Neutral Competition Research Articles

Mechanisms of Germline Stem Cell Competition across Species.

In this review, we introduce the concept of cell competition, which occurs between heterogeneous neighboring cell populations. Cells with higher relative fitness become "winners" that outcompete cells of lower relative fitness ("losers"). We discuss the idea of super-competitors, mutant cells that expand at the expense of wild-type cells. Work on adult stem cells (ASCs) has revealed principles of neutral competition, wherein ASCs can be stochastically lost and replaced, and of biased competition, in which a winning ASC with a competitive advantage replaces its neighbors. Germline stem cells (GSCs) are ASCs that are uniquely endowed with the ability to produce gametes and, therefore, impact the next generation. Mechanisms of GSC competition have been elucidated by studies in Drosophila gonads, tunicates, and the mammalian testis. Competition between ASCs is thought to underlie various forms of cancer, including spermatocytic tumors in the human testis. Paternal age effect (PAE) disorders are caused by de novo mutations in human GSCs that increase their competitive ability and make them more likely to be inherited, leading to skeletal and craniofacial abnormalities in offspring. Given its widespread effects on human health, it is important to study GSC competition to elucidate how cells can become winners or losers.

Unraveling the Metabolic Behavior and Interspecific Interaction Pattern of Lactic Acid Bacteria within Chinese Rice Wine.

The synthetic community of lactic acid bacteria (LAB) is commonly utilized in the food industry for manipulating product properties. However, the intermediate interactions and ecological stability resulting from metabolic differences among various LAB types remain poorly understood. We aimed to analyze the metabolic behavior of single and combined lactic acid bacteria in China rice wine based on microbial succession. Three-stage succession patterns with obligate heterofermentative LAB dominating prefermentation and homofermentative LAB prevailing in main fermentation were observed. Facultative heterofermentative LAB exhibited significant growth. Pairwise coculture interactions revealed 63.5% positive, 34.4% negative, and 2.1% neutral interactions, forming nontransitive and transitive competition modes. Nontransitive competitive combinations demonstrated stability over ∼200 generations through amino acid (mainly aspartic acid, glutamine, and serine) cross-feeding and lactic acid detoxification, which also showed potential for controlling biogenic amines and developing LAB starter cultures. Our findings offer insights into the mechanistic underpinnings of LAB interaction networks.

A transit-amplifying progenitor with biphasic behavior contributes to epidermal renewal.

Transit-amplifying (TA) cells are progenitors that undergo an amplification phase followed by transition into an extinction phase. A long postulated epidermal TA progenitor with biphasic behavior has not yet been experimentally observed in vivo. Here, we identify such a TA population using clonal analysis of Aspm-CreER genetic cell-marking in mice, which uncovers contribution to both homeostasis and injury repair of adult skin. This TA population is more frequently dividing than a Dlx1-CreER-marked long-term self-renewing (e.g. stem cell) population. Newly developed generalized birth-death modeling of long-term lineage tracing data shows that both TA progenitors and stem cells display neutral competition, but only the stem cells display neutral drift. The quantitative evolution of a nascent TA cell and its direct descendants shows that TA progenitors indeed amplify the basal layer before transition and that the homeostatic TA population is mostly in extinction phase. This model will be broadly useful for analyzing progenitors whose behavior changes with their clone age. This work identifies a long-missing class of non-self-renewing biphasic epidermal TA progenitors and has broad implications for understanding tissue renewal mechanisms.

Neutral competition explains the clonal composition of neural organoids.

Neural organoids model the development of the human brain and are an indispensable tool for studying neurodevelopment. Whole-organoid lineage tracing has revealed the number of progenies arising from each initial stem cell to be highly diverse, with lineage sizes ranging from one to more than 20,000 cells. This high variability exceeds what can be explained by existing stochastic models of corticogenesis and indicates the existence of an additional source of stochasticity. To explain this variability, we introduce the SAN model which distinguishes Symmetrically diving, Asymmetrically dividing, and Non-proliferating cells. In the SAN model, the additional source of stochasticity is the survival time of a lineage's pool of symmetrically dividing cells. These survival times result from neutral competition within the sub-population of all symmetrically dividing cells. We demonstrate that our model explains the experimentally observed variability of lineage sizes and derive the quantitative relationship between survival time and lineage size. We also show that our model implies the existence of a regulatory mechanism which keeps the size of the symmetrically dividing cell population constant. Our results provide quantitative insight into the clonal composition of neural organoids and how it arises. This is relevant for many applications of neural organoids, and similar processes may occur in other developing tissues both in vitro and in vivo.

