Bidirectional Feedback Loop Research Articles

The infant parasympathetic nervous system is socially embedded and dynamic at multiple timescales, within and between people.

Human interpersonal capacities emerge from coordinated neural, biological, and behavioral activity unfolding within and between people. However, developmental research to date has allocated comparatively little focus to the dynamic processes of how social interactions emerge across these levels of analysis. Second-person neuroscience and dynamic systems approach together to offer an integrative framework for addressing these questions. This study quantified respiratory sinus arrhythmia and social behavior (∼360 observations per system) from 44 mothers and typically developing 9-month-old infants during a novel modified "still-face" (text message perturbation) task. Stochastic autoregression models indicate that the infant parasympathetic nervous system is coupled within and between people second by second and is sensitive to social context. Intraindividual, we found positive coupling between infants' parasympathetic nervous system activity and their social behavior in the subsequent second, but only during the moments and periods of active caregiver engagement. Between people, we found a bidirectional coregulatory feedback loop: Mothers' parasympathetic activity positively predicted that of their infant in the subsequent second, a form of synchrony that decreased during the text message perturbation and did not fully recover. Conversely, infant parasympathetic activity negatively predicted that of their mother at the subsequent second, a form of synchrony that was invariant over social context. Findings reveal unidirectional parasympathetic coupling within infants and a complementary allostatic feedback loop between mother and infant parasympathetic systems. They offer novel evidence of a dynamic, socially embedded parasympathetic system at previously undocumented timescales, contributing to both basic science and potential clinical targets to better support adaptive, multisystem social development. (PsycInfo Database Record (c) 2024 APA, all rights reserved).

Tumor-associated macrophages: The key player in hepatoblastoma microenvironment and the promising therapeutic target.

The tumor microenvironment of hepatoblastoma (HB), the most common pediatric liver tumor, predominantly exhibits a myeloid immune landscape. in which tumor-associated macrophages (TAMs) are considered the core component. The crosstalk between TAMs and HB cells markedly influences tumor behavior. TAM-derived factors are involved in tumor proliferation and vascular invasion. On the other hand, HB cell secretome attracts, stimulates, and reprograms TAMs to be immunosuppressive in favor of tumor invasion, rather than their innate role in combating tumor growth, such crosstalk sometimes forms bidirectional feedback loops, making the tumor more virulent and resistant to routine therapeutics. Consequently, TAMs are the common denominator of most suggested HB immunotherapeutic strategies. Macrophage immune checkpoint inhibitors, macrophage-mediated antibody-dependent cellular phagocytosis, and the novel chimeric antigen receptor macrophage therapy (CAR Mφ) are currently under trial. In this review, we will summarize the significance of TAMs and their potential role as a therapeutic target in HB.

A Note on Modelling Bidirectional Feedback Loops in Mendelian Randomization Studies

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.

The Role of the Gastrointestinal Microbiome in Liver Disease.

Liver disease is a major global health problem leading to approximately two million deaths a year. This is the consequence of a number of aetiologies, including alcohol-related, metabolic-related, viral infection, cholestatic and immune disease, leading to fibrosis and, eventually, cirrhosis. No specific registered antifibrotic therapies exist to reverse liver injury, so current treatment aims at managing the underlying factors to mitigate the development of liver disease. There are bidirectional feedback loops between the liver and the rest of the gastrointestinal tract via the portal venous and biliary systems, which are mediated by microbial metabolites, specifically short-chain fatty acids (SCFAs) and secondary bile acids. The interaction between the liver and the gastrointestinal microbiome has the potential to provide a novel therapeutic modality to mitigate the progression of liver disease and its complications. This review will outline our understanding of hepatic fibrosis, liver disease, and its connection to the microbiome, which may identify potential therapeutic targets or strategies to mitigate liver disease.

Fragmentation of care between intensive and primary care settings and opportunities for improvement

PurposeTo explore the gaps in care provided across the transitions from the intensive care unit (ICU) to primary care, in order to improve post-ICU care.MethodsSemistructured interviews with three participant groups:...

