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  1. Article ; Online: Supralinear Dependence of the IP

    Csordás, György / Weaver, David / Várnai, Péter / Hajnóczky, György

    Contact (Thousand Oaks (Ventura County, Calif.))

    2024  Volume 7, Page(s) 25152564241229273

    Abstract: Calcium signal propagation from endoplasmic reticulum (ER) to mitochondria regulates a multitude of mitochondrial and cell functions, including oxidative ATP production and cell fate decisions. ... ...

    Abstract Calcium signal propagation from endoplasmic reticulum (ER) to mitochondria regulates a multitude of mitochondrial and cell functions, including oxidative ATP production and cell fate decisions. Ca
    Language English
    Publishing date 2024-02-14
    Publishing country United States
    Document type Journal Article
    ZDB-ID 2964312-0
    ISSN 2515-2564 ; 2515-2564
    ISSN (online) 2515-2564
    ISSN 2515-2564
    DOI 10.1177/25152564241229273
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  2. Article ; Online: Effect of hormone-induced plasma membrane phosphatidylinositol 4,5-bisphosphate depletion on receptor endocytosis suggests the importance of local regulation in phosphoinositide signaling.

    Tóth, Dániel J / Tóth, József T / Damouni, Amir / Hunyady, László / Várnai, Péter

    Scientific reports

    2024  Volume 14, Issue 1, Page(s) 291

    Abstract: Phosphatidylinositol 4,5-bisphosphate (PIP2) has been shown to be critical for the endocytosis of G protein-coupled receptors (GPCRs). We have previously demonstrated that depletion of PIP2 by chemically induced plasma membrane (PM) recruitment of a 5- ... ...

    Abstract Phosphatidylinositol 4,5-bisphosphate (PIP2) has been shown to be critical for the endocytosis of G protein-coupled receptors (GPCRs). We have previously demonstrated that depletion of PIP2 by chemically induced plasma membrane (PM) recruitment of a 5-phosphatase domain prevents the internalization of the β2 adrenergic receptor (β2AR) from the PM to early endosomes. In this study, we tested the effect of hormone-induced PM PIP2 depletion on β2AR internalization using type-1 angiotensin receptor (AT1R) or M3 muscarinic acetylcholine receptor (M3R). We followed the endocytic route of β2ARs in HEK 293T cells using bioluminescence resonance energy transfer between the receptor and endosome marker Rab5. To compare the effect of lipid depletion by different means, we created and tested an AT1R fusion protein that is capable of both recruitment-based and hormone-induced depletion methods. The rate of PM PIP2 depletion was measured using a biosensor based on the PH domain of phospholipase Cδ1. As expected, β2AR internalization was inhibited when PIP2 depletion was evoked by recruiting 5-phosphatase to PM-anchored AT1R. A similar inhibition occurred when wild-type AT1R was activated by adding angiotensin II. However, stimulation of the desensitization/internalization-impaired mutant AT1R (TSTS/4A) caused very little inhibition of β2AR internalization, despite the higher rate of measurable PIP2 depletion. Interestingly, inhibition of PIP2 resynthesis with the selective PI4KA inhibitor GSK-A1 had little effect on the change in PH-domain-measured PM PIP2 levels but did significantly decrease β2AR internalization upon either AT1R or M3R activation, indicating the importance of a locally synthetized phosphoinositide pool in the regulation of this process.
    MeSH term(s) Phosphatidylinositols/metabolism ; Cell Membrane/metabolism ; Endocytosis ; Receptors, Angiotensin/metabolism ; Hormones/metabolism ; Phosphoric Monoester Hydrolases/metabolism ; Phosphatidylinositol 4,5-Diphosphate/metabolism
    Chemical Substances Phosphatidylinositols ; Receptors, Angiotensin ; Hormones ; Phosphoric Monoester Hydrolases (EC 3.1.3.2) ; Phosphatidylinositol 4,5-Diphosphate
    Language English
    Publishing date 2024-01-02
    Publishing country England
    Document type Journal Article
    ZDB-ID 2615211-3
    ISSN 2045-2322 ; 2045-2322
    ISSN (online) 2045-2322
    ISSN 2045-2322
    DOI 10.1038/s41598-023-50732-x
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  3. Article ; Online: Fluorescence imaging detection of nanodomain redox signaling events at organellar contacts.