A generic approach to infer community-level fitness of microbial genes

The gene content in a metagenomic pool defines the function potential of a microbial community. Natural selection, operating on the level of genomes or genes, shapes the evolution of community functions by enriching some genes while depriving the others. Despite the importance of microbiomes in the environment and health, a general metric to evaluate the community-wide fitness of microbial genes remains lacking. In this work, we adapt the classic neutral model of species and use it to predict how the abundances of different genes will be shaped by selection, regardless of at which level the selection acts. We establish a simple metric that quantitatively infers the average survival capability of each gene in a microbiome. We then experimentally validate the predictions using synthetic communities of barcoded Escherichia coli strains undergoing neutral assembly and competition. We further show that this approach can be applied to publicly available metagenomic datasets to gain insights into the environment-function interplay of natural microbiomes.

Addressing biases in replacement series: the importance of reference density selection for interpretation of competition outcomes

AbstractReplacement series are used by researchers to understand how competition-related variables influence dynamics from the individual to the population and community levels, but this approach has been criticized because of inherent biases associated with plant size differences and density-dependent responses. The use of functional densities instead of demographic densities was proposed to minimize those biases. This work explored three models to determine reference densities for replacement series experiments based on (1) maximum biomass, (2) biomass at onset of diminishing returns (i.e., inflection point), and (3) nitrogen (N)-uptake equivalency. Replacement series experiments were conducted using redroot pigweed (Amaranthus hybridus L.):maize (Zea mays L.) and giant foxtail (Setaria faberi Herrm.):maize proportions of 1:0, 0.75:0.25, 0.5:0.5, 0.25:0.75, and 0:1. The monoculture density for each species was established according to the three models. Density selection criteria resulted in major differences in competitive interactions between species. The use of functional densities at which the biomass accumulation inflection point for the smaller species allowed both species to exhibit either increases or decreases in biomass production depending on competitive interactions for all interspecific mixtures. Conversely, the maximum biomass model favored the larger species, almost completely inhibiting the growth of the smaller species, which resulted in a poor characterization of competitive responses of the smaller species. The N uptake equivalency model resulted in interactions closer to the predicted neutral competition. The model based on the biomass accumulation inflection point was the most sensitive and informative across all interspecific mixtures for both species. We propose that to reduce bias associated with species size differences when determining reference densities for replacement series experiments, at least two criteria must be met: (1) the experiment sensitivity allows measuring and quantifying the competitive responses for both species in all mixtures, and (2) the balance between density and carrying capacity of the system minimizes intraspecific competition.

PRINCIPLE OF COMPETITIVE NEUTRALITY FOR STATE-OWNED ENTERPRISES TO AN ACCESS TO JUSTICE ON BUSINESS PRACTICES

This research is entitled” Principle of Competitive Neutrality for State-Owned Enterprises to an Access to Justice on Business Practices”. The background of the problem in this dissertation is that business competition conducted by State-Owned Enterprises (SOE’s) against private business actors is not neutral or fair, so it needs to be based on the principle of competitive neutrality. The principle of competitive neutrality is the principle of competition law that companies must compete on the basis of the superiority of their products and may not take undue advantage. In this case the state has a role as regulator and entrepreneur through SOE’s, so that neutral competition is difficult to fulfill without being based on laws and regulations. The formulations of the problem in this dissertation research are: 1) Constitutional basis of state-owned enterprises in national development; 2) Legal principles of competitive neutrality in international legal instruments; 3) Principle of competitive neutrality in national law. Based on Article 1 paragraph (2) juncto Article 33 paragraph (1), paragraph (2) and paragraph (3) of the 1945 Constitution of the Republic of Indonesia that sovereignty is in the hands of the people, production branches which are important to the state and which affect the livelihood of the people at large are controlled by the state and used for the greatest prosperity the people, and most importantly the economy is structured as a joint effort on the principle of kinship, so principles are important as Competitive Neutrality for SOE’s so that they can work together fairly with private business actors.