Escalating Bi-Directional Feedback Loops between Proinflammatory Microglia and Mitochondria in Ageing and Post-Diagnosis of Parkinson's Disease.

Parkinson's disease (PD) is a chronic and progressive age-related neurodegenerative disease affecting up to 3% of the global population over 65 years of age. Currently, the underlying physiological aetiology of PD is unknown. However, the diagnosed disorder shares many common non-motor symptoms associated with ageing-related neurodegenerative disease progression, such as neuroinflammation, microglial activation, neuronal mitochondrial impairment, and chronic autonomic nervous system dysfunction. Clinical PD has been linked to many interrelated biological and molecular processes, such as escalating proinflammatory immune responses, mitochondrial impairment, lower adenosine triphosphate (ATP) availability, increasing release of neurotoxic reactive oxygen species (ROS), impaired blood brain barrier integrity, chronic activation of microglia, and damage to dopaminergic neurons consistently associated with motor and cognitive decline. Prodromal PD has also been associated with orthostatic hypotension and many other age-related impairments, such as sleep disruption, impaired gut microbiome, and constipation. Thus, this review aimed to present evidence linking mitochondrial dysfunction, including elevated oxidative stress, ROS, and impaired cellular energy production, with the overactivation and escalation of a microglial-mediated proinflammatory immune response as naturally occurring and damaging interlinked bidirectional and self-perpetuating cycles that share common pathological processes in ageing and PD. We propose that both chronic inflammation, microglial activation, and neuronal mitochondrial impairment should be considered as concurrently influencing each other along a continuum rather than as separate and isolated linear metabolic events that affect specific aspects of neural processing and brain function.

Emerging roles of keratinocytes in nociceptive transduction and regulation.

Keratinocytes are the predominant block-building cells in the epidermis. Emerging evidence has elucidated the roles of keratinocytes in a wide range of pathophysiological processes including cutaneous nociception, pruritus, and inflammation. Intraepidermal free nerve endings are entirely enwrapped within the gutters of keratinocyte cytoplasm and form en passant synaptic-like contacts with keratinocytes. Keratinocytes can detect thermal, mechanical, and chemical stimuli through transient receptor potential ion channels and other sensory receptors. The activated keratinocytes elicit calcium influx and release ATP, which binds to P2 receptors on free nerve endings and excites sensory neurons. This process is modulated by the endogenous opioid system and endothelin. Keratinocytes also express neurotransmitter receptors of adrenaline, acetylcholine, glutamate, and γ-aminobutyric acid, which are involved in regulating the activation and migration, of keratinocytes. Furthermore, keratinocytes serve as both sources and targets of neurotrophic factors, pro-inflammatory cytokines, and neuropeptides. The autocrine and/or paracrine mechanisms of these mediators create a bidirectional feedback loop that amplifies neuroinflammation and contributes to peripheral sensitization.

MiR-148a, miR-152 and miR-200b promote prostate cancer metastasis by targeting DNMT1 and PTEN expression.

