Multiple Feedback Loops Research Articles

Fuzzy Multiple Hidden Layer Neural Sliding Mode Control of Active Power Filter With Multiple Feedback Loop

A fuzzy multiple hidden layer neural sliding mode control with multiple feedback loop (FMHLNSMCMFL) is proposed for a single-phase active power filter (APF), where a sliding mode controller is designed to make the current tracking error converge to zero and a new neural network with multiple feedback loops is introduced to approximate unknown dynamics. At the same time, the fuzzy neural network can eliminate chattering, improve the control accuracy and reduce the current distortion rate of APF. Moreover, the proposed double feedback fuzzy double hidden layer recurrent neural network is the weighted sum of fuzzy network and double hidden layer network and has strong global learning ability. The adaptive parameters obtained by Lyapunov function can ensure the asymptotic stability of the system. Simulation and hardware experiments verify the introduced FMHLNSMCMFL scheme is a viable control solution for the APF.

Research on the circadian clock gene HNF4a in different malignant tumors.

Background: The circadian rhythm is produced by multiple feedback loops formed by the core clock genes after transcription and translation, thus regulating various metabolic and physiological functions of the human body. We have shown previously that the abnormal expression of 14 clock genes is related closely to the occurrence and development of different malignant tumors, and these genes may play an anti-cancer or pro-cancer role in different tumors. HNF4a has many typical properties of clock proteins involved in the clock gene negative feedback loop regulation process. We need to explore the function of HNF4a as a circadian clock gene in malignant tumors further. Methods: We used The Cancer Genome Atlas (TCGA) database to download the clinicopathological information of twenty malignant tumors and the corresponding RNA-seq data. The HNF4a RNA-seq data standardized by R language and clinical information were integrated to reveal the relationship between HNF4a and prognosis of patients. Results: Analysis of TCGA data showed that the prognosis of HNF4a was significantly different in BLCA, KIRC, LUSC, and READ. High HNF4a expression is correlated with good prognosis in BLCA, KIRC, and READ but poor prognosis in LUSC. However, HNF4a was associated with the stages, T stages, and lymph node status only in BLCA. Conclusions: HNF4a plays different roles in different malignancies, and the abnormal expression of HNF4a has a great correlation with the biological characteristics of BLCA. The low expression of HNF4a could be a reference index for the metastasis, recurrence, and prognosis of BLCA.

Achieving Education Excellence Through Teacher–Student Duality: An Analysis of NIRF Scores

In the service industry, to get the satisfactory quality outcome, both the customer and server play an important role. It is not a one-way process but a series of multiple continuous feedback loops that define the outcome. The demand levels set between both the customer and server decide whether the result will be extraordinary or ordinary. In the education sector, the customer is the student and the teacher is the server. It would be interesting to analyse this relationship and study its impact. The idea is to use the established, nationally recognized measurement criteria like National Institutional Ranking Framework (NIRF). This system has defined different criteria, of which 50% weightage has been given to teacher and student quality, named as Research and Professional Practice (RP) and Graduation Outcomes (GO). Statistical tools were used to analyse and compare the input criteria and their impact on the outcome. This attempt establishes the relationship between the teacher and student and the importance of the customer–server duality.

STAT3 regulates miR93-mediated apoptosis through inhibiting DAPK1 in renal cell carcinoma.

Signal transducer and activator of transcription 3 (STAT3) is an essential member of the STAT family. STAT3 regulates diverse genes that mediate inflammatory reactions, cell survival, proliferation, and angiogenesis, and it is aberrantly upregulated and activated in various types of malignancies. Furthermore, STAT3 signalling is involved in multiple feedback loops and pathways. In this study, we demonstrate that miR-93-3p plays an oncogenic role in renal cell carcinoma (RCC) by enhancing RCC cell proliferation and suppressing apoptosis. In addition, STAT3 can regulate the transcription of miR-93 by directly binding its promoter region. miR-93 can inhibit death-associated protein kinase 1 (DAPK1) at the protein level. Moreover, STAT3 can block DAPK1 expression at the RNA level. Importantly, we verified that DAPK1 overexpression in turn suppresses the entry of activated STAT3 into the cell nucleus. Thus, this study reveals a potential continuously activated signalling transduction pathway, STAT3-miR93-DAPK1, and may provide a novel clinical therapeutic approach for RCC.