Stem cell homeostasis regulated by hierarchy and neutral competition

Tissue stem cells maintain themselves through self-renewal while constantly supplying differentiating cells. Two distinct models have been proposed as mechanisms of stem cell homeostasis. According to the classical model, there is hierarchy among stem cells, and master stem cells produce stem cells by asymmetric division; whereas, according to the recent model, stem cells are equipotent and neutrally compete. However, the mechanism remains controversial in several tissues and species. Here, we developed a mathematical model linking the two models, named the hierarchical neutral competition (hNC) model. Our theoretical analysis showed that the combination of the hierarchy and neutral competition exhibited bursts in clonal expansion, which was consistent with experimental data of rhesus macaque hematopoiesis. Furthermore, the scaling law in clone size distribution, considered a unique characteristic of the recent model, was satisfied even in the hNC model. Based on the findings above, we proposed the criterion for distinguishing the three models based on experiments.

Quantitative research on production and business activities of state-owned enterprises in the context of applying a neutralcompetition policy

The study focuses on the production and business activities of state-owned enterprise (SOEs) in the context of applying a neutral competition policy through quantitative research methods. The regression results show that 8 factors related to competitive innovation of SOEs in the context of applying a neutral competition policy have a positive impact on the performance of these enterprises’ production and business activities, namely: (i) Research and selection of target market; (ii) Pricing strategy; (iii) Product strategy; (iv) Accompanied service strategy; (v) Distribution strategy; (vi) Promotion strategy; (vii) Communication strategy; (viii) Complementary factors. From there, the study proposes some recommendations for improving the performance of the production and business activities of Vietnamese SOEs in the context of applying a neutral competition policy.

The diffusive Lotka–Volterra competition model in fragmented patches I: Coexistence

It is an ecological imperative that we understand how changes in landscape heterogeneity affect population dynamics and coexistence among species residing in increasingly fragmented landscapes. Decades of research have shown the dispersal process to have major implications for individual fitness, species’ distributions, interactions with other species, population dynamics, and stability. Although theoretical models have played a crucial role in predicting population level effects of dispersal, these models have largely ignored the conditional dependency of dispersal (e.g., responses to patch boundaries, matrix hostility, competitors, and predators). This work is the first in a series where we explore dynamics of the diffusive Lotka–Volterra (L–V) competition model in such a fragmented landscape. This model has been extensively studied in isolated patches, and to a lesser extent, in patches surrounded by an immediately hostile matrix. However, little attention has been focused on studying the model in a more realistic setting considering organismal behavior at the patch/matrix interface. Here, we provide a mechanistic connection between the model and its biological underpinnings and study its dynamics via exploration of nonexistence, existence, and uniqueness of the model’s steady states. We employ several tools from nonlinear analysis, including sub-supersolutions, certain eigenvalue problems, and a numerical shooting method. In the case of weak, neutral, and strong competition, our results mostly match those of the isolated patch or immediately hostile matrix cases. However, in the case where competition is weak towards one species and strong towards the other, we find existence of a maximum patch size, and thus an intermediate range of patch sizes where coexistence is possible, in a patch surrounded by an intermediate hostile matrix when the weaker competitor has a dispersal advantage. These results support what ecologists have long theorized, i.e., a key mechanism promoting coexistence among competing species is a tradeoff between dispersal and competitive ability.

Bacillus subtilis programs the differentiation of intestinal secretory lineages to inhibit Salmonella infection.

The role of intestinal microbiota on fate determination of intestinal epithelial cells has not been extensively examined. In this study, we explore the effect of Bacillus subtilis on programmed intestinal epithelial differentiation. We find that B.subtilis stimulates the differentiation of intestinal secretory cells. Moreover, B.subtilis inhibits the Notch pathway to reduce the expression of hairy and enhancer of split 1, thereby shifting intestinal stem cell differentiation toward a secretory cell fate. Moreover, we demonstrate that the programming effect of B.subtilis on intestinal differentiation is Toll-like receptor 2 pathway dependent. B.subtilis is associated with increased numbers of Paneth and goblet cells in the intestine. This results in the production of antimicrobial peptides to protect the intestinal mucosal barrier against Salmonella typhimurium. This study demonstrates that B.subtilis contributes to the differentiation of secretory cells by affecting Notch pathway signaling to maintain the intestinal barrier.

