Grow now, pay later: When should a bacterium go into debt?

Microbes grow in a wide variety of environments and must balance growth and stress resistance. Despite the prevalence of such trade-offs, understanding of their role in nonsteady environments is limited. In this study, we introduce a mathematical model of "growth debt," where microbes grow rapidly initially, paying later with slower growth or heightened mortality. We first compare our model to a classical chemostat experiment, validating our proposed dynamics and quantifying Escherichia coli's stress resistance dynamics. Extending the chemostat theory to include serial-dilution cultures, we derive phase diagrams for the persistence of "debtor" microbes. We find that debtors cannot coexist with nondebtors if "payment" is increased mortality but can coexist if it lowers enzyme affinity. Surprisingly, weak noise considerably extends the persistence of resistance elements, pertinent for antibiotic resistance management. Our microbial debt theory, broadly applicable across many environments, bridges the gap between chemostat and serial dilution systems.

HAL-X: Scalable hierarchical clustering for rapid and tunable single-cell analysis.

Data clustering plays a significant role in biomedical sciences, particularly in single-cell data analysis. Researchers use clustering algorithms to group individual cells into populations that can be evaluated across different levels of disease progression, drug response, and other clinical statuses. In many cases, multiple sets of clusters must be generated to assess varying levels of cluster specificity. For example, there are many subtypes of leukocytes (e.g. T cells), whose individual preponderance and phenotype must be assessed for statistical/functional significance. In this report, we introduce a novel hierarchical density clustering algorithm (HAL-x) that uses supervised linkage methods to build a cluster hierarchy on raw single-cell data. With this new approach, HAL-x can quickly predict multiple sets of labels for immense datasets, achieving a considerable improvement in computational efficiency on large datasets compared to existing methods. We also show that cell clusters generated by HAL-x yield near-perfect F1-scores when classifying different clinical statuses based on single-cell profiles. Our hierarchical density clustering algorithm achieves high accuracy in single cell classification in a scalable, tunable and rapid manner.

Trapped by a first hypothesis: How rudeness leads to anchoring.

In this article we explore the effect of encounters with rudeness on the tendency to engage in anchoring, one of the most robust and widespread cognitive biases. Integrating the self-immersion framework with the selective accessibility model (SAM), we propose that rudeness-induced negative arousal will narrow individuals' perspectives in a way that will make anchoring more likely. Additionally, we posit that perspective taking and information elaboration will attenuate the effect of rudeness on both negative arousal and subsequent anchoring. Across four experimental studies, we test the impact of exposure to rudeness on anchoring as manifested in a variety of tasks (medical diagnosis, judgment tasks, and negotiation). In a pilot study, we find that rudeness is associated with anchoring among a group of medical students making a medical diagnosis. In Study 1, we show that negative arousal mediates the effect of rudeness on anchoring among medical residents treating a patient, and that perspective taking moderates these effects. Study 2 replicates the results of Study 1 using a common anchoring task, and Study 3 builds on these results by replicating them in a negotiation setting and testing information elaboration as a boundary condition. Across the four studies, we find consistent evidence that rudeness-induced negative arousal leads to anchoring, and that these effects can be mitigated by perspective taking and information elaboration. (PsycInfo Database Record (c) 2022 APA, all rights reserved).

Enzyme regulation and mutation in a model serial-dilution ecosystem.

Microbial communities are ubiquitous in nature and come in a multitude of forms, ranging from communities dominated by a handful of species to communities containing a wide variety of metabolically distinct organisms. This huge range in diversity is not a curiosity-microbial diversity has been linked to outcomes of substantial ecological and medical importance. However, the mechanisms underlying microbial diversity are still under debate, as simple mathematical models only permit as many species to coexist as there are resources. A plethora of mechanisms have been proposed to explain the origins of microbial diversity, but many of these analyses omit a key property of real microbial ecosystems: the propensity of the microbes themselves to change their growth properties within and across generations. In order to explore the impact of this key property on microbial diversity, we expand upon a recently developed model of microbial diversity in fluctuating environments. We implement changes in growth strategy in two distinct ways. First, we consider the regulation of a cell's enzyme levels within short, ecological times, and second we consider evolutionary changes driven by mutations across generations. Interestingly, we find that these two types of microbial responses to the environment can have drastically different outcomes. Enzyme regulation may collapse diversity over long enough times while, conversely, strategy-randomizing mutations can produce a "rich-get-poorer" effect that promotes diversity. This paper makes explicit, using a simple serial-dilutions framework, the conflicting ways that microbial adaptation and evolution can affect community diversity.