MicroRNAs (miRs) modulate the expression of target genes in the signal pathway on transcriptome level. The present study investigated the ‘epigenetic-based miRNA (epi-miRNA)-mRNA’ regulatory network of miR-34b, miR-34c, miR-148a, miR-152, miR-200a and miR-200b epi-miRNAs and their target genes, DNA methyltransferase (DNMT1, 3a and 3b), phosphate and tensin homolog (PTEN) and NK3 Homeobox 1 (NKX3.1), in prostate cancer (PCa) using reverse transcription-quantitative PCR. The expression level of NKX3.1 were not significantly different between the PCa, Met-PCa and control groups. However, in the PCa and Met-PCa groups, the expression level of DNMT1 was upregulated, while DNMT3a, DNMT3b and PTEN were downregulated. Overexpression of DNMT1 (~5 and ~6-fold increase in the PCa and Met-PCa groups respectively) was accompanied by a decreased expression in PTEN, indicating a potential negative association. Both groups indicated that a high level of DNMT1 is associated with the aggressiveness of cancer, and there is a a directly proportional relationship between this gene and PSA, GS and TNM staging. A significant ~2 to ~5-fold decrease in the expression levels of DNMT3a and DNMT3b was found in both groups. In the PCa group, significant associations were identified between miR-34b and DNMT1/DNMT3b; between miR-34c/miR-148a and all target genes; between miR-152 and DNMT1/DNMT3b and PTEN; and between miR-200a/b and DNMT1. In the Met-PCa group, miR-148a, miR-152 and miR-200b exhibited a significant association with all target genes. A significant negative association was identified between PTEN and DNMT1 in the Met-PCa group. It was also revealed that that miR-148a, miR-152 and miR-200b increased the expression of DNMT1 and suppressed PTEN. Furthermore, the ‘epi-miRNA-mRNA’ bidirectional feedback loop was emphasised and the methylation pattern in PCa anti-cancer therapeutics was highlighted.

More than a thought experiment -- conceptualizing and implementing an Urban Living Lab

In the context of growing urbanization,1 cities are focal points of social interactions. Embedded in bi-directional feedback loops with wider regional environments and the global ecosystem, cities present, simultaneously, ideal reference points and vital arenas for generating debates about and testing pathways toward emerging sustainable models of livability and a redefined prosperity. The latter no longer limited to mainstream economic definitions but encompassing a more holistic societal prosperity, nurtured by shared experiences, enhanced knowledge generation and exchange, eclectic encounters and ample space for creative expression. The paper presents the conceptual development of an Urban Living Lab (ULL). It employs existing literature on ULL to enable a basic frame of reference, draws on the concept of contextual logic and a philosophical understanding of flow to inform processes for rolling out such a multi-stakeholder engagement experiment. The paper attempts to conceptualize an approach that employs community participation to define contours of a socially inclusive and livable society. This approach aims at empowering networks for transitioning towards such a society within a specific context.

Human-Machine Collaboration for Fast Land Cover Mapping

We propose incorporating human labelers in a model fine-tuning system that provides immediate user feedback. In our framework, human labelers can interactively query model predictions on unlabeled data, choose which data to label, and see the resulting effect on the model's predictions. This bi-directional feedback loop allows humans to learn how the model responds to new data. We implement this framework for fine-tuning high-resolution land cover segmentation models and compare human-selected points to points selected using standard active learning methods. Specifically, we fine-tune a deep neural network – trained to segment high-resolution aerial imagery into different land cover classes in Maryland, USA – to a new spatial area in New York, USA using both our human-in-the-loop method and traditional active learning methods. The tight loop in our proposed system turns the algorithm and the human operator into a hybrid system that can produce land cover maps of large areas more efficiently than the traditional workflows. Our framework has applications in machine learning settings where there is a practically limitless supply of unlabeled data, of which only a small fraction can feasibly be labeled through human efforts, such as geospatial and medical image-based applications.

Multilayered Control of Protein Turnover by TORC1 and Atg1

The target of rapamycin complex 1 (TORC1) is a master regulator of cell homeostasis, which promotes anabolic reactions and synchronously inhibits catabolic processes such as autophagy-mediated protein degradation. Its prime autophagy target is Atg13, a subunit of the Atg1 kinase complex that acts as the gatekeeper of canonical autophagy. To study whether the activities of TORC1 and Atg1 are coupled through additional, more intricate control mechanisms than simply this linear pathway, we analyzed the epistatic relationship between TORC1 and Atg1 by using quantitative phosphoproteomics. Our invivo data, combined with targeted invitro TORC1 and Atg1 kinase assays, not only uncover numerous TORC1 and Atg1 effectors, but also suggest distinct bi-directional regulatory feedback loops and characterize Atg29 as a commonly regulated downstream target of both TORC1 and Atg1. Thus, an exquisitely multilayered regulatory network appears to coordinate TORC1 and Atg1 activities to robustly tune autophagy in response to nutritional cues.

