Nonmodular oscillator and switch based on RNA decay drive regeneration of multimodal gene expression

Periodic gene expression dynamics are key to cell and organism physiology. Studies of oscillatory expression have focused on networks with intuitive regulatory negative feedback loops, leaving unknown whether other common biochemical reactions can produce oscillations. Oscillation and noise have been proposed to support the capacity of mammalian progenitor cells to restore heterogenous, multimodal expression from extreme subpopulations, but underlying networks and specific roles of noise remained elusive. We use mass-action-based models to show that regulated RNA degradation involving as few as two RNA species, applicable to nearly half of human protein-coding genes, can generate sustained oscillations without imposed feedback. Diverging oscillation periods synergize with noise to robustly restore bimodal expression in cell populations. The global bifurcation organizing this divergence relies on an oscillator and bistable switch which cannot be decomposed into two structural modules. Our work reveals surprisingly rich dynamics of post-transcriptional reactions and a potentially widespread mechanism useful for development and regeneration.

The journey of neutropoiesis: how complex landscapes in bone marrow guide continuous neutrophil lineage determination

Neutrophils are the most abundant white blood cell, and differentiate in homeostasis in the bone marrow from hematopoietic stem cells (HSCs) via multiple intermediate progenitor cells into mature cells that enter the circulation. Recent findings support a continuous model of differentiation in the bone marrow of heterogeneous HSCs and progenitor populations. Cell fate decisions both at the level of proliferation and differentiation are enforced through expression of lineage-determining transcription factors (LDTFs) and their interactions, that are influenced by both intrinsic (intracellular) as well as extrinsic (extracellular) mechanisms. Neutrophil homeostasis is subjected to positive feedback loops, stemming from the gut microbiome, as well as negative feedback loops resulting from the clearance of apoptotic neutrophils by mature macrophages. Finally, the cellular kinetics regarding the replenishing of the mature neutrophil pool is discussed in light of recent, contradictory data.

Identifying the dynamic evolution and feedback process of water resources nexus system considering socioeconomic development, ecological protection, and food security: A practical tool for sustainable water use

The accelerated consumption of water resources caused by the rapid increase in population and urbanization is intensifying the complex interactions across water resources, socioeconomic development, ecological protection, and food security (WSEF), which causes not only the imbalance between water supply and demand but also the vulnerability of both food and ecological systems. Therefore, identifying the dynamic coevolution and feedback process is one of the most crucial ways of achieving the goal of sustainable water use. In this study, we developed an integrated modeling framework to better identify the dynamic interaction and coevolution process of the nexus across WSEF systems in the context of sustainable water uses by coupling system dynamic (SD) model and multi-objective optimization model. The SD model is used to simulate both the dynamic interaction of each agent and the coevolution process of the whole nexus system by positive/negative feedback loops. The multi-objective optimization model is used to quantify the negative feedback loops of the SD model by generating the optimal scheme of different water users. Finally, the model uncertainty considering different weighting factors is analyzed. The framework is applied to the upper reaches of the Guijiang River basin, China. Results show that (i) the rapid economic growth increases the conflict between the water uses for socioeconomic development and ecological protection, intensifying the ecological awareness and resulting in more water shortages of socioeconomic and food agents, which is unable to support such rapid development. (ii) Once the economic growth rate decreases, water resources are able to support economic development with a decreased overload index and stable crop yield, which further contributes to water sustainability. (iii) The river ecological agent is the critical factor that affects the robustness of the model. (iv) The equal consideration of each water usage is the most beneficial to sustainable development. These results highlight the importance of water resources management, considering the tradeoffs across multiple stakeholders, and give a strong reference to policymakers for comprehensive urban planning.

The oscillation of mitotic kinase governs cell cycle latches

SummaryIn order to transmit a eukaryotic cell’s genome accurately from mother cell to daughter cells, it is essential that the basic events of the cell division cycle (DNA synthesis and mitosis) occur once and only once per cycle, i.e., that a cell progresses irreversibly from G1 to S to G2 to M and back to G1. Irreversible progression through the cell cycle is assured by a sequence of ‘latching’ molecular switches, based on molecular interactions among cyclin-dependent kinases and their auxiliary partners. Positive feedback loops (++ or −−) create bistable switches with latching properties, and negative feedback loops drive progression from one stage to the next. In budding yeast (Saccharomyces cerevisiae) these events are coordinated by double-negative feedback loops between Clb-dependent kinases (Clb1-6) and their antagonists (APC:Cdh1 and Sic1). If the coordinating signal is compromised, either by deletion of Clb1-5 proteins or expression of non-degradable Clb2, then irreversibility is lost and yeast cells exhibit multiple rounds of DNA replication or mitotic exit events (Cdc14 endocycles). Using mathematical modelling of a stripped-down control network, we show how endocycles arise because the switches fail to latch, and the gates swing back and forth by the action of the negative feedback loops.

