Nonoptimal Gene Expression Creates Latent Potential for Antibiotic Resistance

This is the final version. Available from Oxford University Press (OUP) via the DOI in this record.Bacteria regulate genes to survive antibiotic stress, but regulation can be far from perfect. When regulation is not optimal, mutations that change gene expression can contribute to antibiotic resistance. It is not systematically understood to what extent natural gene regulation is or is not optimal for distinct antibiotics, and how changes in expression of specific genes quantitatively affect antibiotic resistance. Here we discover a simple quantitative relation between fitness, gene expression, and antibiotic potency, which rationalizes our observation that a multitude of genes and even innate antibiotic defense mechanisms have expression that is critically nonoptimal under antibiotic treatment. First, we developed a pooled-strain drug-diffusion assay and screened Escherichia coli overexpression and knockout libraries, finding that resistance to a range of 31 antibiotics could result from changing expression of a large and functionally diverse set of genes, in a primarily but not exclusively drug-specific manner. Second, by synthetically controlling the expression of single-drug and multidrug resistance genes, we observed that their fitness-expression functions changed dramatically under antibiotic treatment in accordance with a log-sensitivity relation. Thus, because many genes are nonoptimally expressed under antibiotic treatment, many regulatory mutations can contribute to resistance by altering expression and by activating latent defenses.National Institutes of HealthIsraeli Centers of Research Excellence I-CORE ProgramEuropean Research CouncilNational Health and Medical Research Counci

PPM-Decay: A computational model of auditory prediction with memory decay

Statistical learning and probabilistic prediction are fundamental processes in auditory cognition. A prominent computational model of these processes is Prediction by Partial Matching (PPM), a variable-order Markov model that learns by internalizing n-grams from training sequences. However, PPM has limitations as a cognitive model: in particular, it has a perfect memory that weights all historic observations equally, which is inconsistent with memory capacity constraints and recency effects observed in human cognition. We address these limitations with PPM-Decay, a new variant of PPM that introduces a customizable memory decay kernel. In three studies—one with artificially generated sequences, one with chord sequences from Western music, and one with new behavioral data from an auditory pattern detection experiment—we show how this decay kernel improves the model’s predictive performance for sequences whose underlying statistics change over time, and enables the model to capture effects of memory constraints on auditory pattern detection. The resulting model is available in our new open-source R package, ppm (https://github.com/pmcharrison/ppm)

Compounds that select against the tetracycline-resistance efflux pump

This is the author accepted manuscript. The final version is available from Nature Research via the DOI in this recordAccession codes. The sequences reported in this article have been deposited in the National Center for Biotechnology Information Sequence Read Archive database (accession number SRP073071).We developed a competition-based screening strategy to identify compounds that invert the selective advantage of antibiotic resistance. Using our assay, we screened over 19,000 compounds for the ability to select against the TetA tetracycline-resistance efflux pump in Escherichia coli and identified two hits, β-thujaplicin and disulfiram. Treating a tetracycline-resistant population with β-thujaplicin selects for loss of the resistance gene, enabling an effective second-phase treatment with doxycycline.National Institute of Allergy and Infectious DiseasesUS National Institutes of HealthEuropean Union FP7National Science Foundatio

Rapid Brain Responses to Familiar vs. Unfamiliar Music – an EEG and Pupillometry study