Daily experiences of emotional clarity and their association with internalizing symptoms in naturalistic settings.

Although emotional clarity contributes to effective emotion regulation and has been suggested as a target for transdiagnostic interventions, little is known about how emotional clarity impacts symptoms and emotion regulation success in daily life. The present study examined the association of emotional clarity with internalizing symptoms (i.e., depression, social anxiety, panic, and worry) in a clinical sample assessed in naturalistic settings over the course of 10 days, examining both within-person and between-person models. In addition, emotion regulation success was tested as a mediator of the association between emotional clarity and symptoms. The sample consisted of 129 diagnostically heterogeneous adults currently seeking or receiving mental health treatment. Multilevel structural equation modeling indicated that momentary emotional clarity was not significantly associated with subsequent momentary internalizing symptoms at either level, with the exception of a negative association with panic at the between-person level. However, lower momentary emotional clarity was indirectly associated with greater subsequent momentary internalizing symptoms via less successful momentary emotion regulation at both levels, and for some symptoms there was evidence of a bidirectional feedback loop. Overall, the present study provides support for the transdiagnostic nature of emotional clarity and clarifies the mechanisms by which emotional clarity may impact symptoms over time in daily life. Theoretical and clinical implications for the role of emotional clarity in psychopathology are discussed. (PsycINFO Database Record (c) 2019 APA, all rights reserved).

Interaction of photons with a coupled atom-cavity system through a bidirectional time-delayed feedback

In this paper, we have developed a method for describing the dynamics of an arbitrary quantum system under a bidirectional time-delayed feedback loop. For this purpose, we have described the evolution in terms of the time propagation of the quantum system of interest without feedback together with several identical systems, which represent the history of the quantum system under study. This technique provides a numerically efficient solution for describing a system's dynamics in the case of significant time delays in which direct investigation of the state of the reservoirs becomes numerically intractable. Using this method, we have studied two scenarios of multiple scatterings of photons incident on a cavity with a two-level atom positioned inside it, coupled to two waveguides that are connected at their ends. In the first scenario, two photons impinge on the cavity through separate waveguides with a delay between them. We have demonstrated that the maximum difference between the two output photon numbers occurs when the delay between the incident photons becomes close to the inverse of their linewidth. In the second scenario, multiple photons impinge on the cavity through the same waveguide and go through multiple interactions. We have shown that, for a fixed atom-cavity coupling rate, the transmission rate enhances as the number of photons increases and have quantified this enhancement. The developed method enables us to study a broad range of nonlinear dynamics in complex quantum networks.

When is a confounder not a confounder?

When is a confounder not a confounder?

A cybernetical perspective on emotion-cognition interactions as self-directed adaptation in situated decision-makers

Emotion-cognition interactions are often (Simon, 1967; Sloman, 2002) understood as adaptational mechanisms that help to cope bounded decision-makers with constraints and dangers forced upon by their environments. In this work, emotions are regarded as emergent properties of interconnected systems of functional routines – decision-making, memory access, etc. – and associated internal monitoring and modulation systems. Couplings between these mechanisms create internal bidirectional feedback loops that can sustain globally synchronized responses, which have been referred to as “appraisal-emotion”-amalgams (Lewis, 2005). Although emotions have been suggested as crucial components for enabling biological agents to cope with difficulties of decision-making in complex, partially unknown environments (Hanoch, 2002; Muramatsu & Hanoch, 2005; Sloman, 2011), research on artificial emotion models lacks common frameworks to explore design spaces for particular classes of emotionally-influenced systems (Hudlicka, 2008; Sloman, 2002), rendering it difficult to identify basic principles or architectural constraints (Hudlicka, 2008; Sloman, 1999, 2002). This article presents a systems-level framework for modeling emotion-cognition interaction in domain-independent decision-making systems based on Optimal Control Theory as a particular form of self-modulation driven by continual evaluation of the relationship between system and environment.

Oxidative Stress Induces an Interactive Decline in Wnt and Nrf2 Signaling in Degenerating Retinal Pigment Epithelium.

