Multiple Positive Feedback Research Articles

Biomineralized MnO2 Nanoparticle-Constituted Hydrogels Promote Spinal Cord Injury Repair by Modulating Redox Microenvironment and Inhibiting Ferroptosis.

Spinal cord injury (SCI) is one of the most severe injuries, characterized by multiple positive feedback regulatory signaling networks formed by oxidative stress and inflammation in the injury microenvironment, leading to neuronal cell damage and even death. Here, astragaloside IV (AS), known for its regulatory role in ferroptosis, was encapsulated in the cavity of apoferritin (HFn) after an in situ biomineralization process involving MnO2, resulting in the synthesis of HFn@MnO2/AS nanoparticles. These nanoparticles were then dispersed in chitosan/polyvinyl alcohol/glutaraldehyde/sodium β-glycerophosphate (CGPG) hydrogels to form CGPG-HFn@MnO2/AS injectable thermosensitive hydrogels that can scavenge reactive oxygen species (ROS) in the microenvironment. Our findings indicated that the prepared CGPG-HFn@MnO2/AS hydrogel exhibited remarkable efficacy in scavenging ROS in vitro, effectively ameliorating the oxidative stress microenvironment post-SCI. Furthermore, it inhibited oxidative stress-induced ferroptosis in vitro and in vivo by regulating SIRT1 signaling, thereby promoting neuronal cell migration and repair. Hence, the developed hydrogel combining MnO2 and AS exhibited multifaceted abilities to modulate the pathological microenvironment, providing a promising therapeutic strategy for central nervous system (CNS) diseases.

Abstract A022: Immunotherapy of IL-6R Prevents Relapse and Metastasis of Triple-Negative Breast Cancer

Abstract Multiple Copies in T-cell Malignancy-1 (MCT-1 or MCTS1) is a prognostic biomarker for aggressive breast cancers. Overexpressed MCT-1 stimulates the IL-6/IL-6R/gp130/STAT3 axis, promoting epithelial-to-mesenchymal transition, cancer cell stemness and tumor progression. To study the mechanism underlying TNBC immunity and aggressiveness, TNBC cell lines with different MCT-1 expression levels were evaluated. Primary tumor invasion and postsurgical local recurrence and distant metastasis were assessed in orthotopic syngeneic mice given indicated immunotherapy and/or MCT-1 silencing (shMCT-1). We found that shMCT-1 suppresses the transcriptome of inflammatory response and metastatic signaling in TNBC cells and inhibits TNBC progression, metastasis and mortality in xenograft mice. Combined IL-6R immunotherapy and shMCT-1 effect further decreased intratumoral M2 macrophages and T regulatory cells (Tregs) and avoided postsurgical TNBC expansion. Multiple positive feedback loops of the MCT-1/IL-6/IL-6R/CXCL7/PD-L1 axis were identified in TNBC cells, which boost metastatic niches and immunosuppressive microenvironments. MCT-1high/PD-L1high/CXCL7high and CXCL7high/IL-6high/IL-6Rhigh expression patterns predict worse prognosis and poorer survival in breast cancer patients. IL-6R-based immunotherapy more effectively prevented postsurgical TNBC metastasis, recurrence and mortality than anti-PD-L1 immunotherapy. Anti-IL-6R improved helper T, cytotoxic T and natural killer (NK) cells in lymphatic system and decreased Tregs in the recurrent and metastatic tumors, but anti-PD-L1 incapably elevated NK cells. Combined IL-6R and PD-L1 immunotherapies abridged TNBC cell stemness and M2 macrophage activity better than monotherapy. Sequential immunotherapy of PD-L1 and IL-6R demonstrated the best survival outcome, lowest postoperative recurrence and metastasis than synchronized therapy, particularly in shMCT-1 context. Conclusion: Systemic targeting of the MCT-1/IL-6/IL-6R/CXCL7/PD-L1 interconnection enhances the immune surveillance that inhibits aggressiveness of TNBC. Citation Format: Aushia Tanzih Al Haq, Pao-Pao Yang, Christopher Jin, Jou-Ho Shih, Li-Mei Chen, Lu-Hai Wang, Michael P. Snyder, Hsin-Ling Hsu. Immunotherapy of IL-6R Prevents Relapse and Metastasis of Triple-Negative Breast Cancer [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Tumor Immunology and Immunotherapy; 2023 Oct 1-4; Toronto, Ontario, Canada. Philadelphia (PA): AACR; Cancer Immunol Res 2023;11(12 Suppl):Abstract nr A022.