    Booth, David M / Várnai, Péter / Joseph, Suresh K / Hajnóczky, György

    STAR protocols

    2022  Volume 3, Issue 1, Page(s) 101119

    Abstract: This protocol describes how to visualize, detect, and analyze redox signals (oxidative bursts) at the ER-mitochondrial interface. It uses drug-inducible crosslinking to target the genetically encoded glutathione redox sensor Grx1roGFP2 to organellar ... ...

    Abstract This protocol describes how to visualize, detect, and analyze redox signals (oxidative bursts) at the ER-mitochondrial interface. It uses drug-inducible crosslinking to target the genetically encoded glutathione redox sensor Grx1roGFP2 to organellar contact sites to measure local redox changes associated with transient depolarizations of the mitochondrial membrane potential (flickers). The strategy allows imaging of the oxidized to reduced glutathione ratio (GSSG:GSH) in subcellular regions below the diffraction limit with good temporal resolution and minimum phototoxicity. Moreover, the strategy also applies to diverse parameters including pH, H
    MeSH term(s) Hep G2 Cells ; Humans ; Kinetics ; Optical Imaging/methods ; Organelles/metabolism ; Oxidation-Reduction ; Signal Transduction
    Language English
    Publishing date 2022-01-20
    Publishing country United States
    Document type Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
    ISSN 2666-1667
    ISSN (online) 2666-1667
    DOI 10.1016/j.xpro.2021.101119
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  4. Article ; Online: Oxidative bursts of single mitochondria mediate retrograde signaling toward the ER.

    Booth, David M / Várnai, Péter / Joseph, Suresh K / Hajnóczky, György

    Molecular cell

    2021  Volume 81, Issue 18, Page(s) 3866–3876.e2

    Abstract: The emerging role of mitochondria as signaling organelles raises the question of whether individual mitochondria can initiate heterotypic communication with neighboring organelles. Using fluorescent probes targeted to the endoplasmic-reticulum- ... ...

    Abstract The emerging role of mitochondria as signaling organelles raises the question of whether individual mitochondria can initiate heterotypic communication with neighboring organelles. Using fluorescent probes targeted to the endoplasmic-reticulum-mitochondrial interface, we demonstrate that single mitochondria generate oxidative bursts, rapid redox oscillations, confined to the nanoscale environment of the interorganellar contact sites. Using probes fused to inositol 1,4,5-trisphosphate receptors (IP
    MeSH term(s) Calcium/metabolism ; Calcium Channels ; Calcium Signaling/physiology ; Cell Membrane Permeability/physiology ; Endoplasmic Reticulum/metabolism ; Endoplasmic Reticulum/physiology ; HEK293 Cells ; Hep G2 Cells ; Humans ; Inositol 1,4,5-Trisphosphate Receptors/metabolism ; Mitochondria/metabolism ; Mitochondrial Membranes/metabolism ; Oxidation-Reduction ; Protein Transport/physiology ; Respiratory Burst/genetics ; Respiratory Burst/physiology ; Single-Cell Analysis/methods
    Chemical Substances Calcium Channels ; Inositol 1,4,5-Trisphosphate Receptors ; mitochondrial calcium uniporter ; Calcium (SY7Q814VUP)
    Language English
    Publishing date 2021-08-04
    Publishing country United States
    Document type Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
    ZDB-ID 1415236-8
    ISSN 1097-4164 ; 1097-2765
    ISSN (online) 1097-4164
    ISSN 1097-2765
    DOI 10.1016/j.molcel.2021.07.014
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  5. Book ; Online: On Robustness Metrics for Learning STL Tasks

    Varnai, Peter / Dimarogonas, Dimos V.

    2020  

    Abstract: Signal temporal logic (STL) is a powerful tool for describing complex behaviors for dynamical systems. Among many approaches, the control problem for systems under STL task constraints is well suited for learning-based solutions, because STL is equipped ... ...

    Abstract Signal temporal logic (STL) is a powerful tool for describing complex behaviors for dynamical systems. Among many approaches, the control problem for systems under STL task constraints is well suited for learning-based solutions, because STL is equipped with robustness metrics that quantify the satisfaction of task specifications and thus serve as useful rewards. In this work, we examine existing and potential robustness metrics specifically from the perspective of how they can aid such learning algorithms. We show that various desirable properties restrict the form of potential metrics, and introduce a new one based on the results. The effectiveness of this new robustness metric for accelerating the learning procedure is demonstrated through an insightful case study.

