier, and were accessible in online archives, for a total of 1639 articles. The total years examined per newspaper ranged from 5 to 37 years with a median of 27 years, and the overall range was 1978–2014. We quantified how many articles included the term “evolve” and analyzed how this varied with newspaper, country, and time. We found that an overall rate of 18% of articles used the term “evolve” but with significant variation among countries. Newspapers in the United Kingdom had the highest rate (24%), more than double of those in India (9%), the country with the lowest rate. These frequencies were lower than those found in scientific papers from both evolutionary journals and biomedical journals. There were no statistically significant changes in frequency and no trends when “evolve” usage was compared against variables such as newspaper circulation, liberal/conservative bias, time, and state evolution acceptance in U.S. newspapers. This study highlights the globally low usage of the word “evolve” in the popular press. We suggest this low usage may affect public understanding and acceptance of evolutionary concepts

Variation in Mutant Prevention Concentrations

Objectives:Understanding how phenotypic traits vary has been a longstanding goal of evolutionary biologists. When examining antibiotic-resistance in bacteria, it is generally understood that the minimum inhibitory concentration (MIC) has minimal variation specific to each bacterial strain-antibiotic combination. However, there is a less studied resistance trait, the mutant prevention concentration (MPC), which measures the MIC of the most resistant sub-population. Whether and how MPC varies has been poorly understood. Here, we ask a simple, yet important question: How much does the MPC vary, within a single strain-antibiotic association? Using a Staphylococcus species and five antibiotics from five different antibiotic classes—ciprofloxacin, doxycycline, gentamicin, nitrofurantoin, and oxacillin—we examined the frequency of resistance for a wide range of concentrations per antibiotic, and measured the repeatability of the MPC, the lowest amount of antibiotic that would ensure no surviving cells in a 1010 population of bacteria.Results: We found a wide variation within the MPC and distributions that were rarely normal. When antibiotic resistance evolved, the distribution of the MPC changed, with all distributions becoming wider and some multi-modal.Conclusion: Unlike the MIC, there is high variability in the MPC for a given bacterial strain-antibiotic combination

Bold or shy? Examining the risk-taking behavior and neophobia of invasive and non-invasive house sparrows

Bold or shy? Examining the risk-taking behavior and neophobia of invasive and non-invasive house sparrows. Behavior provides a useful framework for understanding specialization, with animal personality aiding our understanding of the invasiveness of birds. Invasions imply dispersion into unknown areas and could require changes in behavior or spatial clustering based on personality. Reduced neophobia and increased exploring behavior could allow individuals to colonize new areas as they test and use non-familiar resources. Here, we hypothesized that house sparrow (Passer domesticus) individuals from invasive populations would exhibit bolder behavior than in non-invasive populations. We assessed risk taking and neophobia in male house sparrows in Barcelona (where it is considered native) and in Mexico City (where it has become widely invasive), captured in two different habitats, urban and non-urban. We assessed latency to enter an experimental cage and to explore it, and latency to feed and feeding time in the presence of a novel object. We found that sparrows from Mexico City, both from urban and non-urban areas, were quicker to enter the experimental cage than the sparrows from Barcelona. The time it took the birds to start exploring the cage gave a similar result. We found no differences between cities or habitats in the latency to feed and feeding time while exposed to a novel object. Our results partially support the view that the invader populations from Mexico City are bolder than those from Barcelona. Behavior is an important component of plasticity and its variability may have an important effect on adaptation to local situations. Future studies should disentangle the underlying mechanisms that explain the different personalities found in populations of different regions, contrasting populations of different densities, and taking different food availability scenarios into account.Peer reviewe

CD28-dependent Activation of Protein Kinase B/Akt Blocks Fas-mediated Apoptosis by Preventing Death-inducing Signaling Complex Assembly

The T cell costimulatory molecule CD28 is important for T cell survival, yet both the signaling pathways downstream of CD28 and the apoptotic pathways they antagonize remain poorly understood. Here we demonstrate that CD4+ T cells from CD28-deficient mice show increased susceptibility to Fas-mediated apoptosis via a phosphatidylinositol 3-kinase (PI3K)-dependent pathway. Protein kinase B (PKBα/Akt1) is an important serine/threonine kinase that promotes survival downstream of PI3K signals. To understand how PI3K-mediated signals downstream of CD28 contribute to T cell survival, we examined Fas-mediated apoptosis in T cells expressing an active form of PKBα. Our data demonstrate that T cells expressing active PKB are resistant to Fas-mediated apoptosis in vivo and in vitro. PKB transgenic T cells show reduced activation of caspase-8, BID, and caspase-3 due to impaired recruitment of procaspase-8 to the death-inducing signaling complex (DISC). Similar alterations are seen in T cells from mice which are haploinsufficient for PTEN, a lipid phosphatase that regulates phosphatidylinositol-3,4,5-trisphosphate (PIP3) and influences PKBα activity. These findings provide a novel link between CD28 and an important apoptosis pathway in vivo, and demonstrate that PI3K/PKB signaling prevents apoptosis by inhibiting DISC assembly

Trajectories of Homoeolog-Specific Expression in Allotetraploid Tragopogon castellanus Populations of Independent Origins

Polyploidization can have a significant ecological and evolutionary impact by providing substantially more genetic material that may result in novel phenotypes upon which selection may act. While the effects of polyploidization are broadly reviewed across the plant tree of life, the reproducibility of these effects within naturally occurring, independently formed polyploids is poorly characterized. The flowering plant genus Tragopogon (Asteraceae) offers a rare glimpse into the intricacies of repeated allopolyploid formation with both nascent (< 90 years old) and more ancient (mesopolyploids) formations. Neo- and mesopolyploids in Tragopogon have formed repeatedly and have extant diploid progenitors that facilitate the comparison of genome evolution after polyploidization across a broad span of evolutionary time. Here, we examine four independently formed lineages of the mesopolyploid Tragopogon castellanus for homoeolog expression changes and fractionation after polyploidization. We show that expression changes are remarkably similar among these independently formed polyploid populations with large convergence among expressed loci, moderate convergence among loci lost, and stochastic silencing. We further compare and contrast these results for T. castellanus with two nascent Tragopogon allopolyploids. While homoeolog expression bias was balanced in both nascent polyploids and T. castellanus, the degree of additive expression was significantly different, with the mesopolyploid populations demonstrating more non-additive expression. We suggest that gene dosage and expression noise minimization may play a prominent role in regulating gene expression patterns immediately after allopolyploidization as well as deeper into time, and these patterns are conserved across independent polyploid lineages