Paradoxical signaling by a secreted molecule leads to homeostasis of cell levels.

A widespread feature of extracellular signaling in cell circuits is paradoxical pleiotropy: the same secreted signaling molecule can induce opposite effects in the responding cells. For example, the cytokine IL-2 can promote proliferation and death of T cells. The role of such paradoxical signaling remains unclear. To address this, we studied CD4(+) T cell expansion in culture. We found that cells with a 30-fold difference in initial concentrations reached a homeostatic concentration nearly independent of initial cell levels. Below an initial threshold, cell density decayed to extinction (OFF-state). We show that these dynamics relate to the paradoxical effect of IL-2, which increases the proliferation rate cooperatively and the death rate linearly. Mathematical modeling explained the observed cell and cytokine dynamics and predicted conditions that shifted cell fate from homeostasis to the OFF-state. We suggest that paradoxical signaling provides cell circuits with specific dynamical features that are robust to environmental perturbations.

Controls for Phylogeny and Robust Analysis in Pareto Task Inference.

Understanding the tradeoffs faced by organisms is a major goal of evolutionary biology. One of the main approaches for identifying these tradeoffs is Pareto task inference (ParTI). Two recent papers claim that results obtained in ParTI studies are spurious due to phylogenetic dependence (Mikami T, Iwasaki W. 2021. The flipping t-ratio test: phylogenetically informed assessment of the Pareto theory for phenotypic evolution. Methods Ecol Evol. 12(4):696-706) or hypothetical p-hacking and population-structure concerns (Sun M, Zhang J. 2021. Rampant false detection of adaptive phenotypic optimization by ParTI-based Pareto front inference. Mol Biol Evol. 38(4):1653-1664). Here, we show that these claims are baseless. We present a new method to control for phylogenetic dependence, called SibSwap, and show that published ParTI inference is robust to phylogenetic dependence. We show how researchers avoided p-hacking by testing for the robustness of preprocessing choices. We also provide new methods to control for population structure and detail the experimental tests of ParTI in systems ranging from ammonites to cancer gene expression. The methods presented here may help to improve future ParTI studies.

Adaptive search space pruning in complex strategic problems.

People have limited computational resources, yet they make complex strategic decisions over enormous spaces of possibilities. How do people efficiently search spaces with combinatorially branching paths? Here, we study players' search strategies for a winning move in a "k-in-a-row" game. We find that players use scoring strategies to prune the search space and augment this pruning by a "shutter" heuristic that focuses the search on the paths emanating from their previous move. This strong pruning has its costs-both computational simulations and behavioral data indicate that the shutter size is correlated with players' blindness to their opponent's winning moves. However, simulations of the search while varying the shutter size, complexity levels, noise levels, branching factor, and computational limitations indicate that despite its costs, a narrow shutter strategy is the dominant strategy for most of the parameter space. Finally, we show that in the presence of computational limitations, the shutter heuristic enhances the performance of deep learning networks in these end-game scenarios. Together, our findings suggest a novel adaptive heuristic that benefits search in a vast space of possibilities of a strategic game.

Environmental susceptibility for all: A data-driven approach suggests individual differences in domain-general and domain-specific patterns of environmental susceptibility.

How we are influenced by our environment is a fundamental question in developmental science. Theories and empirical research have claimed that some individuals are susceptible to environmental influences and others are much less susceptible. The present study addressed four questions: (1) Is environmental susceptibility a continuous or categorical construct? (2) Is environmental susceptibility unidimensional (i.e., domain general) or multidimensional (i.e., domain specific)? (3) Are there genetic contributions to individual differences in environmental susceptibility? (4) What are the temperamental characteristics of different environmental susceptibility patterns? We used child- and mother-report data from a sample of 11-year-old twins (N = 1,507) and applied a novel data-driven approach to assess an environmental susceptibility space, based on simultaneous associations between multiple environmental exposures (18 measures relating to parenting, parent, peer, and twin relationships) and developmental outcomes (10 measures relating to empathy, prosocial behavior, aggression, and self-esteem). The results suggest that the environmental susceptibility space we assessed is better conceptualized as continuous and multidimensional. Different children showed susceptibility to different contexts and variation in domain-general versus domain-specific patterns. A comparison of distances between monozygotic and dizygotic twins within the space demonstrated genetic contributions. Finally, susceptibility patterns could not be differentiated based on a specific temperament trait, but rather related to temperament profiles.

Early warning signals in motion inference.