Agentic processes in cultural evolution: relevance to Anthropocene sustainability

Humans have evolved culturally and perhaps genetically to be unsustainable. We exhibit a deep and consistent pattern of short-term resource exploitation behaviours and institutions. We distinguish agentic and naturally selective forces in cultural evolution. Agentic forces are quite important compared to the blind forces (random variation and natural selection) in cultural evolution and gene-culture coevolution. We need to use the agentic policy-making processes to evade the impact of blind natural selection. We argue that agentic forces became important during our Pleistocene history and into the Anthropocene present. Human creativity in the form of deliberate innovations and the deliberate selective diffusion of technical and social advances drove this process forward for a long time before planetary limits became a serious issue. We review models with multiple positive feedbacks that roughly fit this observed pattern. Policy changes in the case of large-scale existential threats like climate change are made by political and diplomatic agents grasping and moving levers of institutional power in order to avoid the operation of blind natural selection and agentic forces driven by narrow or short-term goals. This article is part of the theme issue ‘Evolution and sustainability: gathering the strands for an Anthropocene synthesis’.

Assessing the Robustness of Arctic Sea Ice Bi‐Stability in the Presence of Atmospheric Feedbacks

AbstractArctic sea‐ice loss is influenced by multiple positive feedbacks, sparking concerns of accelerated loss in the coming years or even a tipping point, where a sea‐ice equilibrium disappears at a given CO2 value and sea ice rapidly evolves to a new steady state. Such a tipping point would imply a bi‐stability of the Arctic climate—where multiple steady‐state Arctic climates are possible at the same CO2 value. Previous works have sought to establish the existence of bi‐stability using a range of models, from zero‐dimensional sea ice thermodynamic models to fully coupled global climate models, with conflicting results. Here, we present a new model of the Arctic that includes both sea‐ice thermodynamics and key atmospheric feedbacks in a simple framework. We exploit the model's simplicity to identify physical mechanisms that control the timing and extent of sea‐ice bi‐stability, and the abruptness of ice loss. We show that longwave radiation feedbacks can have a strong influence on Arctic surface climate from atmospheric temperature increases alone, even without major contributions from clear‐sky moisture or convective clouds suggested previously. While winter sea‐ice bi‐stability is robust to changes in uncertain model parameters in this study, summer sea ice is more sensitive. Finally, our model indicates that positive feedbacks may modulate the CO2 threshold of sea‐ice loss and the width of bi‐stability much more strongly than the abruptness of loss. These results lead to a comprehensive understanding of the conditions that favor Arctic sea‐ice bi‐stability, particularly the role of atmospheric feedbacks, in both future and past climates.

Top‐Down Regulation by a Reindeer Herding System Limits Climate‐Driven Arctic Vegetation Change at a Regional Scale

AbstractWarming‐driven growth of tall woody vegetation in the Arctic has the potential to accelerate climate change through multiple positive feedbacks. Local‐scale evidence suggests that large herbivores limit this vegetation shift, but there is uncertainty at larger, regional scales whether current herbivory pressure is a major top‐down control on ecosystem structure and functioning. Across a 67,000 km2 region of the Yamal Peninsula in West Siberia, we integrated satellite remote sensing with a novel data set mapping the migrations of herds comprising 151,000 domesticated reindeer. Where reindeer numbers varied over space, higher reindeer herbivory pressure was consistently linked with lower coverage of tall woody vegetation. Within areas dominated by this vegetation type, productivity and climate were increasingly decoupled where reindeer density was higher. Our spaceborne fingerprint detection suggests that large herbivores, at current population densities, counteract Arctic vegetation responses to climate change over large spatial scales.