How witnessing rudeness can disrupt psycho-motor performance of dental students.

Rude and disrespectful behaviors are ubiquitous and pervasive in the workplace. The purpose of this study was to examine the effects of witnessed rudeness on dental student psychomotor performance. Using an experimental, between-subjects design, 71 2nd (Sophomore) year dental students witnessed either an experimental (rude) or control (neutral) condition in which a confederate lab manager interacted in a rude or neutral manner with a prospective lab assistant candidate. Students then performed a mock prosthodontics psychomotor examination as part of the fixed prosthodontics preclinical course. Results indicated that those students who arrived at the experimental session cognitively depleted (+1 SD above the mean) and were exposed to the rude condition were significantly more likely to make critical errors when performing a posterior bridge preparation, compared to those students in the control group. There were no significant differences between the rude and control conditions for participants who were not cognitively depleted (-1 SD below the mean). Overall, the findings indicate that for those dental students suffering from cognitive depletion, merely witnessing rudeness can have adverse impacts on psychomotor performance and potentially, eventual patient care.

The effects of rudeness, experience, and perspective-taking on challenging premature closure after pediatric ICU physicians receive hand-off with the wrong diagnosis: a randomized controlled simulation trial.

OBJECTIVES: Rudeness exposure has been shown to inhibit diagnostic performance. The effects of rudeness on challenging a handed-off diagnostic error has not been studied. METHODS: This was a randomized controlled study of attending, fellow, and resident physicians in a tertiary care pediatric ICU. Participants underwent a standardized simulation that started with the wrong diagnosis in hand-off. The hand-off was randomized to neutral vs. rude. Participants were not informed of the randomization nor diagnostic error prior to the simulation. Perspective taking questionnaires were administrated for each participant. Primary outcome was challenging diagnostic error post-simulation. Secondary outcomes included rate and frequency of diagnostic error challenge during simulation. RESULTS: Among 41 simulations (16 residents, 14 fellows, and 11 attendings), the neutral group challenged the diagnostic error more than the rude group (neutral: 71%, rude: 55%, p=0.28). The magnitude of this trend was larger among resident physicians only, although not statistically significant (neutral: 50%, rude: 12.5%, p=0.11). Experience was associated with a higher percentage of challenging diagnostic error (residents: 31%, fellows: 86%, attendings: 82%, p=0.003). Experienced physicians were faster to challenge diagnostic error (p<0.0003), and experience was associated with a greater frequency of diagnostic error challenges (p<0.0001). High perspective taking scores were also associated with 1.63 times more diagnostic error challenges (p=0.007). CONCLUSIONS: Experience was strongly associated with likelihood to challenge diagnostic error. Rudeness may disproportionally hinder diagnostic performance among less experienced physicians. Perspective taking merits further research in possibly reducing diagnostic error momentum.

Multicellular sensing at a feedback-induced critical point.

