scholarly journals Vascular Mechanobiology: Homeostasis, Adaptation, and Disease

2021 ◽  
Vol 23 (1) ◽  
pp. 1-27
Author(s):  
Jay D. Humphrey ◽  
Martin A. Schwartz
Keyword(s):  
Positive Feedback ◽  
Cell Biology ◽  
Multiple Scales ◽  
Vascular Wall ◽  
Feedback Loops ◽  
Future Directions ◽  
Regulatory Pathways ◽  
Negative Feedback Loops ◽  
Optimal Function ◽  
Therapeutic Needs

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.

The principle of homeostasis in the hypothalamus-pituitary-adrenal system: new insight from positive feedback

2007 ◽  
Vol 293 (1) ◽  
pp. R83-R98 ◽  
Author(s):  
A. Peters ◽  
M. Conrad ◽  
C. Hubold ◽  
U. Schweiger ◽  
B. Fischer ◽  
...  
Keyword(s):  
Negative Feedback ◽  
Positive Feedback ◽  
Glucocorticoid Receptors ◽  
Current Knowledge ◽  
Biological Systems ◽  
Feedback Loops ◽  
Endocrine Disorders ◽  
Negative Feedback Loops ◽  
Adrenal System ◽  
Positive And Negative Feedback

Feedback control, both negative and positive, is a fundamental feature of biological systems. Some of these systems strive to achieve a state of equilibrium or “homeostasis”. The major endocrine systems are regulated by negative feedback, a process believed to maintain hormonal levels within a relatively narrow range. Positive feedback is often thought to have a destabilizing effect. Here, we present a “principle of homeostasis,” which makes use of both positive and negative feedback loops. To test the hypothesis that this homeostatic concept is valid for the regulation of cortisol, we assessed experimental data in humans with different conditions (gender, obesity, endocrine disorders, medication) and analyzed these data by a novel computational approach. We showed that all obtained data sets were in agreement with the presented concept of homeostasis in the hypothalamus-pituitary-adrenal axis. According to this concept, a homeostatic system can stabilize itself with the help of a positive feedback loop. The brain mineralocorticoid and glucocorticoid receptors—with their known characteristics—fulfill the key functions in the homeostatic concept: binding cortisol with high and low affinities, acting in opposing manners, and mediating feedback effects on cortisol. This study supports the interaction between positive and negative feedback loops in the hypothalamus-pituitary-adrenal system and in this way sheds new light on the function of dual receptor regulation. Current knowledge suggests that this principle of homeostasis could also apply to other biological systems.

scholarly journals Positive Feedback Promotes Oscillations in Negative Feedback Loops

PLoS ONE ◽  
2014 ◽  
Vol 9 (8) ◽  
pp. e104761 ◽  
Author(s):  
Bharath Ananthasubramaniam ◽  
Hanspeter Herzel
Keyword(s):  
Negative Feedback ◽  
Positive Feedback ◽  
Feedback Loops ◽  
Negative Feedback Loops

scholarly journals A synthetic gene circuit for measuring autoregulatory feedback control.

2015 ◽  
Author(s):  
Miquel Angel Schikora-Tamarit ◽  
Carlos Toscano-Ochoa ◽  
Julia Domingo Espinos ◽  
Lorena Espinar ◽  
Lucas Carey
Keyword(s):  
High Throughput ◽  
Negative Feedback ◽  
Positive Feedback ◽  
Feedback Loop ◽  
Rna Binding ◽  
Rna Binding Proteins ◽  
Feedback Regulation ◽  
Feedback Loops ◽  
Expression Noise ◽  
Negative Feedback Loops