QD/2D Hybrid Nanoscrolls: A New Class of Materials for High-Performance Polarized Photodetection and Ultralow Threshold Laser Action.

Nanoscrolls are a class of nanostructures where atomic layers of 2D materials are stacked consecutively in a coaxial manner to form a 1D spiral topography. Self-assembly of chemical vapor deposition grown 2D WS2 monolayer into quasi-1D van der Waals scroll structure instigates a plethora of unique physiochemical properties significantly different from its 2D counterparts. The physical properties of such nanoscrolls can be greatly manipulated upon hybridizing them with high-quantum-yield colloidal quantum dots, forming 0D/2D structures. The efficient dissociation of excitons at the heterojunctions of QD/2D hybridized nanoscrolls exhibits a 3000-fold increased photosensitivity compared to the pristine 2D-material-based nanoscroll. The synergistic effects of confined geometry and efficient QD scatterers produce a nanocavity with multiple feedback loops, resulting in coherent lasing action with an unprecedentedly low lasing threshold. Predominant localization of the excitons along the circumference of this helical scroll results in a 12-fold brighter emission for the parallel-polarized transition compared to the perpendicular one, as confirmed by finite-difference time-domain simulation. The versatility of hybridized nanoscrolls and their unique properties opens up a powerful route for not-yet-realized devices toward practical applications.

Grand Challenges, Covid‐19 and the Future of Organizational Scholarship

Grand Challenges, Covid‐19 and the Future of Organizational Scholarship

Cholesterol Homeostasis: An In Silico Investigation into How Aging Disrupts Its Key Hepatic Regulatory Mechanisms.

Simple SummaryCardiovascular disease is the leading cause of death worldwide. High blood cholesterol levels are associated with an increased risk of this condition. How high levels of blood cholesterol result in cardiovascular disease during aging is a difficult question to answer. Computational models have been used over the years to help understand this problem, as they are capable of representing complex systems such as this. The aim of this work was to use a computational model of cholesterol metabolism to better understand why, in certain studies involving the oldest old (persons ≥ 85 years), high blood cholesterol levels have been associated with a decreased risk of death. Using our computational model, we found that key age-associated changes to how cholesterol is processed in the liver could be responsible for this observation. The findings from our work contribute to our understanding of cholesterol metabolism in older people and how treatments could be developed in the future to promote healthy aging.The dysregulation of intracellular cholesterol homeostasis is associated with several age-related diseases, most notably cardiovascular disease (CVD). Research in this area has benefitted from using computational modelling to study the inherent complexity associated with the regulation of this system. In addition to facilitating hypothesis exploration, the utility of modelling lies in its ability to represent an array of rate limiting enzymatic reactions, together with multiple feedback loops, which collectively define the dynamics of cholesterol homeostasis. However, to date no model has specifically investigated the effects aging has on this system. This work addresses this shortcoming by explicitly focusing on the impact of aging on hepatic intracellular cholesterol homeostasis. The model was used to investigate the experimental findings that reactive oxygen species induce the total activation of 3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) reductase (HMGCR). Moreover, the model explored the impact of an age-related decrease in hepatic acetyl-CoA acetyltransferase 2 (ACAT2). The model suggested that an increase in the activity of HMGCR does not have as significant an impact on cholesterol homeostasis as a decrease in hepatic ACAT2 activity. According to the model, a decrease in the activity of hepatic ACAT2 raises free cholesterol (FC) and decreases low-density lipoprotein cholesterol (LDL-C) levels. Increased acetyl CoA synthesis resulted in a reduction in the number of hepatic low-density lipoprotein receptors, and increased LDL-C, FC, and cholesterol esters. The rise in LDL-C was restricted by elevated hepatic FC accumulation. Taken together these findings have important implications for healthspan. This is because emerging clinical data suggest hepatic FC accumulation is relevant to the pathogenesis of non-alcoholic fatty liver disease (NAFLD), which is associated with an increased risk of CVD. These pathophysiological changes could, in part, help to explain the phenomenon of increased mortality associated with low levels of LDL-C which have been observed in certain studies involving the oldest old (≥85 years).