The ability to infer intention lies at the basis of many social interactions played out via motor actions. We consider a simple paradigm of this ability in humans using data from experiments simulating an antagonistic game between an Attacker and a Blocker. Evidence shows early inference of an Attacker move by as much as 100ms but the nature of the informational cues signaling the impending move remains unknown. We show that the transition to action has the hallmark of a critical transition that is accompanied by early warning signals. These early warning signals occur as much as 130 ms before motion ensues-showing a sharp rise in motion autocorrelation at lag-1 and a sharp rise in the autocorrelation decay time. The early warning signals further correlate strongly with Blocker response times. We analyze the variance of the motion near the point of transition and find that it diverges in a manner consistent with the dynamics of a fold-transition. To test if humans can recognize and act upon these early warning signals, we simulate the dynamics of fold-transition events and ask people to recognize the onset of directional motion: participants react faster to fold-transition dynamics than to its uncorrelated counterpart. Together, our findings suggest that people can recognize the intent and onset of motion by inferring its early warning signals.

The utility of paradoxical components in biological circuits.

A recurring theme in biological circuits is the existence of components that are antagonistically bifunctional, in the sense that they simultaneously have two opposing effects on the same target or biological process. Examples include bifunctional enzymes that carry out two opposing reactions such as phosphorylating and dephosphorylating the same target, regulators that activate and also repress a gene in circuits called incoherent feedforward loops, and cytokines that signal immune cells to both proliferate and die. Such components are termed "paradoxical", and in this review we discuss how they can provide useful features to cell circuits that are otherwise difficult to achieve. In particular, we summarize how paradoxical components can provide robustness, generate temporal pulses, and provide fold-change detection, in which circuits respond to relative rather than absolute changes in signals.

Robust control of nitrogen assimilation by a bifunctional enzyme in E. coli.

Bacteria regulate the assimilation of multiple nutrients to enable growth. How is balanced utilization achieved, despite fluctuations in the concentrations of the enzymes that make up the regulatory circuitry? Here we address this question by studying the nitrogen system of E. coli. A mechanism based on the avidity of a bifunctional enzyme, adenylyltransferase (AT/AR), to its multimeric substrate, glutamine synthetase, is proposed to maintain a robust ratio between two key metabolites, glutamine and α-ketoglutarate. This ratio is predicted to be insensitive to variations in protein levels of the core circuit and to the rate of nitrogen utilization. We find using mass spectrometry that the metabolite ratio is robust to variations in protein levels and that this robustness depends on the bifunctional enzyme. Moreover, robustness carries through to the bacteria growth rate. Interrupting avidity by adding a monofunctional AT/AR mutant to the native system abolishes robustness, as predicted by the proposed mechanism.

Inferring biological tasks using Pareto analysis of high-dimensional data.

We present the Pareto task inference method (ParTI; http://www.weizmann.ac.il/mcb/UriAlon/download/ParTI) for inferring biological tasks from high-dimensional biological data. Data are described as a polytope, and features maximally enriched closest to the vertices (or archetypes) allow identification of the tasks the vertices represent. We demonstrate that human breast tumors and mouse tissues are well described by tetrahedrons in gene expression space, with specific tumor types and biological functions enriched at each of the vertices, suggesting four key tasks.

Mapping differentiation under mixed culture conditions reveals a tunable continuum of T cell fates.

Cell differentiation is typically directed by external signals that drive opposing regulatory pathways. Studying differentiation under polarizing conditions, with only one input signal provided, is limited in its ability to resolve the logic of interactions between opposing pathways. Dissection of this logic can be facilitated by mapping the system's response to mixtures of input signals, which are expected to occur in vivo, where cells are simultaneously exposed to various signals with potentially opposing effects. Here, we systematically map the response of naïve T cells to mixtures of signals driving differentiation into the Th1 and Th2 lineages. We characterize cell state at the single cell level by measuring levels of the two lineage-specific transcription factors (T-bet and GATA3) and two lineage characteristic cytokines (IFN-γ and IL-4) that are driven by these transcription regulators. We find a continuum of mixed phenotypes in which individual cells co-express the two lineage-specific master regulators at levels that gradually depend on levels of the two input signals. Using mathematical modeling we show that such tunable mixed phenotype arises if autoregulatory positive feedback loops in the gene network regulating this process are gradual and dominant over cross-pathway inhibition. We also find that expression of the lineage-specific cytokines follows two independent stochastic processes that are biased by expression levels of the master regulators. Thus, cytokine expression is highly heterogeneous under mixed conditions, with subpopulations of cells expressing only IFN-γ, only IL-4, both cytokines, or neither. The fraction of cells in each of these subpopulations changes gradually with input conditions, reproducing the continuous internal state at the cell population level. These results suggest a differentiation scheme in which cells reflect uncertainty through a continuously tuneable mixed phenotype combined with a biased stochastic decision rather than a binary phenotype with a deterministic decision.

Geometry of the Gene Expression Space of Individual Cells.