The operation of SOEs in the context of applying a neutral competition policy

This paper studies the operations of state-owned enterprises (SOEs) in the context of applying a neutral competition policy in Vietnam. The results of expert interviews and statistical analysis show the current situation of the operations of these enterprises. The SOEs have achieved many remarkable achievements in terms of operations, but there are still certain limitations that need to be overcome soon. Therefore, the study proposes some recommendations for improving the operational performance of the SOEs in the context of applying the current neutral competition policy in Vietnam.

Emergent spatial patterns of coexistence in species-rich plant communities.

Statistical physics has proved essential to analyze multiagent environments. Motivated by the empirical observation of various nonequilibrium features in Barro Colorado and other ecological systems, we analyze a plant-species abundance model of neutral competition, presenting analytical evidence of scale-invariant plant clusters and nontrivial emergent modular correlations. Such first theoretical confirmation of a scale-invariant region, based on percolation processes, reproduces the key features in natural rainforest ecosystems and can confer the most stable equilibrium for ecosystems with vast biodiversity.

Agent-based neutral competition in two-community networks.

Competition between alternative states is an essential process in social and biological networks. Neutral competition can be represented by an unbiased random drift process in which the states of vertices (e.g., opinions, genotypes, or species) in a network are updated by repeatedly selecting two connected vertices. One of these vertices copies the state of the selected neighbor. Such updates are repeated until all vertices are in the same "consensus" state. There is no unique rule for selecting the vertex pair to be updated. Real-world processes comprise three limiting factors that can influence the selected edge and the direction of spread: (1) the rate at which a vertex sends a state to its neighbors, (2) the rate at which a state is received by a neighbor, and (3) the rate at which a state can be exchanged through a connecting edge. We investigate how these three limitations influence neutral competition in networks with two communities generated by a stochastic block model. By using Monte Carlo simulations, we show how the community structure and update rule determine the states' success probabilities and the time until a consensus is reached. We present a heterogeneous mean-field theory that agrees well with the Monte Carlo simulations. The effectiveness of the heterogeneous mean-field theory implies that quantitative predictions about the consensus are possible even if empirical data (e.g., from ecological fieldwork or observations of social interactions) do not allow a complete reconstruction of all edges in the network.

Neutral competition boosts cycles and chaos in simulated food webs.

Similarity of competitors has been proposed to facilitate coexistence of species because it slows down competitive exclusion, thus making it easier for equalizing mechanisms to maintain diverse communities. On the other hand, previous studies suggest that chaotic ecosystems can have a higher biodiversity. Here, we link these two previously unrelated findings, by analysing the dynamics of food web models. We show that near-neutrality of competition of prey, in the presence of predators, increases the chance of developing chaotic dynamics. Moreover, we confirm that chaotic dynamics correlate with a higher biodiversity.

Neutral competition in a deterministically changing environment: Revisiting continuum approaches

Environmental variation can play an important role in ecological competition by influencing the relative advantage between competing species. Here, we consider such effects by extending a classical, competitive Moran model to incorporate an environment that fluctuates periodically in time. We adapt methods from work on these classical models to investigate the effects of the magnitude and frequency of environmental fluctuations on two important population statistics: the probability of fixation and the mean time to fixation. In particular, we find that for small frequencies, the system behaves similar to a system with a constant fitness difference between the two species, and for large frequencies, the system behaves similar to a neutrally competitive model. Most interestingly, the system exhibits nontrivial behavior for intermediate frequencies. We conclude by showing that our results agree quite well with recent theoretical work on competitive models with a stochastically changing environment, and discuss how the methods we develop ease the mathematical analysis required to study such models.

The impact of hypocrisy on opinion formation: A dynamic model.

