It is well established that microRNA-21 (miR-21) targets phosphatase and tensin homolog (PTEN), facilitating epithelial-to-mesenchymal transition (EMT) and drug resistance in cancer. Recent evidence indicates that PTEN activates its pseudogene-derived long non-coding RNA, PTENP1, which in turn inhibits miR-21. However, the dynamics of PTEN, miR-21, and PTENP1 in the DNA damage response (DDR) remain unclear. Thus, we propose a dynamic Boolean network model by integrating the published literature from various cancers. Our model shows good agreement with the experimental findings from breast cancer, hepatocellular carcinoma (HCC), and oral squamous cell carcinoma (OSCC), elucidating how DDR activation transitions from the intra-S phase to the G2 checkpoint, leading to a cascade of cellular responses such as cell cycle arrest, senescence, autophagy, apoptosis, drug resistance, and EMT. Model validation underscores the roles of PTENP1, miR-21, and PTEN in modulating EMT and drug resistance. Furthermore, our analysis reveals nine novel feedback loops, eight positive and one negative, mediated by PTEN and implicated in DDR cell fate determination, including pathways related to drug resistance and EMT. Our work presents a comprehensive framework for investigating cellular responses following DDR, underscoring the therapeutic potential of targeting PTEN, miR-21, and PTENP1 in cancer treatment.

This paper presents causal loop diagrams (CLDs) as tools for studying complex public health problems like health inequality. These problems often involve feedback loops-a characteristic of complex systems not fully integrated into mainstream epidemiology. CLDs are conceptual models that visualize connections between system variables. They are commonly developed through literature reviews or participatory methods with stakeholder groups. These diagrams often uncover feedback loops among variables across scales (e.g. biological, psychological and social), facilitating cross-disciplinary insights. We illustrate their use through a case example involving the feedback loop between sleep problems and depressive symptoms. We outline a typical step-by-step process for developing CLDs in epidemiology. These steps are defining a specific problem, identifying the key system variables involved, mapping these variables and analysing the CLD to find new insights and possible intervention targets. Throughout this process, we suggest triangulating between diverse sources of evidence, including domain knowledge, scientific literature and empirical data. CLDs can also be evaluated to guide policy changes and future research by revealing knowledge gaps. Finally, CLDs may be iteratively refined as new evidence emerges. We advocate for more widespread use of complex systems tools, like CLDs, in epidemiology to better understand and address complex public health problems.

Structural equation models (SEMs) involving feedback loops may offer advantages over standard instrumental variables estimators in terms of modelling causal effects in the presence of bidirectional relationships. In the following note, we show that in the case of a single \"exposure\" and \"outcome\" variable, modelling relationships using a SEM with a simple bidirectional linear feedback loop offers no advantage over traditional instrumental variables estimators in terms of consistency (i.e. both approaches yield consistent estimates of the causal effect, provided that causal estimates are obtained in both directions). In the case of finite samples, traditional IV estimators and SEM exhibited similar power across many of the conditions we examined, although which method performed best depended on the residual correlation between variables and the strength of the instruments. In particular, the power of SEM was insensitive to the residual correlation between variables, whereas the power of the Wald estimator/2SLS improved (deteriorated) relative to SEM as the magnitude of the residual correlation increased (decreased) assuming a positive causal effect of the exposure on the outcome. The power of SEM improved relative to the Wald estimator/2SLS as the instruments explained more residual variance in the \"outcome\" variable.

BACKGROUND: Population physical activity promotion (PPAP) is one of the most effective noncommunicable disease prevention strategies, yet coordination is lacking around the world. Whole-of-system approaches and complex systems methods are called for to advance PPAP. This paper reports on a project which (1) used an Attributes Framework with system mapping (group model building and causal loop diagramming of feedback loops) and (2) identified potential leverage points to address the challenge of effective coordination of multisectoral PPAP in British Columbia.
METHODS: Key findings from stakeholder interviews and workshops described the current system for PPAP in terms of attributes and dimensions in the framework. These were translated into variables and used in group model building. Participants prioritized the importance of variables to address the coordination challenge and then created causal loop diagrams in 3 small groups. One collective causal loop diagram was created, and top priority variables and associated feedback loops were highlighted to explore potential leverage points.
RESULTS: Leverage points included the relationships and feedback loops among priority variables: political leadership, visible policy support and governance, connectivity for knowledge translation, collaborative multisector grants, multisector collaboration, and integrating co-benefits. Leveraging and altering \"vicious\" cyclical patterns to increase coordinated multisector PPAP are key.
CONCLUSIONS: The Attributes Framework, group model building and causal loop diagrams, and emergent feedback loops were useful to explore potential leverage points to address the challenge of multisectoral coordination of PPAP. Future research could apply the same methods in other jurisdictions and compare and contrast resultant frameworks, variables, feedback loops, and leverage points.