There is a revolution in the ability to analyze gene expression of single cells in a tissue. To understand this data we must comprehend how cells are distributed in a high-dimensional gene expression space. One open question is whether cell types form discrete clusters or whether gene expression forms a continuum of states. If such a continuum exists, what is its geometry? Recent theory on evolutionary trade-offs suggests that cells that need to perform multiple tasks are arranged in a polygon or polyhedron (line, triangle, tetrahedron and so on, generally called polytopes) in gene expression space, whose vertices are the expression profiles optimal for each task. Here, we analyze single-cell data from human and mouse tissues profiled using a variety of single-cell technologies. We fit the data to shapes with different numbers of vertices, compute their statistical significance, and infer their tasks. We find cases in which single cells fill out a continuum of expression states within a polyhedron. This occurs in intestinal progenitor cells, which fill out a tetrahedron in gene expression space. The four vertices of this tetrahedron are each enriched with genes for a specific task related to stemness and early differentiation. A polyhedral continuum of states is also found in spleen dendritic cells, known to perform multiple immune tasks: cells fill out a tetrahedron whose vertices correspond to key tasks related to maturation, pathogen sensing and communication with lymphocytes. A mixture of continuum-like distributions and discrete clusters is found in other cell types, including bone marrow and differentiated intestinal crypt cells. This approach can be used to understand the geometry and biological tasks of a wide range of single-cell datasets. The present results suggest that the concept of cell type may be expanded. In addition to discreet clusters in gene-expression space, we suggest a new possibility: a continuum of states within a polyhedron, in which the vertices represent specialists at key tasks.

Would you like to play together? Adults' attachment and the mirror game.

Why is it easy for some people to play together and difficult for others? In this interdisciplinary pilot study, we looked at dyadic interaction in motion as a paradigm to explore the expression of attachment in adulthood. We used a device that gives simple, quantitative and automated indicators for the quality of interaction while playing the mirror game. Forty-seven participants played the mirror game with the same gender-matched expert players. In addition, participants were interviewed on the Adult Attachment Interview to assess their quality of attachment. Using high resolution kinematic measures, we found that secure attachment was correlated with high complexity of the game and low synchrony compared to insecure attachment. The findings suggest that security of attachment is related to a more exploratory and less rigid game than insecure-dismissing attachment. These preliminary findings imply that high resolution analysis of simple movement interaction could carry information about attachment behavior.

Design principles of cell circuits with paradoxical components.

Biological systems display complex networks of interactions both at the level of molecules inside the cell and at the level of interactions between cells. Networks of interacting molecules, such as transcription networks, have been shown to be composed of recurring circuits called network motifs, each with specific dynamical functions. Much less is known about the possibility of such circuit analysis in networks made of communicating cells. Here, we study models of circuits in which a few cell types interact by means of signaling molecules. We consider circuits of cells with architectures that seem to recur in immunology. An intriguing feature of these circuits is their use of signaling molecules with a pleiotropic or paradoxical role, such as cytokines that increase both cell growth and cell death. We find that pleiotropic signaling molecules can provide cell circuits with systems-level functions. These functions include for different circuits maintenance of homeostatic cell concentrations, robust regulation of differentiation processes, and robust pulses of cells or cytokines.

Fold-change detection and scalar symmetry of sensory input fields.

Recent studies suggest that certain cellular sensory systems display fold-change detection (FCD): a response whose entire shape, including amplitude and duration, depends only on fold changes in input and not on absolute levels. Thus, a step change in input from, for example, level 1 to 2 gives precisely the same dynamical output as a step from level 2 to 4, because the steps have the same fold change. We ask what the benefit of FCD is and show that FCD is necessary and sufficient for sensory search to be independent of multiplying the input field by a scalar. Thus, the FCD search pattern depends only on the spatial profile of the input and not on its amplitude. Such scalar symmetry occurs in a wide range of sensory inputs, such as source strength multiplying diffusing/convecting chemical fields sensed in chemotaxis, ambient light multiplying the contrast field in vision, and protein concentrations multiplying the output in cellular signaling systems. Furthermore, we show that FCD entails two features found across sensory systems, exact adaptation and Weber's law, but that these two features are not sufficient for FCD. Finally, we present a wide class of mechanisms that have FCD, including certain nonlinear feedback and feed-forward loops. We find that bacterial chemotaxis displays feedback within the present class and hence, is expected to show FCD. This can explain experiments in which chemotaxis searches are insensitive to attractant source levels. This study, thus, suggests a connection between properties of biological sensory systems and scalar symmetry stemming from physical properties of their input fields.

Mind-bending geometry: Children's and adults' intuitions about linearity on spheres.