Humans have a demonstrated tendency to copy or imitate the behavior and attitude of others and actively influence each other’s opinions. In plenty of empirical contexts, publicly revealed opinions are not necessarily in line with internal opinions, causing complex social influence dynamics. We study to what extent hypocrisy is sustained during opinion formation and how hidden opinions change the convergence to consensus in a group. We build and analyze a modified version of the voter model with hypocrisy in a complete graph with a neutral competition between two alternatives. We compare the process from various initial conditions, varying the proportions between the two opinions in the external (revealed) and internal (hidden) layer. According to our results, hypocrisy always prolongs the time needed for reaching a consensus. In a complete graph, this time span increases linearly with group size. We find that the group-level opinion emerges in two steps: (1) a fast and directional process, during which the number of the two kinds of hypocrites equalizes; and (2) a slower, random drift of opinions. During stage (2), the ratio of opinions in the external layer is approximately equal to the ratio in the internal layer; that is, the hidden opinions do not differ significantly from the revealed ones at the group level. We furthermore find that the initial abundances of opinions, but not the initial prevalence of hypocrisy, predicts the mean consensus time and determines the opinions’ probabilities of winning. These insights highlight the unimportance of hypocrisy in consensus formation under neutral conditions. Our results have important societal implications in relation to hidden voter preferences in polls and improve our understanding of opinion formation in a more realistic setting than that of conventional voter models.

Wnt ligands influence tumour initiation by controlling the number of intestinal stem cells

Many epithelial stem cell populations follow a pattern of stochastic stem cell divisions called 'neutral drift'. It is hypothesised that neutral competition between stem cells protects against the acquisition of deleterious mutations. Here we use a Porcupine inhibitor to reduce Wnt secretion at a dose where intestinal homoeostasis is maintained despite a reduction of Lgr5+ stem cells. Functionally, there is a marked acceleration in monoclonal conversion, so that crypts become rapidly derived from a single stem cell. Stem cells located further from the base are lost and the pool of competing stem cells is reduced. We tested whether this loss of stem cell competition would modify tumorigenesis. Reduction of Wnt ligand secretion accelerates fixation of Apc-deficient cells within the crypt leading to accelerated tumorigenesis. Therefore, ligand-based Wnt signalling influences the number of stem cells, fixation speed of Apc mutations and the speed and likelihood of adenoma formation.

Neutral Competition for Drosophila Follicle and Cyst Stem Cell Niches Requires Vesicle Trafficking Genes.

The process of selecting for cellular fitness through competition plays a critical role in both development and disease. The germarium, a structure at the tip of the ovariole of a Drosophila ovary, contains two follicle stem cells (FSCs) that undergo neutral competition for the stem cell niche. Using the FSCs as a model, we performed a genetic screen through a collection of 126 mutants in essential genes on the X chromosome to identify candidates that increase or decrease competition for the FSC niche. We identified ∼55 and 6% of the mutations screened as putative FSC hypo- or hyper-competitors, respectively. We found that a large majority of mutations in vesicle trafficking genes (11 out of the 13 in the collection of mutants) are candidate hypo-competition alleles, and we confirmed the hypo-competition phenotype for four of these alleles. We also show that Sec16 and another COPII vesicle trafficking component, Sar1, are required for follicle cell differentiation. Lastly, we demonstrate that, although some components of vesicle trafficking are also required for neutral competition in the cyst stem cells of the testis, there are important tissue-specific differences. Our results demonstrate a critical role for vesicle trafficking in stem cell niche competition and differentiation, and we identify a number of putative candidates for further exploration.

Intestinal Stem Cell Pool Regulation in Drosophila.

SummaryIntestinal epithelial renewal is mediated by intestinal stem cells (ISCs) that exist in a state of neutral drift, wherein individual ISC lineages are regularly lost and born but ISC numbers remain constant. To test whether an active mechanism maintains stem cell pools in the Drosophila midgut, we performed partial ISC depletion. In contrast to the mouse intestine, Drosophila ISCs failed to repopulate the gut after partial depletion. Even when the midgut was challenged to regenerate by infection, ISCs retained normal proportions of asymmetric division and ISC pools did not increase. We discovered, however, that the loss of differentiated midgut enterocytes (ECs) slows when ISC division is suppressed and accelerates when ISC division increases. This plasticity in rates of EC turnover appears to facilitate epithelial homeostasis even after stem cell pools are compromised. Our study identifies unique behaviors of Drosophila midgut cells that maintain epithelial homeostasis.