Cells have evolved a highly sophisticated web of cytoprotective systems to neutralize unwanted oxidative stress, but are challenged by unique modern day stresses such as cigarette smoking and ingestion of a high-fat diet (HFD). Age-related disease, such as age-related macular degeneration (AMD), the most common cause of blindness among the elderly in Western societies, develops in part, when oxidative stress overwhelms cytoprotective systems to injure tissue. Since most studies focus on the protection by a single protective system, the aim of this study was to investigate the impact of more than one cytoprotective system against oxidative stress. Wingless (Wnt) and nuclear factor-erythroid 2-related factor 2 (Nrf2), two fundamental signaling systems that are vital to cell survival, decline after mice are exposed to chronic cigarette smoke and HFD, two established AMD risk factors, in a bidirectional feedback loop through phosphorylated glycogen synthase kinase 3 beta. Decreased Wnt and Nrf2 signaling leads to retinal pigment epithelial dysfunction and apoptosis, and a phenotype that is strikingly similar to geographic atrophy (GA), an advanced form of AMD with no effective treatment. This study is the first to show that chronic oxidative stress from common modern day environmental exposures reduces two fundamental and vital cytoprotective networks in a bidirectional feedback loop, and their decline leads to advanced disease phenotype. Our data offer new insights into how combined modern oxidative stresses of cigarette smoking and HFD contribute to GA through an interactive decline in Wnt and Nrf2 signaling. Antioxid. Redox Signal. 29, 389-407.

Telomerase reverse transcriptase coordinates with the epithelial-to-mesenchymal transition through a feedback loop to define properties of breast cancer stem cells.

ABSTRACTTelomerase and its core component, telomerase reverse transcriptase (hTERT), are critical for stem cell compartment integrity. Normal adult stem cells have the longest telomeres in a given tissue, a property mediated by high hTERT expression and high telomerase enzymatic activity. In contrast, cancer stem cells (CSCs) have short telomeres despite high expression of hTERT, indicating that the role of hTERT in CSCs is not limited to telomere elongation and/or maintenance. The function of hTERT in CSCs remains poorly understood. Here, we knocked down hTERT expression in CSCs and observed a morphological shift to a more epithelial phenotype, suggesting a role for hTERT in the epithelial-to-mesenchymal transition (EMT) of CSCs. Therefore, in this study, we systematically explored the relationship between hTERT and EMT and identified a reciprocal, bi-directional feedback loop between hTERT and EMT in CSCs. We found that hTERT expression is mutually exclusive to the mesenchymal phenotype and that, reciprocally, loss of the mesenchymal phenotype represses hTERT expression. We also showed that hTERT plays a critical role in the expression of key CSC markers and nuclear β-catenin localization, increases the percentage of cells with side-population properties, and upregulates the CD133 expression. hTERT also promotes chemoresistance properties, tumorsphere formation and other important functional CSC properties. Subsequently, hTERT knockdown leads to the loss of the above advantages, indicating a loss of CSC properties. Our findings suggest that targeting hTERT might improve CSCs elimination by transitioning them from the aggressive mesenchymal state to a more steady epithelial state, thereby preventing cancer progression.

Protocol of a Pilot Study of Technology-Enabled Coproduction in Pediatric Chronic Illness Care.