LDO With Improved Common Gate Class-AB OTA Handles any Load Capacitors and Provides Fast Response to Load Transients

This article proposes an LDO with fast response to load transients that can handle any practical capacitive loads. These features are mainly due to a novel frequency compensation circuit tailored for its error amplifier, which is based on an improved version of the popular common gate amplifier. A simple yet effective approach to the small-signal analysis of LDO with multiple feedback loops is employed to analyse intuitively the LDO and derive key design constraints. Simulation and measurement results performed on a test chip implemented in standard 130nm CMOS process validated the proposed LDO. It requires only $0.7\mu \text{A}$ quiescent current but exhibits an excellent response to load transients: when the load current jumps from 0A to 100mA in $1\mu \text{s}$ the output voltage presents an undershoot of 76mV and an overshoot of 198mV, without decoupling capacitors. It compares well against seven LDOs designed with common gate error amplifiers for similar levels of supply voltage, output voltage and current and against seven fast LDOs employing different error amplifiers. A figure-of-merit that considers the quiescent current, the maximum load current and capacitance, as well as the output voltage deviation, yielded a value for our LDO 39.8 times better than for the nearer competitor that employs common gate amplifier and 6 times better than the one employing a different error amplifier. When considering edge time and process scaling the performance of the proposed LDO is 4.8, respectively 4.5, times better than the second best in both comparisons.

WheelCon: A Wheel Control-Based Gaming Platform for Studying Human Sensorimotor Control.

Feedback control theory has been extensively implemented to theoretically model human sensorimotor control. However, experimental platforms capable of manipulating important components of multiple feedback loops lack development. This paper describes WheelCon, an open-source platform aimed at resolving such insufficiencies. Using only a computer, a standard display, and inexpensive gaming steering wheel equipped with a force feedback motor, WheelCon safely simulates the canonical sensorimotor task of riding a mountain bike down a steep, twisting, bumpy trail. The platform provides flexibility, as will be demonstrated in the demos provided, so that researchers may manipulate the disturbances, delay, and quantization (data rate) in the layered feedback loops, including a high-level advanced plan layer and a low-level delayed reflex layer. In this paper, we illustrate WheelCon's graphical user interface (GUI), the input and output of existing demos, and how to design new games. In addition, we present the basic feedback model and the experimental results from the demo games, which align well with the model's prediction. The WheelCon platform can be downloaded at https://github.com/Doyle-Lab/WheelCon. In short, the platform is featured to be cheap, simple to use, and flexible to program for effective sensorimotor neuroscience research and control engineering education.

Abstract 5506: A computational model for the PI3K/Akt/mTOR pathway predicts PTEN as a negative feedback loop