Circadian rhythms are generated by complex interactions among genes and proteins. Self-sustained ∼24 h oscillations require negative feedback loops and sufficiently strong nonlinearities that are the product of molecular and network switches. Here, we review common mechanisms to obtain switch-like behavior, including cooperativity, antagonistic enzymes, multisite phosphorylation, positive feedback, and sequestration. We discuss how network switches play a crucial role as essential components in cellular circadian clocks, serving as integral parts of transcription-translation feedback loops that form the basis of circadian rhythm generation. The design principles of network switches and circadian clocks are illustrated by representative mathematical models that include bistable systems and negative feedback loops combined with Hill functions. This work underscores the importance of negative feedback loops and network switches as essential design principles for biological oscillations, emphasizing how an understanding of theoretical concepts can provide insights into the mechanisms generating biological rhythms.

The increased movement of humans throughout the world allowed the transportation of several species, such as Moringa oleifera Lam. (moringa), into biomes far away from their native habitation. Native to India, moringa is a versatile, drought-tolerant, and fast-growing tree that is easily adaptable to wide-ranging tropical and sub-tropical conditions around the world. It is used in cosmetics, as food and medicine for humans, livestock feed, crop biostimulant, and green manure. Even though moringa is an alien species to South Africa, its production is increasing, and its numerous uses are recognised by communities. Moringa forms part of a highly complex (social, ecological, and economic) system. This is because it is on the Species Under Surveillance for Possible Eradication or Containment Targets (SUSPECT) list under the National Environmental Management Biodiversity Act (NEM:BA) of South Africa. Listing species that are regarded as beneficial to communities on national regulations can cause conflicts and uncertainties among various stakeholders (i.e., environmental policymakers, farmers, rural communities, and government bodies). In this paper, a systems thinking approach was applied to address complex and conflicting issues linked to the production and overall status (economic, ecological, legal, and social) of moringa in South Africa. The Causal Loop Diagram (CLD) was developed to present a broad insight into the complexity of moringa in South Africa and assist in underscoring the feedback mechanisms within the system. Moreover, the CLD indicated that the position of moringa within the country comprised a variety of interdependent variables of government policies, environment, and society, which are interconnected into a multifaceted system. The potential conflict dimensions and types associated with allocating moringa an impact category within the South African context were identified, and this may serve as a useful tool for facilitating engagements and decision-making processes among stakeholders in resolving the status of moringa in South Africa.

The endoplasmic reticulum (ER) plays a crucial role in cellular homeostasis. When ER stress is generated, an autophagic self-digestive process is activated to promote cell survival; however, cell death is induced in the case of excessive levels of ER stress. The aim of the present study was to investigate the effect of a natural compound called sulforaphane (SFN) upon ER stress. Our goal was to investigate how SFN-dependent autophagy activation affects different stages of ER stress induction. We approached our scientific analysis from a systems biological perspective using both theoretical and molecular biological techniques. We found that SFN induced the various cell-death mechanisms in a concentration- and time-dependent manner. The short SFN treatment at low concentrations promoted autophagy, whereas the longer treatment at higher concentrations activated cell death. We proved that SFN activated autophagy in a mTORC1-dependent manner and that the presence of ULK1 was required for its function. A low concentration of SFN pre- or co-treatment combined with short and long ER stress was able to promote cell survival via autophagy induction in each treatment, suggesting the potential medical importance of SFN in ER stress-related diseases.