Feedback in sensory biochemical networks can give rise to bifurcations in cells' behavioral response. These bifurcations share many properties with thermodynamic critical points. Evidence suggests that biological systems may operate near these critical points, but the functional benefit of doing so remains poorly understood. Here we investigate a simple biochemical model with nonlinear feedback and multicellular communication to determine if criticality provides a functional benefit in terms of the ability to gain information about a stochastic chemical signal. We find that when signal fluctuations are slow, the mutual information between the signal and the intracellular readout is maximized at criticality, because the benefit of high signal susceptibility outweighs the detriment of high readout noise. When cells communicate, criticality gives rise to long-range correlations in readout molecule number among cells. Consequently, we find that communication increases the mutual information between a given cell's readout and the spatial average of the signal across the population. Finally, we find that both with and without communication, the sensory benefits of criticality compete with critical slowing down, such that the information rate, as opposed to the information itself, is minimized at the critical point. Our results reveal the costs and benefits of feedback-induced criticality for multicellular sensing.

Nutrient levels and trade-offs control diversity in a serial dilution ecosystem.

Microbial communities feature an immense diversity of species and this diversity is linked to outcomes ranging from ecosystem stability to medical prognoses. Yet the mechanisms underlying microbial diversity are under debate. While simple resource-competition models don't allow for coexistence of a large number of species, it was recently shown that metabolic trade-offs can allow unlimited diversity. Does this diversity persist with more realistic, intermittent nutrient supply? Here, we demonstrate theoretically that in serial dilution culture, metabolic trade-offs allow for high diversity. When a small amount of nutrient is supplied to each batch, the serial dilution dynamics mimic a chemostat-like steady state. If more nutrient is supplied, community diversity shifts due to an 'early-bird' effect. The interplay of this effect with different environmental factors and diversity-supporting mechanisms leads to a variety of relationships between nutrient supply and diversity, suggesting that real ecosystems may not obey a universal nutrient-diversity relationship.

In most environments, organisms compete for limited resources. The number and relative abundance of species that an ecosystem can host is referred to as 'species diversity'. The competitive-exclusion principle is a hypothesis which proposes that, in an ecosystem, competition for resources results in decreased diversity: only species best equipped to consume the available resources thrive, while their less successful competitors die off. However, many natural ecosystems foster a wide array of species despite offering relatively few resources. Researchers have proposed many competing theories to explain how this paradox can emerge, but they have mainly focused on ecosystems where nutrients are steadily supplied. By contrast, less is known about the way species diversity is maintained when nutrients are only intermittently available, for example in ecosystems that have seasons. To address this question, Erez, Lopez et al. modeled communities of bacteria in which nutrients were repeatedly added and then used up. Depending on conditions, a variety of relationships between the amount of nutrient supplied and community diversity could emerge, suggesting that ecosystems do not follow a simple, universal rule that dictates species diversity. In particular, the resulting communities displayed a higher diversity of microbes than the limit imposed by the competitive-exclusion principle. Further observations allowed Erez, Lopez et al. to suggest guiding principles for when diversity in ecosystems will be maintained or lost. In this framework, 'early-bird' species, which rapidly use a subset of the available nutrients, grow to dominate the ecosystem. Even though 'late-bird' species are more effective at consuming the remaining resources, they cannot compete with the increased sheer numbers of the 'early-birds', leading to a 'rich-get-richer' phenomenon. Oceanic plankton, arctic permafrost and many other threatened, resource-poor ecosystems across the world can dramatically influence our daily lives. Closer to home, shifts in the microbe communities that live on the surface of the human body and in the digestive system are linked to poor health. Understanding how species diversity emerges and changes will help to protect our external and internal environments.

Cell-to-Cell Information at a Feedback-Induced Bifurcation Point.

A ubiquitous way that cells share information is by exchanging molecules. Yet, the fundamental ways that this information exchange is influenced by intracellular dynamics remain unclear. Here we use information theory to investigate a simple model of two interacting cells with internal feedback. We show that cell-to-cell molecule exchange induces a collective two-cell critical point and that the mutual information between the cells peaks at this critical point. Information can remain large far from the critical point on a manifold of cellular states but scales logarithmically with the correlation time of the system, resulting in an information-correlation time trade-off. This trade-off is strictly imposed, suggesting the correlation time as a proxy for the mutual information.

A Metabolic Pathway for Activation of Dietary Glucosinolates by a Human Gut Symbiont.