Abstract The PI3K/Akt/mTOR pathway regulation is of paramount importance in numerous homeostatic physiologic processes. While it is often seen to be hyperactivated in many cancers including a majority of breast cancers, it is repressed in type-2 diabetes. In cancers this hyperactivation could be due to an overexpression or a mutation of a growth factor receptor, mutation of the PI3K or any activating mutation in the pathway leading to increased cell growth and tumorigenesis. PTEN is the negative regulator of this pathway and is also often mutated or is lower in abundance. The PI3K pathway has multiple feedback loops that serves to return the pathway output to its basal value following a perturbation. We asked in this context if PTEN could be controlled through a negative feedback loop.We assembled a collection of breast cancer cell lines (Her2+, ER/PR+, TN), plotted their normalized PTEN vs Akt and ran an unsupervised k-means clustering algorithm on the data points. We found that the PTEN high and low clusters showed a positive correlation between Akt and PTEN implying a positive regulation of PTEN by Akt. We then built a computational model for PI3K pathway with the output of the pathway connected directly back to PTEN in a feedback loop. We trained the computational model on BT474 cells (Her2+ system) and found that just 2 flavors of the model were sufficient to represent the Akt, PTEN values of all the cell lines in the PTEN-high cluster. We then expanded the model to learn the dynamics of the system during PI3K inhibition (by selective drugs) by including the Foxo driven growth factor receptor upregulation feedback loop. For training we modeled PTEN as a sum of two exponentially decaying terms and learnt the parameters of the model by fitting the experimental data to model output. By simulating different PTEN decay rates we showed that the Foxo driven feedback loop along with the rate of PTEN decay played an important role in determining the extent of the Akt rebound. However, the computational model with the Akt connected directly to PTEN failed to reproduce the PTEN decay seen during PI3K inhibition suggesting the presence of further downstream mechanisms. We then expanded the model to include mTOR and its substrates 4EBP1 and S6K, which are negative and positive regulators of PTEN translation, respectively. We trained the model on the phosho-4EBP1 and phosho-S6K time profiles obtained during PI3K inhibition and found that these additional mechanisms completely captured the PTEN dynamics seen during PI3K inhibition. As a prediction we also showed that the model captures the abrogation of PTEN decrease in 4EBP1-KO cells along with a concomitant lower rebound in Akt.Thus, here we develop an experimentally validated model of the PI3K/Akt pathway with multiple feedback loops and show that it accurately models the PTEN dynamics during PI3K inhibition and provides quantitative support for PTEN regulation through a negative feedback loop. Citation Format: Kiran Vanaja, Radha Mukherjee, Neal Rosen, Andre Levchenko. A computational model for the PI3K/Akt/mTOR pathway predicts PTEN as a negative feedback loop [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 5506.

Modeling the Control of Meiotic Cell Divisions: Entry, Progression, and Exit

Upon nitrogen starvation, Schizosaccharomyces pombe exit the mitotic cell cycle and become irreversibly committed to the completion of meiosis program. Meiotic cell divisions are coordinated with sporulation events to produce haploid spores. In the last few decades, experiments on fission yeast have revealed different molecular players involved in two meiotic cell divisions, meiosis I (MI) and meiosis II (MII). How the MI entry, MI-to-MII transition, and MII exit occur because of the dynamics of the regulatory network is not well understood. In this work, we developed a comprehensive mathematical model of the network that describes the temporal dynamics of meiotic progression. The model accounts for the phenotypes of several experimental data (single and multiple mutations). We demonstrate the control strategy involving multiple feedback loops to yield two successive division cycles. The differential regulation of anaphase-promoting complex/cyclosome (APC/C) coactivators and its inhibitors is crucial for the dynamics of both MI-to-MII transition and MII exit. This model generates mechanistic insights that help in further experiments and modeling.

The Weak State Trap

Development outcomes come in ‘clusters’ that seem difficult to exit. Using original data from Colombia, we present evidence of the interconnection between two critical political components: state weakness and clientelism. State weakness creates the right environment for clientelism to flourish. Clientelism sets in place a structure of incentives for politicians and citizens that is detrimental to building state capacity. We show that vote buying, as a measure of clientelism, and tax evasion, as a measure of state weakness, are highly correlated at the micro level. We also report evidence that both practices are widely accepted in society, a result consistent with a deeply entrenched relationship of mutually reinforcing influences. Finally, we propose a set of mechanisms that underlie the hypothesis that a weak state and widespread clientelism are part of a political equilibrium with multiple feedback loops. Our results suggest that state weakness is a trap that is likely hard to exit. Institutional subscribers to the NBER working paper series, and residents of developing countries may download this paper without additional charge at www.nber.org.