    Comment: The paper has been accepted for publishing in the Proceedings of the 2020 American Control Conference (ACC)
    Keywords Electrical Engineering and Systems Science - Systems and Control
    Subject code 006
    Publishing date 2020-03-12
    Publishing country us
    Document type Book ; Online
    Database BASE - Bielefeld Academic Search Engine (life sciences selection)

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  6. Book ; Online: Guided Policy Improvement for Satisfying STL Tasks using Funnel Adaptation

    Varnai, Peter / Dimarogonas, Dimos V.

    2020  

    Abstract: We introduce a sampling-based learning method for solving optimal control problems involving task satisfaction constraints for systems with partially known dynamics. The control problems are defined by a cost to be minimized and a task to be satisfied, ... ...

    Abstract We introduce a sampling-based learning method for solving optimal control problems involving task satisfaction constraints for systems with partially known dynamics. The control problems are defined by a cost to be minimized and a task to be satisfied, given in the language of signal temporal logic (STL). The complex nature of possible tasks generally makes them difficult to satisfy through random exploration, which limits the practical feasibility of the learning algorithm. Recent work has shown, however, that using a controller to guide the learning process by leveraging available knowledge of system dynamics to aid task satisfaction is greatly beneficial for improving the sample efficiency of the method. Motivated by these findings, this work introduces a controller derivation framework which naturally leads to computationally efficient controllers capable of offering such guidance during the learning process. The derived controllers aim to satisfy a set of so-called robustness specifications or funnels that are imposed on the temporal evolutions of the atomic propositions composing the STL task. Ideally, these specifications are prescribed in a way such that their satisfaction would lead to satisfaction of the STL task. In practice, however, such ideal funnels are not necessarily known a priori, and the guidance the controller offers depends on their estimates. This issue is hereby addressed by introducing an adaptation scheme for automatically updating the funnels during the learning procedure, thus diminishing the role of their initial, user-specified values. The effectiveness of the resulting learning algorithm is demonstrated by two simulation case studies.

    Comment: 17 pages, IJRR submission (under review)
    Keywords Electrical Engineering and Systems Science - Systems and Control
    Subject code 004
    Publishing date 2020-04-12
    Publishing country us
    Document type Book ; Online
    Database BASE - Bielefeld Academic Search Engine (life sciences selection)

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  7. Book ; Online: Gradient-Based STL Control with Application to Nonholonomic Systems

    Varnai, Peter / Dimarogonas, Dimos V.

    2019  

    Abstract: In this paper, we study the control of dynamical systems under temporal logic task specifications using gradient-based methods relying on quantitative measures that express the extent to which the tasks are satisfied. A class of controllers capable of ... ...

    Abstract In this paper, we study the control of dynamical systems under temporal logic task specifications using gradient-based methods relying on quantitative measures that express the extent to which the tasks are satisfied. A class of controllers capable of providing satisfaction guarantees for simple systems and specifications is introduced and then extended for the case of unicycle-like dynamics. The possibility of combining such controllers in order to tackle more complex task specifications while retaining their computational efficiency is examined, and the practicalities related to an effective combination are demonstrated through a simulation study. The introduced framework for controller design lays ground for future work in the direction of effectively combining such elementary controllers for the purpose of aiding exploration in learning algorithms.
    Keywords Electrical Engineering and Systems Science - Systems and Control
    Publishing date 2019-09-05
    Publishing country us
    Document type Book ; Online
    Database BASE - Bielefeld Academic Search Engine (life sciences selection)

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  8. Book ; Online: Prescribed Performance Control Guided Policy Improvement for Satisfying Signal Temporal Logic Tasks

    Varnai, Peter / Dimarogonas, Dimos V.

    2019  

    Abstract: Signal temporal logic (STL) provides a user-friendly interface for defining complex tasks for robotic systems. Recent efforts aim at designing control laws or using reinforcement learning methods to find policies which guarantee satisfaction of these ... ...

    Abstract Signal temporal logic (STL) provides a user-friendly interface for defining complex tasks for robotic systems. Recent efforts aim at designing control laws or using reinforcement learning methods to find policies which guarantee satisfaction of these tasks. While the former suffer from the trade-off between task specification and computational complexity, the latter encounter difficulties in exploration as the tasks become more complex and challenging to satisfy. This paper proposes to combine the benefits of the two approaches and use an efficient prescribed performance control (PPC) base law to guide exploration within the reinforcement learning algorithm. The potential of the method is demonstrated in a simulated environment through two sample navigational tasks.