Consumption of glucosinolates, pro-drug-like metabolites abundant in Brassica vegetables, has been associated with decreased risk of certain cancers. Gut microbiota have the ability to metabolize glucosinolates, generating chemopreventive isothiocyanates. Here, we identify a genetic and biochemical basis for activation of glucosinolates to isothiocyanates by Bacteroides thetaiotaomicron, a prominent gut commensal species. Using a genome-wide transposon insertion screen, we identified an operon required for glucosinolate metabolism in B. thetaiotaomicron. Expression of BT2159-BT2156 in a non-metabolizing relative, Bacteroides fragilis, resulted in gain of glucosinolate metabolism. We show that isothiocyanate formation requires the action of BT2158 and either BT2156 or BT2157 in vitro. Monocolonization of mice with mutant BtΔ2157 showed reduced isothiocyanate production in the gastrointestinal tract. These data provide insight into the mechanisms by which a common gut bacterium processes an important dietary nutrient.

Critical slowing down in biochemical networks with feedback.

Near a bifurcation point, the response time of a system is expected to diverge due to the phenomenon of critical slowing down. We investigate critical slowing down in well-mixed stochastic models of biochemical feedback by exploiting a mapping to the mean-field Ising universality class. We analyze the responses to a sudden quench and to continuous driving in the model parameters. In the latter case, we demonstrate that our class of models exhibits the Kibble-Zurek collapse, which predicts the scaling of hysteresis in cellular responses to gradual perturbations. We discuss the implications of our results in terms of the tradeoff between a precise and a fast response. Finally, we use our mapping to quantify critical slowing down in T cells, where the addition of a drug is equivalent to a sudden quench in parameter space.

Quantifying the Dynamics of Hematopoiesis by In Vivo IdU Pulse-Chase, Mass Cytometry, and Mathematical Modeling.

We present a new method to directly quantify the dynamics of differentiation of multiple cellular subsets in unperturbed mice. We combine a pulse-chase protocol of 5-iodo-2'-deoxyuridine (IdU) injections with subsequent analysis by mass cytometry (CyTOF) and mathematical modeling of the IdU dynamics. Measurements by CyTOF allow for a wide range of cells to be analyzed at once, due to the availability of a large staining panel without the complication of fluorescence spillover. These are also compatible with direct detection of integrated iodine signal, with minimal impact on immunophenotyping based on the surface markers. Mathematical modeling beyond a binary classification of surface marker abundance allows for a continuum of cellular states as the cells transition from one state to another. Thus, we present a complete and robust method for directly quantifying differentiation at the systemic level, allowing for system-wide comparisons between different mouse strains and/or experimental conditions. Published 2019. This article is a U.S. Government work and is in the public domain in the USA.

Universality of biochemical feedback and its application to immune cells.

We map a class of well-mixed stochastic models of biochemical feedback in steady state to the mean-field Ising model near the critical point. The mapping provides an effective temperature, magnetic field, order parameter, and heat capacity that can be extracted from biological data without fitting or knowledge of the underlying molecular details. We demonstrate this procedure on fluorescence data from mouse T cells, which reveals distinctions between how the cells respond to different drugs. We also show that the heat capacity allows inference of the absolute molecule number from fluorescence intensity. We explain this result in terms of the underlying fluctuations, and we demonstrate the generality of our work.

Incivility and Patient Safety: A Longitudinal Study of Rudeness, Protocol Compliance, and Adverse Events.