How Poor is Poor? A novel look at multidimensional poverty in the UK

The integrated nature of well-being produces difficulty in evaluating poverty levels and one issue is the neglected of human life aspects, multiple feedback loops, and an over-emphasis on income. In the light of current structural changes a multidimensional poverty measure (MPI), which includes some of those missing dimensions, closely related to the well-being of individuals, is constructed in this paper. Using data from the EU Statistics on Income and Living Conditions Survey, this paper provides a fresh insight into the analysis of multidimensional poverty in the United Kingdom. One of the distinctive feature of the study is the use of polychoric factor loadings to estimate dimensional weights of the MPI, in addition to more arbitrary weighting schemes. This technique consists of a coherent hierarchy of principles, to verify which of the many acknowledged dimensions of poverty hold both theoretical and practical importance. Findings indicate that, the MPI is highly consistent with the conventional measures of poverty and multidimensional poverty has decreased over the period of examination.

European Cohesion Policy performance and citizens’ awareness: A holistic System Dynamics framework

As Cohesion Policy constitutes the major funding scheme of the European Union, not only does literature explore if the policy’s performance is satisfactory but as well investigates the extent to which the policy is effectively communicated to citizens. To integrate analysis of implementation and communication, we develop a novel qualitative framework that elicits a holistic analysis of the causal mechanisms behind: (i) the distribution of the Cohesion Policy funds, their management at a local managing authority level and the related impact on projects’ quality, and (ii) the communication processes that underpin citizens’ awareness about the Union’s role in funded projects. The multilevel nature and the dynamic behaviour of the system, as well as its multiple feedback loops, render System Dynamics as the appropriate approach to model its complexity. The proposed framework aims at stimulating a focused discussion on Cohesion Policy through providing policy-making insights for designing efficient schemes to improve not only actual performance but, more importantly, perceived performances, as well as for supporting research in the field from a new organisational point of view.

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.

Neural Differentiation Dynamics Controlled by Multiple Feedback Loops in a Comprehensive Molecular Interaction Network

Mathematical model simulation is a useful method for understanding the complex behavior of a living system. The construction of mathematical models using comprehensive information is one of the techniques of model construction. Such a comprehensive knowledge-based network tends to become a large-scale network. As a result, the variation of analyses is limited to a particular kind of analysis because of the size and complexity of the model. To analyze a large-scale regulatory network of neural differentiation, we propose a contractive method that preserves the dynamic behavior of a large network. The method consists of the following two steps: comprehensive network building and network reduction. The reduction phase can extract network loop structures from a large-scale regulatory network, and the subnetworks were combined to preserve the dynamics of the original large-scale network. We confirmed that the extracted loop combination reproduced the known dynamics of HES1 and ASCL1 before and after differentiation, including oscillation and equilibrium of their concentrations. The model also reproduced the effects of the overexpression and knockdown of the Id2 gene. Our model suggests that the characteristic change in HES1 and ASCL1 expression in the large-scale regulatory network is controlled by a combination of four feedback loops, including a large loop, which has not been focused on. The model extracted by our method has the potential to reveal the critical mechanisms of neural differentiation. The method is applicable to other biological events.

The Effect of Time-Dependent Drive and Delayed Feedback Loop in Two-Dimensional Gene Regulatory Network

The gene regulatory network within a cell plays a major role in controlling the embryonic development and cellular differentiation process. Recent advances in reprogramming a differentiated cell back to a pluripotent cell fate has rekindled interest in a quantitative understanding of the epigenetic landscape describing cellular differentiation. Reprogramming is a complex multistep process, involving multiple feedback loops. While the importance of feedback loops is well appreciated, most models assume instantaneous feedback, while real biological feedback often involves a time delay between the signal and the response. In the present work, we propose a theoretical model based on a two-gene regulatory motif to investigate the role of time delay in the regulation of gene expression level. In particular, we focus on the interplay between time-delayed feedback loops and time-dependent external chemical drive and their effect on dynamics. We observed that the concentration of the two transcription factors can undergo sustained oscillations and we speculate that this oscillatory state may provide an explanation of certain puzzling experiments on the reprogramming process. We also observe transdifferentiation-like behavior, where one differentiated state transitions to another without passing through an intermediate stem cell state, which phenomenon has also been observed in experiments.