Human listeners exhibit marked sensitivity to familiar music, perhaps most readily revealed by popular “name that tune” games, in which listeners often succeed in recognizing a familiar song based on extremely brief presentation. In this work, we used electroencephalography (EEG) and pupillometry to reveal the temporal signatures of the brain processes that allow differentiation between a familiar, well liked, and unfamiliar piece of music. In contrast to previous work, which has quantified gradual changes in pupil diameter (the so-called “pupil dilation response”), here we focus on the occurrence of pupil dilation events. This approach is substantially more sensitive in the temporal domain and allowed us to tap early activity with the putative salience network. Participants (N = 10) passively listened to snippets (750 ms) of a familiar, personally relevant and, an acoustically matched, unfamiliar song, presented in random order. A group of control participants (N = 12), who were unfamiliar with all of the songs, was also tested. We reveal a rapid differentiation between snippets from familiar and unfamiliar songs: Pupil responses showed greater dilation rate to familiar music from 100–300 ms post-stimulus-onset, consistent with a faster activation of the autonomic salience network. Brain responses measured with EEG showed a later differentiation between familiar and unfamiliar music from 350 ms post onset. Remarkably, the cluster pattern identified in the EEG response is very similar to that commonly found in the classic old/new memory retrieval paradigms, suggesting that the recognition of brief, randomly presented, music snippets, draws on similar processes

Shaping bacterial population behavior through computer-interfaced control of individual cells

This is the final version. Available from Springer Nature via the DOI in this record.Strains and data are available from the authors upon request. Custom scripts for the described setup are available as Supplementary Software.Bacteria in groups vary individually, and interact with other bacteria and the environment to produce population-level patterns of gene expression. Investigating such behavior in detail requires measuring and controlling populations at the single-cell level alongside precisely specified interactions and environmental characteristics. Here we present an automated, programmable platform that combines image-based gene expression and growth measurements with on-line optogenetic expression control for hundreds of individual Escherichia coli cells over days, in a dynamically adjustable environment. This integrated platform broadly enables experiments that bridge individual and population behaviors. We demonstrate: (i) population structuring by independent closed-loop control of gene expression in many individual cells, (ii) cell-cell variation control during antibiotic perturbation, (iii) hybrid bio-digital circuits in single cells, and freely specifiable digital communication between individual bacteria. These examples showcase the potential for real-time integration of theoretical models with measurement and control of many individual cells to investigate and engineer microbial population behavior.European Union's Seventh Frame ProgrammeAustrian Science FundAgence Nationale de la RechercheAgence Nationale de la RechercheAgence Nationale de la Recherch

Enhanced deviant responses in patterned relative to random sound sequences

The brain draws on knowledge of statistical structure in the environment to facilitate detection of new events. Understanding the nature of this representation is a key challenge in sensory neuroscience. Specifically, it is unknown whether real-time perception of rapidly-unfolding sensory signals is driven by a coarse or detailed representation of the proximal stimulus history. We recorded electroencephalography brain responses to frequency outliers in regularly-patterned (REG) versus random (RAND) tone-pip sequences which were generated anew on each trial. REG and RAND sequences were matched in frequency content and span, only differing in the specific order of the tone-pips. Stimuli were very rapid, limiting conscious reasoning in favour of automatic processing of regularity. Listeners were naïve and performed an incidental visual task. Outliers within REG evoked a larger response than matched outliers in RAND. These effects arose rapidly (within 80 msec) and were underpinned by distinct sources from those classically associated with frequency-based deviance detection. These findings are consistent with the notion that the brain continually maintains a detailed representation of ongoing sensory input and that this representation shapes the processing of incoming information. Predominantly auditory-cortical sources code for frequency deviance whilst frontal sources are associated with tracking more complex sequence structure

Spatiotemporal microbial evolution on antibiotic landscapes

This is the author accepted manuscript. The final version is available from the American Association for the Advancement of Science via the DOI in thisA key aspect of bacterial survival is the ability to evolve while migrating across spatially varying environmental challenges. Laboratory experiments, however, often study evolution in well-mixed systems. Here, we introduce an experimental device, the microbial evolution and growth arena (MEGA)-plate, in which bacteria spread and evolved on a large antibiotic landscape (120 × 60 centimeters) that allowed visual observation of mutation and selection in a migrating bacterial front.While resistance increased consistently, multiple coexisting lineages diversified both phenotypically and genotypically. Analyzing mutants at and behind the propagating front,we found that evolution is not always led by the most resistant mutants; highly resistant mutants may be trapped behindmore sensitive lineages.TheMEGA-plate provides a versatile platformfor studying microbial adaption and directly visualizing evolutionary dynamics.National Defense Science and Engineering Graduate fellowshipNIHEuropean Union FP