Virtuous cycles and research for a regenerative urban ecology: The case of urban wood systems in Baltimore

The field of urban ecology has progressed since the mid-1990s through four major phases: an ecology in, of, for, and with cities. This progression reflects an interest to address the complexity of urban systems with social-ecological approaches. Further, this progression signifies an interest to address societal issues by co-designing and co-producing research in collaboration with diverse stakeholders from government, non-governmental organizations (NGOs), businesses, and community associations. What remains unaddressed in this progression is a research mission orientation. While there may be a range of goals for an ecology with cities, a focus on regenerative urban ecologies is crucial. Regenerative ecologies may be seen as an endpoint along a continuum from degenerative ecologies to sustainability to regenerative ecologies. Regenerative ecologies rely upon feedback loops, similar to coral reefs and climax forests. In urban systems, these feedbacks in social-ecological systems may be considered virtuous cycles that create reinforcing, positive benefits for people and nature over time. Virtuous cycles or feedbacks are often conceived as a singular, positive feedback loop. However, virtuous cycles may be most impactful, adaptive, and resilient when they contain multiple positive and negative feedbacks and synergies. Research has several important roles in advancing virtuous cycles and regenerative urban ecologies. In this paper, we use our urban wood systems project in Baltimore as both a case study and model to illustrate an approach and lessons learned for regenerative ecologies, virtuous cycles, and the role of research. We conclude with lessons learned and consider opportunities and constraints for virtuous cycles, research, and regenerative urban ecologies in Baltimore and to other urban systems.

Modern Semi-Active Control Schemes for a Suspension with MR Actuator for Vibration Attenuation

This article describes semi-active modern control schemes for a quarter-vehicle suspension with a magnetorheological damper (MRD) to attenuate vibrations and simultaneously improve the passenger comfort and the vehicle road-holding. The first solution is a multiple positive position feedback (MPPF) control scheme to attenuate the vibration amplitude at the two modal frequencies. The second solution is based on elementary passivity considerations on the exact regulation error dynamics passive output. The passive output feedback is used to improve the control aims. Finally, the third solution deals with a disturbance rejection control (DRC) based on an extended state observer. The three proposed control schemes consider an inverse polynomial model of a commercial MRD for numerical implementation and are evaluated by comfort and road-holding performance indexes proposed in the literature. Furthermore, the effects of variation in the sprung mass (emulating different number of passengers) on the controllers’ performance is analysed. The numerical results show in both scenarios (constant and variable sprung mass) that passivity based control (PBC) and DRC improve the performance indexes compared with the classical sky-hook control and the open-loop systems with a different constant current input for the MRD. Obtained results for damping force and power consumption are within the operation range of the considered commercial MRD showing the viability for experimental implementation of the proposed control schemes.

Arctic crustose coralline alga resilient to recent environmental change

AbstractRising atmospheric carbon dioxide is warming Arctic seawater at a rate twice the global average due to multiple positive feedbacks. Thus, warming is disproportionately influencing data‐poor Arctic marine ecosystems. Subarctic flora are an important component of these ecosystems, along with the less biodiverse flora endemic to the Arctic. Warming will likely lead to an increasing dominance of subarctic flora that will be initially successful due to a shorter sea ice period. Benthic crustose coralline algae presently flourishes in subarctic regions where they are key substrate builders that influence community structure through provision of habitat for a variety of benthic organisms. Here we evaluate changes in the skeletal resilience of long‐lived subarctic crustose coralline alga Clathromorphum compactum to variability in seawater temperature and sea ice (the later which influences salinity and solar irradiance reaching the seafloor) across latitudes in the northwest Atlantic and Arctic Oceans. We demonstrate that average growth and calcification rate significantly decreases in C. compactum toward higher latitudes due to colder temperatures and more fresh waters. Skeletal density also declines toward higher latitudes but displays specimen‐specific variability. However, through a common growth period (1984–2001), density increased at all locations which we interpret to be a response to warmer and more well‐lit benthic environments. At the most northerly site, growth and calcification also increased with density, suggesting warming and declining Arctic sea ice in the spring may benefit this species at its upper latitudinal limits. As a result, continued warming may enhance the presence of C. compactum in Arctic regions.

Understanding MAPK Signaling Pathways in Apoptosis.