Auto regulatory feedback loops occur in the regulation of molecules ranging from ATP to MAP kinases to zinc. Negative feedback loops can increase a system′s robustness, while positive feedback loops can mediate transitions between cell states. Recent genome-wide experimental and computational studies predict hundreds of novel feedback loops. However, not all physical interactions are regulatory, and many experimental methods cannot detect self-interactions. Our understanding of regulatory feedback loops is therefore hampered by the lack of high-throughput methods to experimentally quantify the presence, strength, and temporal dynamics of auto regulatory feedback loops. Here we present a mathematical and experimental framework for high-throughput quantification of feedback regulation, and apply it to RNA binding proteins (RBPs) in yeast. Our method is able to determine the existence of both direct and indirect positive and negative feedback loops, and to quantify the strength of these loops. We experimentally validate our model using two RBPs which lack native feedback loops, and by the introduction of synthetic feedback loops. We find that the the RBP Puf3 does not natively participate in any direct or indirect feedback regulation, but that replacing the native 3′UTR with that of COX17 generates an auto-regulatory negative feedback loop which reduces gene expression noise. Likewise, the RBP Pub1 does not natively participate in any feedback loops, but a synthetic positive feedback loop involving Pub1 results in increased expression noise. Our results demonstrate a synthetic experimental system for quantifying the existence and strength of feedback loops using a combination of high-throughput experiments and mathematical modeling. This system will be of great use in measuring auto-regulatory feedback by RNA binding proteins, a regulatory motif that is difficult to quantify using existing high-throughput methods.

scholarly journals Overlaid positive and negative feedback loops shape dynamical properties of PhoPQ two-component system

2021 ◽  
Vol 17 (1) ◽  
pp. e1008130
Author(s):  
Satyajit D Rao ◽  
Oleg A Igoshin
Keyword(s):  
Steady State ◽  
Negative Feedback ◽  
Positive Feedback ◽  
Feedback Loops ◽  
General Mechanism ◽  
Response Dynamics ◽  
Negative Feedback Loops ◽  
Two Component ◽  
Positive And Negative Feedback ◽  
Dynamical Properties

Bacteria use two-component systems (TCSs) to sense environmental conditions and change gene expression in response to those conditions. To amplify cellular responses, many bacterial TCSs are under positive feedback control, i.e. increase their expression when activated. Escherichia coli Mg2+ -sensing TCS, PhoPQ, in addition to the positive feedback, includes a negative feedback loop via the upregulation of the MgrB protein that inhibits PhoQ. How the interplay of these feedback loops shapes steady-state and dynamical responses of PhoPQ TCS to change in Mg2+ remains poorly understood. In particular, how the presence of MgrB feedback affects the robustness of PhoPQ response to overexpression of TCS is unclear. It is also unclear why the steady-state response to decreasing Mg2+ is biphasic, i.e. plateaus over a range of Mg2+ concentrations, and then increases again at growth-limiting Mg2+. In this study, we use mathematical modeling to identify potential mechanisms behind these experimentally observed dynamical properties. The results make experimentally testable predictions for the regime with response robustness and propose a novel explanation of biphasic response constraining the mechanisms for modulation of PhoQ activity by Mg2+ and MgrB. Finally, we show how the interplay of positive and negative feedback loops affects the network’s steady-state sensitivity and response dynamics. In the absence of MgrB feedback, the model predicts oscillations thereby suggesting a general mechanism of oscillatory or pulsatile dynamics in autoregulated TCSs. These results improve the understanding of TCS signaling and other networks with overlaid positive and negative feedback.

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

2021 ◽  
Author(s):  
Anish Hebbar ◽  
Ankush Moger ◽  
Kishore Hari ◽  
Mohit Kumar Jolly
Keyword(s):  
Negative Feedback ◽  
Network Topology ◽  
Positive Feedback ◽  
Biological Networks ◽  
Continuous Model ◽  
Feedback Loops ◽  
Large Networks ◽  
Structural Robustness ◽  
Negative Feedback Loops ◽  
Positive And Negative Feedback

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.

scholarly journals Overlaid positive and negative feedback loops shape dynamical properties of PhoPQ two-component system

2020 ◽  
Author(s):  
Satyajit D Rao ◽  
Oleg A Igoshin
Keyword(s):  
Steady State ◽  
Negative Feedback ◽  
Positive Feedback ◽  
Feedback Loops ◽  
Dynamic Responses ◽  
Negative Feedback Loops ◽  
Two Component ◽  
Positive And Negative Feedback ◽  
Gene Regulatory ◽  
Dynamical Properties