BACKGROUND: Little is known about the impact of social interactions on iatrogenesis and lapses in patient safety. METHODS: This field-based experience-sampling study of primarily nurses in a general hospital explored the impact of rudeness on patient safety performance, state depletion (that is, exhaustion of mental energy for reflective behavior), and team processes (for example, information sharing). Objective measures of performance were compliance with hand hygiene and medication preparation protocols, as well as archival reports of adverse events. Data were analyzed by department shift (480 shifts [15 days] in 16 departments). RESULTS: A total of 231 rudeness incidents were reported in 98 shifts, most stemming from a patient or family. Compliance with hand hygiene was significantly lower up to 24 hours after rudeness exposure (p = 0.03). Rudeness significantly increased team members' state depletion (p = 0.002) and was associated with decreased information sharing (p = 0.046) but was not directly associated with adverse events or level of compliance with medication and hand hygiene protocols. However, the adverse indirect effect of shifts' temporal proximity to rudeness on poor compliance with medication preparation and team members' information sharing via state depletion was significant. Rudeness exposure was also associated with increased rate of adverse events in the subsequent 24 hours, although this association was not statistically significant. CONCLUSION: Rudeness exposure was associated with reduced team member compliance with infection control and medication protocols via greater team member state depletion and diminished information sharing.

Expressions of Gratitude and Medical Team Performance.

BACKGROUND AND OBJECTIVES: Exposure to negative social interactions (such as rudeness) has robust adverse implications on medical team performance. However, little is known regarding the effects of positive social interactions. We hypothesized that expressions of gratitude, a prototype of positive social interaction, would enhance medical teams' effectiveness. Our objective was to study the performance of NICU teams after exposure to expressions of gratitude from alternative sources. METHODS: Forty-three NICU teams (comprising 2 physicians and 2 nurses) participated in training workshops of acute care simulations. Teams were randomly assigned to 1 of 4 conditions: (1) maternal gratitude (in which the mother of a preterm infant expressed gratitude to NICU teams, such as the one that treated her child), (2) expert gratitude (in which a physician expert expressed gratitude to teams for participating in the training), (3) combined maternal and expert gratitude, or (4) control (same agents communicated neutral statements). The simulations were evaluated (5-point Likert scale: 1 = failed and 5 = excellent) by independent judges (blind to team exposure) using structured questionnaires. RESULTS: Maternal gratitude positively affected teams' performances (3.9 ± 0.9 vs 3.6 ± 1.0; P = .04), with most of this effect explained by the positive impact of gratitude on team information sharing (4.3 ± 0.8 vs 4.0 ± 0.8; P = .03). Forty percent of the variance in team information sharing was explained by maternal gratitude. Information sharing predicted team performance outcomes, explaining 33% of the variance in diagnostic performance and 41% of the variance in therapeutic performance. CONCLUSIONS: Patient-expressed gratitude significantly enhances medical team performance, with much of this effect explained by enhanced information sharing.

Energizing leaders via self-reflection: A within-person field experiment.

The leader role is demanding and depleting, explaining why many leaders struggle to remain engaged while doing their job. In this study, we present theory and an intervention focused on improving leader energy. Integrating cognitive energetics theory (Kruglanski et al., 2012) with leader identity theory and expressive writing research, we develop and test a positive leader self-reflection intervention, which asks leaders to reflect on aspects of their selves that make them good leaders. We expected that this intervention would improve leaders' access to and application of their energy in ways that would make them more influential at work. We tested these theoretical expectations in an experimental experience sampling study where, as expected, we found that leaders experienced less depletion and through it heightened work engagement on intervention versus control days. Work engagement, in turn, improved perceived prosocial impact and clout, two markers of leaders' influence at work. We conceptually replicated the depletion-reducing effect of the intervention in a second study and showed that its effectiveness was specific to those who held leadership roles within their organizations. We discuss the theoretical and practical implications of the intervention and of our findings. (PsycINFO Database Record (c) 2018 APA, all rights reserved).

Modeling of cytometry data in logarithmic space: When is a bimodal distribution not bimodal?