MAPK (mitogen-activated protein kinase) signaling pathways regulate a variety of biological processes through multiple cellular mechanisms. In most of these processes, such as apoptosis, MAPKs have a dual role since they can act as activators or inhibitors, depending on the cell type and the stimulus. In this review, we present the main pro- and anti-apoptotic mechanisms regulated by MAPKs, as well as the crosstalk observed between some MAPKs. We also describe the basic signaling properties of MAPKs (ultrasensitivity, hysteresis, digital response), and the presence of different positive feedback loops in apoptosis. We provide a simple guide to predict MAPKs’ behavior, based on the intensity and duration of the stimulus. Finally, we consider the role of MAPKs in osmostress-induced apoptosis by using Xenopus oocytes as a cell model. As we will see, apoptosis is plagued with multiple positive feedback loops. We hope this review will help to understand how MAPK signaling pathways engage irreversible cellular decisions.

Clusters, economic performance, and social cohesion: a system dynamics approach

ABSTRACT Cluster policies pervade all regions of the world to promote employment growth, innovation and entrepreneurship. Yet, research mostly focuses on cluster economic performance, but less on regional social cohesion, which is important when economic growth coexists with deprivation, poverty and inequality. The paper’s aim is to understand both the economic and the social dynamics of clusters by developing a theoretical model based on system dynamics. It shows that clusters with positive economic performance do not necessarily lead to regional social cohesion. Multiple positive economic-related feedback processes can be mitigated by negative social-related feedback processes. Implications for academics and policy-makers are proposed.

Towards a City-Based Cultural Ecosystem Service Innovation Framework as Improved Public-Private-Partnership Model—A Case Study of Kaohsiung Dome

This paper explains the concept of a city-based cultural ecosystem service, and how innovations and systematic operations management can help an international city to improve the efficiency and effectiveness of the Public-Private Partnership (PPP) model. Previous studies suggest that most of the PPP models focus on the operation and analysis of PPP construction projects, limited attention of the subsequent operations and management for PPP facilities. This paper thus proposed an integrated PPP management framework with the principles of Cultural Ecosystem Service (CES) and open innovation to support better operations management of PPP projects. While the management of modern PPP projects will inevitably encounter the challenges of cross-disciplinary management and service innovation in the period of operations management, Cultural Ecosystem Service Innovation (CESI) framework is useful to support the practice and continuous improvement. A real-world case of Kaohsiung Dome in Taiwan has been benchmarked and analyzed with empirical data. With in-depth expert interviews, the paper demonstrates the use of CESI framework to support business strategy and operations management for sustainable system development and shared values. Management implications were addressed to promote multiple positive feedbacks with the government, enterprises, and the general public and jointly strive to support the development of a benchmarked city.

Quantitative proteomic profiling of extracellular matrix and site-specific collagen post-translational modifications in an in vitro model of lung fibrosis

Lung fibrosis is characterized by excessive deposition of extracellular matrix (ECM), in particular collagens, by fibroblasts in the interstitium. Transforming growth factor-β1 (TGF-β1) alters the expression of many extracellular matrix (ECM) components produced by fibroblasts, but such changes in ECM composition as well as modulation of collagen post-translational modification (PTM) levels have not been comprehensively investigated. Here, we performed mass spectrometry (MS)-based proteomics analyses to assess changes in the ECM deposited by cultured lung fibroblasts from idiopathic pulmonary fibrosis (IPF) patients upon stimulation with transforming growth factor β1 (TGF-β1). In addition to the ECM changes commonly associated with lung fibrosis, MS-based label-free quantification revealed profound effects on enzymes involved in ECM crosslinking and turnover as well as multiple positive and negative feedback mechanisms of TGF-β1 signaling. Notably, the ECM changes observed in this in vitro model correlated significantly with ECM changes observed in patient samples. Because collagens are subject to multiple PTMs with major implications in disease, we implemented a new bioinformatic platform to analyze MS data that allows for the comprehensive mapping and site-specific quantitation of collagen PTMs in crude ECM preparations. These analyses yielded a comprehensive map of prolyl and lysyl hydroxylations as well as lysyl glycosylations for 15 collagen chains. In addition, site-specific PTM analysis revealed novel sites of prolyl-3-hydroxylation and lysyl glycosylation in type I collagen. Interestingly, the results show, for the first time, that TGF-β1 can modulate prolyl-3-hydroxylation and glycosylation in a site-specific manner. Taken together, this proof of concept study not only reveals unanticipated TGF-β1 mediated regulation of collagen PTMs and other ECM components but also lays the foundation for dissecting their key roles in health and disease.The proteomic data has been deposited to the ProteomeXchange Consortium via the MassIVE partner repository with the data set identifier MSV000082958.