AbstractBacteria use two-component systems (TCSs) to sense environmental conditions and change gene expression to adapt to those conditions. To amplify cellular responses, many bacterial TCSs are under positive feedback control, i.e. increase their own expression when activated. In E. coli, Mg2+-sensing TCS, PhoPQ, in addition to the positive feedback includes a negative feedback via upregulation of MgrB protein that inhibits PhoQ. How interplay of these feedback loops shapes steady state and dynamical responses of PhoPQ TCS to change in Mg2+remains poorly understood. In particular, how the presence of MgrB feedback affects the robustness of PhoPQ response to overexpression of TCS is unclear. It is also unclear why the steady state response to decreasing Mg2+is biphasic, i.e. plateaus over a range of Mg2+concentrations and then increases again at growth-limiting Mg2+. In this study, we use mathematical modeling to identify potential mechanisms behind these experimentally observed dynamical properties. The results make experimentally testable predictions for the regime with response robustness and propose novel explanation of biphasic response constraining the mechanisms for modulation of PhoQ activity by Mg2+and MgrB. Finally, we show how interplay of positive and negative feedback loops affect networks steady-state sensitivity and response dynamics. In the absence of MgrB feedback, the model predicts oscillations thereby suggesting a general mechanism of oscillatory or pulsatile dynamics in autoregulated TCSs. These results help better understanding of TCS signaling and other networks with overlaid positive and negative feedback.Author summaryFeedback loops are commonly observed in bacterial gene-regulatory networks to enable proper dynamical responses to stimuli. Positive feedback loops often amplify the response to stimulus, whereas negative feedback loops are known to speed-up the response and increase robustness. Here we demonstrate how combination of positive and negative feedback in network sensing extracellular ion concentrations affects its steady state and dynamic responses. We utilize published experimental data to calibrate mathematical models of the gene regulatory network. The resulting model quantitatively matches experimentally observed behavior and can make predictions on the mechanism of negative feedback control. Our results show the advantages of such a combination feedback loops and predict the effect of their perturbation on the steady state and dynamic responses. This study improves our understanding of how feedback loops shape dynamical properties of signaling networks.

scholarly journals Enterprise search: A state of the art

2019 ◽  
Vol 36 (2) ◽  
pp. 60-69
Author(s):  
Paul H Cleverley ◽  
Simon Burnett
Keyword(s):  
Oil And Gas ◽  
Search Task ◽  
State Of The Art ◽  
Feedback Loops ◽  
Future Directions ◽  
Business Outcomes ◽  
Technological Advances ◽  
Enterprise Search ◽  
Level Model ◽  
Systems Thinking Approach

Enterprise search is changing. The explosion of information within organizations, technological advances and availability of free OpenSource machine learning libraries offer many possibilities. Eighteen informants from practice, academia, search technology vendors and large organizations (Oil and Gas, Governments, Pharmaceuticals, Aerospace and Retail) were interviewed to assess challenges and future directions. The findings confirmed the existence of the ‘Google Habitus’, technology propaganda and a need to transcend disciplines for a Systems thinking approach toward enterprise search. This encompasses information management, user search literacy, governance, learning feedback loops as well as technology. A novel four-level model for enterprise search use cases is presented, covering search as a utility, search as an answer machine, search task apps and a discovery engine. This could be used to reframe enterprise search perceptions, expanding possibilities and improving business outcomes.

scholarly journals FGF2 Translationally Induced by Hypoxia Is Involved in Negative and Positive Feedback Loops with HIF-1α

PLoS ONE ◽  
2008 ◽  
Vol 3 (8) ◽  
pp. e3078 ◽  
Author(s):  
Caroline Conte ◽  
Elodie Riant ◽  
Céline Toutain ◽  
Françoise Pujol ◽  
Jean-François Arnal ◽  
...  
Keyword(s):  
Positive Feedback ◽  
Feedback Loops
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