    Comment: This is the extended version of the paper accepted to the 2019 American Control Conference (ACC), Philadelphia (to be published)
    Keywords Computer Science - Systems and Control
    Subject code 629
    Publishing date 2019-03-11
    Publishing country us
    Document type Book ; Online
    Database BASE - Bielefeld Academic Search Engine (life sciences selection)

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  9. Article: Oxidative bursts of single mitochondria mediate retrograde signaling toward the ER

    Booth, David M. / Várnai, Péter / Joseph, Suresh K. / Hajnóczky, György

    Molecular cell. 2021 Sept. 16, v. 81, no. 18

    2021  

    Abstract: The emerging role of mitochondria as signaling organelles raises the question of whether individual mitochondria can initiate heterotypic communication with neighboring organelles. Using fluorescent probes targeted to the endoplasmic-reticulum- ... ...

    Abstract The emerging role of mitochondria as signaling organelles raises the question of whether individual mitochondria can initiate heterotypic communication with neighboring organelles. Using fluorescent probes targeted to the endoplasmic-reticulum-mitochondrial interface, we demonstrate that single mitochondria generate oxidative bursts, rapid redox oscillations, confined to the nanoscale environment of the interorganellar contact sites. Using probes fused to inositol 1,4,5-trisphosphate receptors (IP₃Rs), we show that Ca²⁺ channels directly sense oxidative bursts and respond with Ca²⁺ transients adjacent to active mitochondria. Application of specific mitochondrial stressors or apoptotic stimuli dramatically increases the frequency and amplitude of the oxidative bursts by enhancing transient permeability transition pore openings. Conversely, blocking interface Ca²⁺ transport via elimination of IP₃Rs or mitochondrial calcium uniporter channels suppresses ER-mitochondrial Ca²⁺ feedback and cell death. Thus, single mitochondria initiate local retrograde signaling by miniature oxidative bursts and, upon metabolic or apoptotic stress, may also amplify signals to the rest of the cell.
    Keywords apoptosis ; calcium ; fluorescence ; inositols ; mitochondria ; permeability
    Language English
    Dates of publication 2021-0916
    Size p. 3866-3876.e2.
    Publishing place Elsevier Inc.
    Document type Article
    ZDB-ID 1415236-8
    ISSN 1097-4164 ; 1097-2765
    ISSN (online) 1097-4164
    ISSN 1097-2765
    DOI 10.1016/j.molcel.2021.07.014
    Database NAL-Catalogue (AGRICOLA)

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  10. Article ; Online: The Evidence REVEAL Study: Exploring the Use of Real-World Evidence and Complex Clinical Trial Design by the European Pharmaceutical Industry.

    Varnai, Peter / Davé, Anoushka / Farla, Kristine / Nooijen, Anke / Petrosova, Liana

    Clinical pharmacology and therapeutics

    2020  Volume 110, Issue 5, Page(s) 1180–1189

    Abstract: The rapid evolution of science and technology allows innovative approaches to generate new types of evidence about the effectiveness of medical product development so as to speed up patients' access to better diagnostics and treatment. Our study explored ...

    Abstract The rapid evolution of science and technology allows innovative approaches to generate new types of evidence about the effectiveness of medical product development so as to speed up patients' access to better diagnostics and treatment. Our study explored how two emerging approaches, the use of real-world evidence (RWE) and complex clinical trial (CCT) design, are currently being used by the pharmaceutical industry to support premarketing authorization of medical product development and reviewed the international landscape for regulatory acceptance of such novel approaches. Combining evidence from a literature review, company survey, and interviews with international regulators and experts, we found that 80% of Europe-based pharmaceutical companies have used RWE and 50% have used CCTs, in some capacity. Further, we present case examples of how companies are using these approaches and how international regulators are preparing for such developments. To conclude, we provide a set of recommendations for European industry and regulators to consider so that these novel approaches achieve their full potential within the EU regulatory system.
    MeSH term(s) Clinical Trials as Topic/methods ; Clinical Trials as Topic/statistics & numerical data ; Data Analysis ; Drug Industry/methods ; Drug Industry/statistics & numerical data ; Europe/epidemiology ; Humans
    Language English
    Publishing date 2020-12-17
    Publishing country United States
    Document type Journal Article ; Review
    ZDB-ID 123793-7
    ISSN 1532-6535 ; 0009-9236
    ISSN (online) 1532-6535
    ISSN 0009-9236
    DOI 10.1002/cpt.2103
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