Feedback-controlled chemical reaction networks (FCRNs) are indispensable for various biological processes, such as cellular mechanisms, patterns, and signaling pathways. Through the intricate interplay of many feedback loops (FLs), FCRNs maintain a stable internal cellular environment. Currently, creating minimalistic synthetic cells is the long-term objective of systems chemistry, which is motivated by such natural integrity. The design, kinetic optimization, and analysis of FCRNs to exhibit functions akin to those of a cell still pose significant challenges. Indeed, reaching synthetic homeostasis is essential for engineering synthetic cell components. However, maintaining homeostasis in artificial systems against various agitations is a difficult task. Several biological events can provide us with guidelines for a conceptual understanding of homeostasis, which can be further applicable in designing artificial synthetic systems. In this regard, we organize our review with artificial homeostasis systems driven by FCRNs at different length scales, including homogeneous, compartmentalized, and soft material systems. First, we stretch a quick overview of FCRNs in different molecular and supramolecular systems, which are the essential toolbox for engineering different nonlinear functions and homeostatic systems. Moreover, the existing history of synthetic homeostasis in chemical and material systems and their advanced functions with self-correcting, and regulating properties are also emphasized.

Understanding how phytoplankton interacts with local and regional drivers as well as their feedbacks is a great challenge, and quantitative analyses of the regulating role of human activities and climate changes on these feedback loops are also limited. By using monthly monitoring dataset (2000-2017) from Lake Taihu and empirical dynamic modelling to construct causal networks, we quantified the strengths of causal feedbacks among phytoplankton, local environments, zooplankton, meteorology as well as global climate oscillation. Prevalent bidirectional causal linkages between phytoplankton biomass (chlorophyll a) and the tested drivers were found, providing holistic and quantitative evidence of the ubiquitous feedback loops. Phytoplankton biomass exhibited the highest feedbacks with total inorganic nitrogen and ammonia and the lowest with nitrate. The feedbacks between phytoplankton biomass and environmental factors from 2000 to 2017 could be classified into two groups: the local environments (e.g., nutrients, pH, transparency, zooplankton biomass)-driven enhancement loops promoting the response of the phytoplankton biomass, and the climate (e.g., wind speed)-driven regulatory loops suppressing it. The two counterbalanced groups modified the emergent macroecological patterns. Our findings revealed that the causal feedback networks loosened significantly after 2007 following nutrient loading reduction and unsuccessful biomanipulation restoration attempts by stocking carp. The strength of enhancement loops underwent marked decreases leading to reduced phytoplankton responses to the tested drivers, while the climate (decreasing wind speed, warming winter)-driven regulatory loops increased- like a tug-of-war. To counteract the self-amplifying feedback loops, the present eutrophication mitigation efforts, especially nutrient reduction, should be continued, and introduction of alternative measures to indirectly regulate the critical components (e.g., pH, Secchi depth, zooplankton biomass) of the loops would be beneficial.

Burn-out leads to reduced worker well-being, long-term absenteeism, and high costs for employers and society. Determinants at different levels may affect burn-out in an interrelated and dynamic manner. The aim of the present study was to apply a broader systems perspective by exploring and visualizing the complex system of determinants at different levels (living conditions, working conditions, and societal developments) underlying the prevalence of burn-out in the Netherlands.
During three group model building (GMB) sessions with in total eight experts on workers\' mental health, a causal loop diagram (CLD) was developed and relevant feedback loops were identified. For the selection of determinants to be included in the CLD a recently published overview of determinants on burn-out at different levels was used. Experts could also add factors that were not listed in the overview.
The final CLD consists of 20 factors and depicts a central position of working conditions. Societal developments (e.g., access to mental health care, size of the working population, rougher social climate, etc.) were mostly located at the outside of the CLD and barely integrated in feedback loops. Several reinforcing feedback loops resulting in an increase of the prevalence of burn-out were identified in which the factors (very) high workload, imbalance between work and private life, and insufficient recovery time play an important role. Also, several balancing loops were found that visualize the crucial role of functional support from supervisors to prevent burn-out among workers.
Applying a broader systems perspective, including determinants at different levels, offers new insights into dynamic feedback loops that contribute to the prevalence of burn-out. Supervisors, amongst others, have a considerable impact on the system underlying the high prevalence of burn-out and may therefore contribute to its prevention. Even though societal developments were less integrated in feedback loops, they might be considered drivers of existing feedback loops. The results from this study confirm that determinants at various levels underly the prevalence of burn-out. To be able to address the diversity of determinants underlying a high prevalence of burn-out, a complex system approach can be helpful.