Flexible-link robots with combined trajectory tracking and vibration control

This work deals with asymptotic trajectory tracking and active damping injection on a flexible-link robot by application of Multiple Positive Position Feedback. The flexible-link robot is modeled and validated by using finite element methods and experimental modal analysis, and then a reduced order model of the flexible-link robot dynamics, up to the first dominant vibration modes, is employed for experimental evaluation on a test rig. Then, a combined control scheme is synthesized in two parts: first, a Sliding-Mode Control based on a cascaded Proportional-Integral-Derivative for regulation and trajectory tracking tasks, via a direct current motor torque as the control input for the overall system dynamics, and, second, a Multiple Positive Position Feedback for active vibration control and attenuation of residual vibrations on the tip position, via the input voltage applied to a piezoelectric patch actuator attached directly on the flexible beam. The results are evaluated on an experimental platform, where the dynamic performance of the overall active vibration control scheme leads to fast and effective tracking results, with damping ratios increased up to 300%.

Substrate concentration effect on gene expression in genetic circuits with additional positive feedback

In gene regulatory networks, gene regulation loops often occur with multiple positive feedback, multiple negative feedback and coupled positive and negative feedback forms. In above gene regulation loops, auto-activation loops are ubiquitous regulatory motifs. This paper aims to investigate a two-component dual-positive feedback genetic circuit, which consists of a double negative feedback circuit and an additional positive feedback loop (APFL). We study effect of substrate concentration on gene expression in the single and the networked systems with APFLs, respectively. We find that substrate concentration can tune stochastic switch behavior in the signal system and then we explore relationship of substrate concentration with positive feedback strength in aspect of stochastic switch behavior. Furthermore, we also discuss gene expression and stochastic switch behavior in the networked systems with APFLs. Based on analysis in the networked systems, we discover that genes express in some specific cells and do not express in the other cells when the expression achieves its steady state. These results can be used to well explain the character of regionalization in the expression of genes and the phenomenon of gene differentiation.

Digital signaling network drives the assembly of the AIM2-ASC inflammasome

The AIM2-ASC inflammasome is a filamentous signaling platform essential for mounting host defense against cytoplasmic dsDNA arising not only from invading pathogens but also from damaged organelles. Currently, the design principles of its underlying signaling network remain poorly understood at the molecular level. We show here that longer dsDNA is more effective in inducing AIM2 assembly, its self-propagation, and downstream ASC polymerization. This observation is related to the increased probability of forming the base of AIM2 filaments, and indicates that the assembly discerns small dsDNA as noise at each signaling step. Filaments assembled by receptor AIM2, downstream ASC, and their joint complex all persist regardless of dsDNA, consequently generating sustained signal amplification and hysteresis. Furthermore, multiple positive feedback loops reinforce the assembly, as AIM2 and ASC filaments accelerate the assembly of nascent AIM2 with or without dsDNA. Together with a quantitative model of the assembly, our results indicate that an ultrasensitive digital circuit drives the assembly of the AIM2-ASC inflammasome.

Parallel arrangements of positive feedback loops limit cell-to-cell variability in differentiation.

Cellular differentiations are often regulated by bistable switches resulting from specific arrangements of multiple positive feedback loops (PFL) fused to one another. Although bistability generates digital responses at the cellular level, stochasticity in chemical reactions causes population heterogeneity in terms of its differentiated states. We hypothesized that the specific arrangements of PFLs may have evolved to minimize the cellular heterogeneity in differentiation. In order to test this we investigated variability in cellular differentiation controlled either by parallel or serial arrangements of multiple PFLs having similar average properties under extrinsic and intrinsic noises. We find that motifs with PFLs fused in parallel to one another around a central regulator are less susceptible to noise as compared to the motifs with PFLs arranged serially. Our calculations suggest that the increased resistance to noise in parallel motifs originate from the less sensitivity of bifurcation points to the extrinsic noise. Whereas estimation of mean residence times indicate that stable branches of bifurcations are robust to intrinsic noise in parallel motifs as compared to serial motifs. Model conclusions are consistent both in AND- and OR-gate input signal configurations and also with two different modeling strategies. Our investigations provide some insight into recent findings that differentiation of preadipocyte to mature adipocyte is controlled by network of parallel PFLs.

