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

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 describe Escherichia coli phage 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). Both tolC and LPS-related mutants arise readily during fluctuation assays, with tolC mutations becoming more common during the evolution experiments. In support of the trade-off hypothesis, phage resistance via tolC mutations 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.

Prefrontal circuits guiding social preference: Implications in autism spectrum disorder.

Although Autism Spectrum Disorder (ASD) is increasing in diagnostic prevalence, treatment options are inadequate largely due to limited understanding of ASD's underlying neural mechanisms. Contributing to difficulties in treatment development is the vast heterogeneity of ASD, from physiological causes to clinical presentations. Recent studies suggest that distinct genetic and neurological alterations may converge onto similar underlying neural circuits. Therefore, an improved understanding of neural circuit-level dysfunction in ASD may be a more productive path to developing broader treatments that are effective across a greater spectrum of ASD. Given the social preference behavioral deficits commonly seen in ASD, dysfunction in circuits mediating social preference may contribute to the atypical development of social cognition. We discuss some of the animal models used to study ASD and examine the function and effects of dysregulation of the social preference circuits, notably the medial prefrontal cortex-amygdala and the medial prefrontal cortex-nucleus accumbens circuits, in these animal models. Using the common circuits underlying similar behavioral disruptions of social preference behaviors as an example, we highlight the importance of identifying disruption in convergent circuits to improve the translational success of animal model research for ASD treatment development.