Mal de Debarquement Syndrome: A Matter of Loops?

Mucci, Viviana; Indovina, Iole; Browne, Cherylea J.; Blanchini, Franco; Giordano, Giulia; Marinelli, Lucio; Burlando, Bruno

doi:10.3389/fneur.2020.576860

Cited by 13 publications

(17 citation statements)

References 86 publications

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“…These parameters are expected to act as bifurcation parameters able to convert the system from monostable to bistable and vice versa (Figure 1c). It must be noted that this kind of model has already been applied to a series of pathogenic mechanisms, a few representative examples of which include cancer [16], immunological disorders [5], neurological problems [17], and neurodegenerative diseases [18]. The mathematical evaluation of these loops can be used to identify the bifurcation parameters that drive the transition from monostability to multistability, thus determining the switch from a "physiological" to a "pathological" steady state condition [8].…”

Section: Loop Dynamicsmentioning

confidence: 99%

A New Bistable Switch Model of Alzheimer’s Disease Pathogenesis

Burlando

Losacco

Villa

et al. 2022

IJMS

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We propose a model to explain the pathogenesis of Alzheimer’s disease (AD) based on the theory that any disease affecting a healthy organism originates from a bistable feedback loop that shifts the system from a physiological to a pathological condition. We focused on the known double inhibitory loop involving the cellular prion protein (PrPC) and the enzyme BACE1 that produces amyloid-beta (Aβ) peptides. BACE1 is inhibited by PrPC, but its inhibitory activity is lost when PrPC binds to Aβ oligomers (Aβo). Excessive Aβo formation would switch the loop to a pathogenic condition involving the Aβo-PrPC-mGluR5 complex, Fyn kinase activation, tau, and NMDAR phosphorylation, ultimately leading to neurodegeneration. Based on the emerging role of cyclic nucleotides in Aβ production, and thereby in synaptic plasticity and cognitive processes, cAMP and cGMP can be considered as modulatory factors capable of inducing the transition from a physiological steady state to a pathogenic one. This would imply that critical pharmacological targets for AD treatment lie within pathways that lead to an imbalance of cyclic nucleotides in neurons. If this hypothesis is confirmed, it will provide precise indications for the development of preventive or therapeutic treatments for the disease.

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Section: Loop Dynamicsmentioning

confidence: 99%

A New Bistable Switch Model of Alzheimer’s Disease Pathogenesis

Burlando

Losacco

Villa

et al. 2022

IJMS

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“…( 2021 ), Mucci et al. ( 2020 ) and the references therein). In our context, perfect adaptation to a sinusoidal signal of frequency is equivalent to the condition , namely, it is equivalent to considering ( 17 ) with .…”

Section: Robust Adaptation Analysis For Uncertain Systemsmentioning

confidence: 98%

Vertex results for the robust analysis of uncertain biochemical systems

et al. 2022

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We consider the problem of assessing the sensitivity of uncertain biochemical systems in the presence of input perturbations (either constant or periodic) around a stable steady state. In particular, we propose approaches for the robust sensitivity analysis of systems with uncertain parameters assumed to take values in a hyper-rectangle. We highlight vertex results, which allow us to check whether a property is satisfied for all parameter choices in the hyper-rectangle by simply checking whether it is satisfied for all parameter choices at the vertices of the hyper-rectangle. We show that, for a vast class of systems, including (bio)chemical reaction networks with mass-action kinetics, the system Jacobian has a totally multiaffine structure (namely, all minors of the Jacobian matrix are multiaffine functions of the uncertain parameters), which can be exploited to obtain several vertex results. We consider different problems: robust non-singularity; robust stability of the steady-state; robust steady-state sensitivity analysis, in the case of constant perturbations; robust frequency-response sensitivity analysis, in the presence of periodic perturbations; and robust adaptation analysis. The developed theory is then applied to gain insight into some examples of uncertain biochemical systems, including the incoherent feed-forward loop, the coherent feed-forward loop, the Brusselator oscillator and the Goldbeter oscillator.

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“…A rapidly increasing number of pathogenic processes are being modeled as bistable switches, a few representative examples of which include cancer (Kim et al, 2007;Huang et al, 2014), prion infections (Kellershohn and Laurent, 2001), immunological disorders (Beutler, 2009), dermatitis (Dominguez-Huttinger et al, 2017), neurological problems (Mucci et al, 2020), and neurodegenerative diseases (De Caluwe and Dupont, 2013;Burlando et al, 2020). In other cases, a bistable model has not been explicitly used to describe pathogenesis, but a positive loop has been nevertheless invoked (Beutler, 2009;Norwitz et al, 2019).…”

Section: A Loopomic Hypothesis In Pathophysiologymentioning

confidence: 99%

A general hypothesis of multistable systems in pathophysiology

Burlando

2022

F1000Res

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Despite intensive investigations numerous diseases remain etiologically puzzling and recalcitrant to treatments. A hypothesis is proposed here assuming that these difficulties are due to an unsuitable approach to the mechanisms of life, which is subjugated by an apparent complexity and fails to grasp the uniformity that lays behind. The stability of metabolism, despite the enormous complex of chemical reactions, suggests that reciprocal control is a prerequisite of life. Negative feedback loops have been known for a long time to maintain homeostasis, while more recently, different life processes involved in transitions or changes have been modeled by positive loops giving rise to bistable switches, also including various diseases. The present hypothesis makes a generalization, by assuming that any functional element of a biological system is involved in a positive or a negative feedback loop. Consequently, the hypothesis holds that the starting mechanism of any disease that affects a healthy human can be conceptually reduced to a bistable or multistationary loop system, thus providing a unifying model leading to the discovery of critical therapeutic targets.

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Mal de Debarquement Syndrome: A Matter of Loops?

Cited by 13 publications

References 86 publications

A New Bistable Switch Model of Alzheimer’s Disease Pathogenesis

A New Bistable Switch Model of Alzheimer’s Disease Pathogenesis

Vertex results for the robust analysis of uncertain biochemical systems

A general hypothesis of multistable systems in pathophysiology

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