BackgroundPediatric chronic illness care models are traditionally organized around acute episodes of care and may not meet the needs of patients and their families. Interventions that extend the patient-clinician interaction beyond the health care visit, allow for asynchronous and bidirectional feedback loops that span visits and daily life, and facilitate seamless sharing of information are needed to support a care delivery system that is more collaborative, continuous, and data-driven. Orchestra is a mobile health technology platform and intervention designed to transform the management of chronic diseases by optimizing patient-clinician coproduction of care.ObjectiveThe aim of this study is to assess the feasibility, acceptability, and preliminary impact of the Orchestra technology and intervention in the context of pediatric chronic illness care.MethodsThis study will be conducted in the cystic fibrosis and inflammatory bowel disease clinics at Cincinnati Children’s Hospital Medical Center. We will enroll interested patients and their caregivers to work with clinicians to use the Orchestra technology platform and care model over a 6-month period. In parallel, we will use quality improvement methods to improve processes for integrating Orchestra into clinic workflows and patient/family lifestyles. We will use surveys, interviews, technology use data, and measures of clinical outcomes to assess the feasibility, acceptability, and preliminary impact of Orchestra. Outcome measures will include assessments of: (1) enrollment and dropout rates; (2) duration of engagement/sustained use; (3) symptom and patient-reported outcome tracker completion rates; (4) perceived impact on treatment plan, communication with the clinical team, visit preparation, and overall care; (5) changes in disease self-efficacy and engagement in care; and (6) clinical outcomes and health care utilization.ResultsParticipant recruitment began in mid-2015, with results expected in 2017.ConclusionsChronic disease management needs a dramatic transformation to support more collaborative, effective, and patient-centered care. This study is unique in that it is testing not only the impact of technology, but also the necessary processes that facilitate patient and clinician collaboration. This pilot study is designed to examine how technology-enabled coproduction can be implemented in real-life clinical contexts. Once the Orchestra technology and intervention are optimized to ensure feasibility and acceptability, future studies can test the effectiveness of this approach to improve patient outcomes and health care value.

Gaucher-Associated Parkinsonism

Gaucher disease is associated with Parkinson’s disease (PD) by mutations in glucocerebrosidase (GCase). The gene encoding GCase, glucosidase beta acid (GBA), is an important risk factor for PD. Findings from large studies have shown that patients with PD have an increased frequency of mutations in GBA and that GBA mutation carriers exhibit diverse parkinsonian phenotypes and Lewy body pathology. Although the mechanism for this association remains elusive, some hypotheses have been proposed to explain it, including gain of function caused by GBA mutations, which increases α-synuclein (α-syn) aggregation, loss of function due to lysosomal enzyme deficiency, which affects α-syn clearance, and even a bidirectional feedback loop, but each of these hypotheses has its limitations. It is also worth noting that many findings have implicated the interaction between α-syn and GCase, indicating the essential role of the interaction in the pathogenesis of GBA-associated parkinsonism. Therefore, the current review focuses on α-syn and GCase, and it provides some new thoughts that may be helpful for understanding the α-syn-GCase interaction and unraveling the exact mechanism underlying GBA-associated parkinsonism.

Modeling the effective connectivity of the visual network in healthy and photosensitive, epileptic baboons.

The baboon provides a model of photosensitive, generalized epilepsy. This study compares cerebral blood flow responses during intermittent light stimulation (ILS) between photosensitive (PS) and healthy control (CTL) baboons using H 2 (15) O-PET. We examined effective connectivity associated with visual stimulation in both groups using structural equation modeling (SEM). Eight PS and six CTL baboons, matched for age, gender and weight, were classified on the basis of scalp EEG findings performed during the neuroimaging studies. Five H 2 (15) O-PET studies were acquired alternating between resting and activation (ILS at 25Hz) scans. PET images were acquired in 3D mode and co-registered with MRI. SEM demonstrated differences in neural connectivity between PS and CTL groups during ILS that were not previously identified using traditional activation analyses. First-level pathways consisted of similar posterior-to-anterior projections in both groups. While second-level pathways were mainly lateralized to the left hemisphere in the CTL group, they consisted of bilateral anterior-to-posterior projections in the PS baboons. Third- and fourth-level pathways were only evident in PS baboons. This is the first functional neuroimaging study used to model the photoparoxysmal response (PPR) using a primate model of photosensitive, generalized epilepsy. Evidence of increased interhemispheric connectivity and bidirectional feedback loops in the PS baboons represents electrophysiological synchronization associated with the generation of epileptic discharges. PS baboons demonstrated decreased model stability compared to controls, which may be attributed to greater variability in the driving response or PPRs, or to the influence of regions not included in the model.