Support for Adjusting the Intentions of Family Members and Users Regarding Care Service Use: Aimed at Care Management

In Japan, there are key healthcare professionals for home nursing care for elderly people called Care Managers. The care manager coordinates the service while adjusting the family situation and the user’s intentions. The purpose of this study was to examine the practical structure of support for adjusting the intentions of family members and users regarding care service use. Data from seven cases, where family members and users have different intentions regarding care service use, were analyzed using the grounded theory approach. The phenomenon of “confirmation of discrepancies” was discovered with six sub-categories: adjusting the intentions of users and their families, effort to restore relationships, expression of intention to refuse involvement, expression of desire for adjustment, arrangement of opportunities for adjustment of intentions, and appropriate service adjustment. Four patterns occurred in the process of “confirmation of discrepancies”: smooth adjustment, restoration and promotion of mutual relationships, failure to reach an agreement, and negative feedback loops. These patterns were based on a combination of the care managers’ degree of understanding strength, the managers’ degree of insistence, the managers’ degree of representation of mutual feelings, the degree of managers’ prediction of life prospects, the degree of trust in care managers, and the degree of expression of family anxiety.

Interplay of positive and negative feedback loops governs robustness in multistable biological networks

Biological networks are widely reported to be robust to both external and internal perturbations. However, the exact mechanisms and design principles that enable robustness are not yet fully understood. Here we investigated dynamic and structural robustness in biological networks with regards to phenotypic distribution and plasticity. We use two different approaches to simulate these networks: a computationally inexpensive, parameter-independent continuous model, and an ODE-based parameter-agnostic framework (RACIPE), both of which yield similar phenotypic distributions. Using perturbations to network topology and by varying network parameters, we show that multistable biological networks are structurally and dynamically more robust as compared to their randomized counterparts. These features of robustness are governed by an interplay of positive and negative feedback loops embedded in these networks. Using a combination of the number of negative and positive feedback loops weighted by their lengths and sign, we identified a metric that can explain the structural and dynamical robustness of these networks. This metric enabled us to compare networks across multiple sizes, and the network principles thus obtained can be used to identify fragilities in large networks without simulating their dynamics. Our analysis highlights a network topology based approach to quantify robustness in multistable biological networks.

Differences in evolutionary accessibility determine which equally effective regulatory motif evolves to generate pulses

Transcriptional regulatory networks (TRNs) are enriched for certain “motifs”. Motif usage is commonly interpreted in adaptationist terms, i.e. that the optimal motif evolves. But certain motifs can also evolve more easily than others. Here, we computationally evolved TRNs to produce a pulse of an effector protein. Two well-known motifs, type 1 incoherent feed-forward loops (I1FFLs) and negative feedback loops (NFBLs), evolved as the primary solutions. The relative rates at which these two motifs evolve depend on selection conditions, but under all conditions, either motif achieves similar performance. I1FFLs generally evolve more often than NFBLs. Selection for a tall pulse favors NFBLs, while selection for a fast response favors I1FFLs. I1FFLs are more evolutionarily accessible early on, before the effector protein evolves high expression; when NFBLs subsequently evolve, they tend to do so from a conjugated I1FFL-NFBL genotype. In the empirical S. cerevisiae TRN, output genes of NFBLs had higher expression levels than those of I1FFLs. These results suggest that evolutionary accessibility, and not relative functionality, shapes which motifs evolve in TRNs, and does so as a function of the expression levels of particular genes.

Vascular Mechanobiology: Homeostasis, Adaptation, and Disease

Cells of the vascular wall are exquisitely sensitive to changes in their mechanical environment. In healthy vessels, mechanical forces regulate signaling and gene expression to direct the remodeling needed for the vessel wall to maintain optimal function. Major diseases of arteries involve maladaptive remodeling with compromised or lost homeostatic mechanisms. Whereas homeostasis invokes negative feedback loops at multiple scales to mediate mechanobiological stability, disease progression often occurs via positive feedback that generates mechanobiological instabilities. In this review, we focus on the cell biology, wall mechanics, and regulatory pathways associated with arterial health and how changes in these processes lead to disease. We discuss how positive feedback loops arise via biomechanical and biochemical means. We conclude that inflammation plays a central role in overriding homeostatic pathways and suggest future directions for addressing therapeutic needs.

A holistic study of factors governing small and medium enterprises in India

Purpose The purpose of this paper is to identify the input, process and output factors (along with their manifest variables) of small and medium enterprises (SMEs), and to establish cause and effect relationships amongst the factors and sub-factors. Systems thinking, a holistic approach, is used to carry out qualitative analysis of the feedback loops. Design/methodology/approach A well-structured questionnaire was developed to gather the relevant data to identify the factors affecting the performance of SMEs in a holistic manner. A total of 150 responses were collected during November 2015–March 2016. Factor analysis and path analysis were used to establish causal relationships between input, process and output factors. The systems thinking approach has been used for qualitative analysis. Findings Feedback loops have been identified amongst input-process-output-input factors and amongst sub-factors. They enabled authors to infer that the managers/owners of SMEs are systems thinkers, if not completely, at least partially. Six negative feedback loops and one positive feedback loop prevail. System behaviour arises out of the interaction of positive and negative feedback loops; it appears that in the long-run, the SMEs attain their target levels. The following inferences are drawn: circular relationships are identified amongst input, processes and organisational performance (OP), modern management tools such as just in times, Kanban have long-term benefits and are perceived as ineffective by small enterprises and formal financing and functional transparency enhances OP. Originality/value Systems thinking, a holistic approach, has been used to study the effect of input, process and output factors on one another. Such studies are sparse, especially, in the Indian context. Many studies have been conducted to study the effect of input and of processes on performance such as innovation, information technology, human resource, technology, government regulation on performance of SMEs in a silo but, rarely all together. The qualitative analysis adds value to the research. Many of the outcomes of the research have been largely discussed in Indian print media which indicates the pragmatic approach of the research.