Humans appear to intuitively grasp definitions foundational to formal geometry, like definitions that describe points as infinitely small and lines as infinitely long. Nevertheless, previous studies exploring human's intuitive natural geometry have consistently focused on geometric principles in planar Euclidean contexts and thus may not comprehensively characterize humans' capacity for geometric reasoning. The present study explores whether children and adults can reason about linearity in spherical contexts. We showed 48 children (age range: 6-8 years) and 48 adults from the U.S. Northeast two different paths between the same two points on pictures of spheres and asked them to judge which path was the most efficient for an actor to get from a starting point to a goal object. In one kind of trial, both paths looked curved in the pictures, and in another kind of trial, the correct curved-looking path was paired with an incorrect straight-looking path. Adults were successful on both kinds of trials, and although children often chose the incorrect straight-looking path, they were surprisingly successful at identifying the efficient path when comparing two that were curved. Children thus may build on a natural geometry that gives us humans intuitions that are not limited to the formal axioms of Euclidean geometry or even to the Euclidean plane. (PsycInfo Database Record (c) 2023 APA, all rights reserved).

Euclid's Random Walk: Developmental Changes in the Use of Simulation for Geometric Reasoning.

Euclidean geometry has formed the foundation of architecture, science, and technology for millennia, yet the development of human's intuitive reasoning about Euclidean geometry is not well understood. The present study explores the cognitive processes and representations that support the development of humans' intuitive reasoning about Euclidean geometry. One-hundred-twenty-five 7- to 12-year-old children and 30 adults completed a localization task in which they visually extrapolated missing parts of fragmented planar triangles and a reasoning task in which they answered verbal questions about the general properties of planar triangles. While basic Euclidean principles guided even young children's visual extrapolations, only older children and adults reasoned about triangles in ways that were consistent with Euclidean geometry. Moreover, a relation beteen visual extrapolation and reasoning appeared only in older children and adults. Reasoning consistent with Euclidean geometry may thus emerge when children abandon incorrect, axiomatic-based reasoning strategies and come to reason using mental simulations of visual extrapolations.

Bio-behavioral synchrony is a potential mechanism for mate selection in humans.

The decision with whom to form a romantic bond is of great importance, yet the biological or behavioral mechanisms underlying this selective process in humans are largely unknown. Classic evolutionary theories of mate selection emphasize immediate and static features such as physical appearance and fertility. However, they do not explain how initial attraction temporally unfolds during an interaction, nor account for mutual physiological or behavioral adaptations that take place when two people become attracted. Instead, recent theories on social bonding emphasize the importance of co-regulation during social interactions (i.e., the social coordination of physiology and behavior between partners), and predict that co-regulation plays a role in bonding with others. In a speed-date experiment of forty-six heterosexual dates, we recorded the naturally occurring patterns of electrodermal activity and behavioral motion in men and women, and calculated their co-regulation during the date. We demonstrate that co-regulation of behavior and physiology is associated with the date outcome: when a man and a woman synchronize their electrodermal activity and dynamically tune their behavior to one another, they are more likely to be romantically and sexually attracted to one another. This study supports the hypothesis that co-regulation of sympathetic and behavioral rhythms between a man and a woman serves as a mechanism that promotes attraction.

The development of creative search strategies.

How does creativity develop? Creativity is a multi-faceted behavior and thus it is difficult to find measures for creativity that are both precise and comparable across development. Here, we examine the development of creativity using a "creative foraging" task. The task measures different facets of creativity which we compare between 4- to 8-year-old children and adults. We find that compared to adults, children spend a higher percentage of their search exploring, and their exploitation phases are less efficient. Moreover, children orient their search to a different and smaller region of the search space, but within that space they produce more unique creative products. Lastly, as children grow up, their creative products become more adult-like and their uniqueness decreases. Together, these results suggest that creative search changes across development, in the search strategy employed, in how the space of possibilities is navigated, and in what ideas are ultimately chosen.

Publisher Correction: Creative exploration as a scale-invariant search on a meaning landscape.

An amendment to this paper has been published and can be accessed via a link at the top of the paper.

The more the merrier? Increasing group size may be detrimental to decision-making performance in nominal groups.

Demonstrability-the extent to which group members can recognize a correct solution to a problem-has a significant effect on group performance. However, the interplay between group size, demonstrability and performance is not well understood. This paper addresses these gaps by studying the joint effect of two factors-the difficulty of solving a problem and the difficulty of verifying the correctness of a solution-on the ability of groups of varying sizes to converge to correct solutions. Our empirical investigations use problem instances from different computational complexity classes, NP-Complete (NPC) and PSPACE-complete (PSC), that exhibit similar solution difficulty but differ in verification difficulty. Our study focuses on nominal groups to isolate the effect of problem complexity on performance. We show that NPC problems have higher demonstrability than PSC problems: participants were significantly more likely to recognize correct and incorrect solutions for NPC problems than for PSC problems. We further show that increasing the group size can actually decrease group performance for some problems of low demonstrability. We analytically derive the boundary that distinguishes these problems from others for which group performance monotonically improves with group size. These findings increase our understanding of the mechanisms that underlie group problem-solving processes, and can inform the design of systems and processes that would better facilitate collective decision-making.