Multiscale positive feedbacks contribute to unidirectional gastric disease progression induced by helicobacter pylori infection

BackgroundHelicobacter Pylori (HP) is the most common risk factor for gastric cancer. Nearly half the world’s population is infected with HP, but only a small percentage of those develop significant pathology. The bacteria itself does not directly cause cancer; rather it promotes an environment that is conducive to tumor formation. Upon infection, HP induces transcriptional changes in the host, leading to enhanced proliferation and host immune response. In addition, HP causes direct damage to gastric epithelial cells.ResultsWe present a multiscale mechanistic model of HP induced changes. The model includes four modules representing the host transcriptional changes in response to infection, gastric atrophy, the Hedgehog pathway response, and the restriction point that controls cell cycle. This model was able to recapture a number of literature reported observations and was used as an “in silico” representation of the biological system for further analysis. Dynamical analysis of the model revealed that HP might induce the activation of multiple interplayed positive feedbacks, which in turn might result in a “ratchet ladder” system that promotes a unidirectional progression of gastric disease.ConclusionsThe current multiscale model is able to recapitulate the observed experimental features of HP host interactions and provides dynamic insights on the epidemiologically observed heterogeneity in disease progression. This model provides a solid framework that can be further expanded and validated to include additional experimental evidence, to understand the complex multi-pathway interactions characterizing HP infection, and to design novel treatment protocols for HP induced diseases.

Bi-stability in type 2 diabetes mellitus multi-organ signalling network.

Type 2 diabetes mellitus (T2DM) is believed to be irreversible although no component of the pathophysiology is irreversible. We show here with a network model that the apparent irreversibility is contributed by the structure of the network of inter-organ signalling. A network model comprising all known inter-organ signals in T2DM showed bi-stability with one insulin sensitive and one insulin resistant attractor. The bi-stability was made robust by multiple positive feedback loops suggesting an evolved allostatic system rather than a homeostatic system. In the absence of the complete network, impaired insulin signalling alone failed to give a stable insulin resistant or hyperglycemic state. The model made a number of correlational predictions many of which were validated by empirical data. The current treatment practice targeting obesity, insulin resistance, beta cell function and normalization of plasma glucose failed to reverse T2DM in the model. However certain behavioural and neuro-endocrine interventions ensured a reversal. These results suggest novel prevention and treatment approaches which need to be tested empirically.

Feedback Loops of the Mammalian Circadian Clock Constitute Repressilator.

Mammals evolved an endogenous timing system to coordinate their physiology and behaviour to the 24h period of the solar day. While it is well accepted that circadian rhythms are generated by intracellular transcriptional feedback loops, it is still debated which network motifs are necessary and sufficient for generating self-sustained oscillations. Here, we systematically explore a data-based circadian oscillator model with multiple negative and positive feedback loops and identify a series of three subsequent inhibitions known as “repressilator” as a core element of the mammalian circadian oscillator. The central role of the repressilator motif is consistent with time-resolved ChIP-seq experiments of circadian clock transcription factors and loss of rhythmicity in core clock gene knockouts.

Network motifs modulate druggability of cellular targets.

Druggability refers to the capacity of a cellular target to be modulated by a small-molecule drug. To date, druggability is mainly studied by focusing on direct binding interactions between a drug and its target. However, druggability is impacted by cellular networks connected to a drug target. Here, we use computational approaches to reveal basic principles of network motifs that modulate druggability. Through quantitative analysis, we find that inhibiting self-positive feedback loop is a more robust and effective treatment strategy than inhibiting other regulations, and adding direct regulations to a drug-target generally reduces its druggability. The findings are explained through analytical solution of the motifs. Furthermore, we find that a consensus topology of highly druggable motifs consists of a negative feedback loop without any positive feedback loops, and consensus motifs with low druggability have multiple positive direct regulations and positive feedback loops. Based on the discovered principles, we predict potential genetic targets in Escherichia coli that have either high or low druggability based on their network context. Our work establishes the foundation toward identifying and predicting druggable targets based on their network topology.