Reward Enhances Online Participants’ Engagement With a Demanding Auditory Task

Online recruitment platforms are increasingly used for experimental research. Crowdsourcing is associated with numerous benefits but also notable constraints, including lack of control over participants’ environment and engagement. In the context of auditory experiments, these limitations may be particularly detrimental to threshold-based tasks that require effortful listening. Here, we ask whether incorporating a performance-based monetary bonus improves speech reception performance of online participants. In two experiments, participants performed an adaptive matrix-type speech-in-noise task (where listeners select two key words out of closed sets). In Experiment 1, our results revealed worse performance in online (N = 49) compared with in-lab (N = 81) groups. Specifically, relative to the in-lab cohort, significantly fewer participants in the online group achieved very low thresholds. In Experiment 2 (N = 200), we show that a monetary reward improved listeners’ thresholds to levels similar to those observed in the lab setting. Overall, the results suggest that providing a small performance-based bonus increases participants’ task engagement, facilitating a more accurate estimation of auditory ability under challenging listening conditions

Governance in Large Nonprofit Health Systems: Current Profile and Emerging Patterns

From the foreword: Nonprofit healthcare organizations are not exempt from good governance. In fact, more today than ever, the hospitals and health care systems of this country must have the discipline and commitment to organize their governance structures and practices to provide forward-thinking leadership and stand up to scrutiny from any type of evaluation and review. As we move from “sick care” organizations to “health care” organizations with accountability for the health of the population of our communities from birth to end-of-life, the role of governance becomes even more critical. Fourteen of the largest and most notable health care systems in this country have been included in a research study to examine their governance structures and practices in relation to nine benchmarks. The CEOs and board members of these organizations were interviewed about their structures, processes and cultures, and then compared to national best practices. The study also included close review of pertinent system documents. This report is a must read for hospital and health care system CEOs and boards. It provides evidence-based outcomes that will assist an organization in advancing its governance practices. This study outlines critical success factors for governance structure and performance. It answers many questions that boards may be struggling with today and provides advancing actions. The research methodology is thorough and reliable with specific outcomes that provide high-performance opportunities. Each CEO who participated in the research study has written about a best practice in his or her respective organization that advances governance responsibility. These insights add a personal dimension to this report.https://uknowledge.uky.edu/hsm_book/1000/thumbnail.jp

Perception of Filtered Speech by Children with Developmental Dyslexia and Children with Specific Language Impairments

Here we use two filtered speech tasks to investigate children’s processing of slow (<4 Hz) versus faster (∼33 Hz) temporal modulations in speech. We compare groups of children with either developmental dyslexia (Experiment 1) or speech and language impairments (SLIs, Experiment 2) to groups of typically-developing (TD) children age-matched to each disorder group. Ten nursery rhymes were filtered so that their modulation frequencies were either low-pass filtered (<4 Hz) or band-pass filtered (22 – 40 Hz). Recognition of the filtered nursery rhymes was tested in a picture recognition multiple choice paradigm. Children with dyslexia aged 10 years showed equivalent recognition overall to TD controls for both the low-pass and band-pass filtered stimuli, but showed significantly impaired acoustic learning during the experiment from low-pass filtered targets. Children with oral SLIs aged 9 years showed significantly poorer recognition of band pass filtered targets compared to their TD controls, and showed comparable acoustic learning effects to TD children during the experiment. The SLI samples were also divided into children with and without phonological difficulties. The children with both SLI and phonological difficulties were impaired in recognizing both kinds of filtered speech. These data are suggestive of impaired temporal sampling of the speech signal at different modulation rates by children with different kinds of developmental language disorder. Both SLI and dyslexic samples showed impaired discrimination of amplitude rise times. Implications of these findings for a temporal sampling framework for understanding developmental language disorders are discusse