Recent efforts in systems immunology lead researchers to build quantitative models of cell activation and differentiation. One goal is to account for the distributions of proteins from single-cell measurements by flow cytometry or mass cytometry as readout of biological regulation. In that context, large cell-to-cell variability is often observed in biological quantities. We show here that these readouts, viewed in logarithmic scale may result in two easily-distinguishable modes, while the underlying distribution (in linear scale) is unimodal. We introduce a simple mathematical test to highlight this mismatch. We then dissect the flow of influence of cell-to-cell variability proposing a graphical model which motivates higher-dimensional analysis of the data. Finally we show how acquiring additional biological information can be used to reduce uncertainty introduced by cell-to-cell variability, helping to clarify whether the data is uni- or bimodal. This communication has cautionary implications for manual and automatic gating strategies, as well as clustering and modeling of single-cell measurements. © 2018 International Society for Advancement of Cytometry.

Feeling happy and (over)confident: the role of positive affect in metacognitive processes.

The relationship between affect and metacognitive processes has been largely overlooked in both the affect and the metacognition literatures. While at the core of many affect-cognition theories is the notion that positive affective states lead people to be more confident, few studies systematically investigated how positive affect influences confidence and strategic behaviour. In two experiments, when participants were free to control answer interval to general knowledge questions (e.g. QUESTION: "in what year", answer: "it was between 1970 and 1985"), participants induced with positive affect outperformed participants in a neutral affect condition. However, in Experiment 1 positive affect participants showed larger overconfidence than neutral affect participants. In Experiment 2, enhanced salience of social cues eliminated this overconfidence disadvantage of positive affect relative to neutral affect participants, without compromising their enhanced performance. Notably, in both experiments, positive affect led to compromised social norms regarding the answers' informativeness. Implications for both affect and metacognition are discussed.

Rude color glasses: The contaminating effects of witnessed morning rudeness on perceptions and behaviors throughout the workday.

Using an experimental experience sampling design, we investigate how witnessing morning rudeness influences workers' subsequent perceptions and behaviors throughout the workday. We posit that a single exposure to rudeness in the morning can contaminate employees' perceptions of subsequent social interactions leading them to perceive greater workplace rudeness throughout their workday. We expect that these contaminated perceptions will have important ramifications for employees' work behaviors. In a 10-day study of 81 professional and managerial employees, we find that witnessed morning rudeness leads to greater perceptions of workplace rudeness throughout the workday and that those perceptions, in turn, predict lower task performance and goal progress and greater interaction avoidance and psychological withdrawal. We also find that the contaminating effect of morning rudeness depends on core self-evaluations (CSE)-employees high (vs. low) in CSE are affected less by exposure to morning rudeness. We discuss implications for practice and theory. (PsycINFO Database Record

Rudeness and Medical Team Performance.

OBJECTIVES: Rudeness is routinely experienced by medical teams. We sought to explore the impact of rudeness on medical teams' performance and test interventions that might mitigate its negative consequences. METHODS: Thirty-nine NICU teams participated in a training workshop including simulations of acute care of term and preterm newborns. In each workshop, 2 teams were randomly assigned to either an exposure to rudeness (in which the comments of the patient's mother included rude statements completely unrelated to the teams' performance) or control (neutral comments) condition, and 2 additional teams were assigned to rudeness with either a preventative (cognitive bias modification [CBM]) or therapeutic (narrative) intervention. Simulation sessions were evaluated by 2 independent judges, blind to team exposure, who used structured questionnaires to assess team performance. RESULTS: Rudeness had adverse consequences not only on diagnostic and intervention parameters (mean therapeutic score 3.81 ± 0.36 vs 4.31 ± 0.35 in controls, P < .01), but also on team processes (such as information and workload sharing, helping and communication) central to patient care (mean teamwork score 4.04 ± 0.34 vs 4.43 ± 0.37, P < .05). CBM mitigated most of these adverse effects of rudeness, but the postexposure narrative intervention had no significant effect. CONCLUSIONS: Rudeness has robust, deleterious effects on the performance of medical teams. Moreover, exposure to rudeness debilitated the very collaborative mechanisms recognized as essential for patient care and safety. Interventions focusing on teaching medical professionals to implicitly avoid cognitive distraction such as CBM may offer a means to mitigate the adverse consequences of behaviors that, unfortunately, cannot be prevented.