Are Kynurenines Accomplices or Principal Villains in Dementia? Maintenance of Kynurenine Metabolism.

Worldwide, 50 million people suffer from dementia, a group of symptoms affecting cognitive and social functions, progressing severely enough to interfere with daily life. Alzheimer’s disease (AD) accounts for most of the dementia cases. Pathological and clinical findings have led to proposing several hypotheses of AD pathogenesis, finding a presence of positive feedback loops and additionally observing the disturbance of a branch of tryptophan metabolism, the kynurenine (KYN) pathway. Either causative or resultant of dementia, elevated levels of neurotoxic KYN metabolites are observed, potentially upregulating multiple feedback loops of AD pathogenesis. Memantine is an N-methyl-D-aspartate glutamatergic receptor (NMDAR) antagonist, which belongs to one of only two classes of medications approved for clinical use, but other NMDAR modulators have been explored so far in vain. An endogenous KYN pathway metabolite, kynurenic acid (KYNA), likewise inhibits the excitotoxic NMDAR. Besides its anti-excitotoxicity, KYNA is a multitarget compound that triggers anti-inflammatory and antioxidant activities. Modifying the KYNA level is a potential multitarget strategy to normalize the disturbed KYN pathway and thus to alleviate juxtaposing AD pathogeneses. In this review, the maintenance of KYN metabolism by modifying the level of KYNA is proposed and discussed in search for a novel lead compound against the progression of dementia.

Circadian rhythms in adaptive immunity.

The circadian clock provides organisms with the ability to track time of day, allowing them to predict and respond to cyclical changes in the external environment. In mammals this clock consists of multiple auto-regulatory feedback loops generated by a network of circadian clock proteins. This network provides the fundamental basis for rhythms in behaviour and physiology. This clockwork machinery exists in most cells, including those of the immune system. In recent years evidence has emerged highlighting the important role of molecular clocks in dictating the response of immune pathways. While initial work highlighted the effect of the clock in the 'first line of defence', the innate immune system, it has become increasingly apparent that it also plays a role in the more tailored, later-stage adaptive immune response. This review provides an overview of the role of the circadian cycle in the adaptive immune response. We interrogate the depth of knowledge on cell intrinsic clocks within adaptive immune cells and how these cells may be temporally directed by extrinsic rhythmic signals. We discuss the role of the circadian clock in diseases associated with adaptive immunity such as multiple sclerosis, asthma and parasitic infection. We also discuss the current knowledge on timing of vaccination, and the implications this may have on how we can harness and modulate temporal gating of the adaptive immune response in a clinical setting.

Dynamic simulation of urbanization and eco-environment coupling: Current knowledge and future prospects

Urbanization and eco-environment coupling is a research hotspot. Dynamic simulation of urbanization and eco-environment coupling needs to be improved because the processes of coupling are complex and statistical methods are limited. Systems science and cross-scale coupling allow us to define the coupled urbanization and eco-environment system as an open complex giant system with multiple feedback loops. We review the current state of dynamic simulation of urbanization and eco-environment coupling and find that: (1) The use of dynamic simulation is an increasing trend, the relevant theory is being developed, and modeling processes are being improved; (2) Dynamic simulation technology has become diversified, refined, intelligent and integrated; (3) Simulation is mainly performed for three aspects of the coupling, multiple regions and multiple elements, local coupling and telecou-pling, and regional synergy. However, we also found some shortcomings: (1) Basic theories are inadequately developed and insufficiently integrated; (2) The methods of unifying systems and sharing data are behind the times; (3) Coupling relations and the dynamic characteristics of the main driving elements are not fully understood or completely identified. Additionally, simulation of telecoupling does not quantify parameters and is not systemically unified, and therefore cannot be used to represent spatial synergy. In the future, we must promote communication between research networks, technology integration and data sharing to identify the processes governing change in coupled relations and in the main driving elements in urban agglomerations. Finally, we must build decision support systems to plan and ensure regional sustainable urbanization.