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  1. Article ; Online: Deconstructing the integrated oscillator model for pancreatic β-cells.

    Bertram, Richard / Marinelli, Isabella / Fletcher, Patrick A / Satin, Leslie S / Sherman, Arthur S

    Mathematical biosciences

    2023  Volume 365, Page(s) 109085

    Abstract: Electrical bursting oscillations in the β-cells of pancreatic islets have been a focus of investigation for more than fifty years. This has been aided by mathematical models, which are descendants of the pioneering Chay-Keizer model. This article ... ...

    Abstract Electrical bursting oscillations in the β-cells of pancreatic islets have been a focus of investigation for more than fifty years. This has been aided by mathematical models, which are descendants of the pioneering Chay-Keizer model. This article describes the key biophysical and mathematical elements of this model, and then describes the path forward from there to the Integrated Oscillator Model (IOM). It is both a history and a deconstruction of the IOM that describes the various elements that have been added to the model over time, and the motivation for adding them. Finally, the article is a celebration of the 40th anniversary of the publication of the Chay-Keizer model.
    Language English
    Publishing date 2023-10-04
    Publishing country United States
    Document type Journal Article
    ZDB-ID 1126-5
    ISSN 1879-3134 ; 0025-5564
    ISSN (online) 1879-3134
    ISSN 0025-5564
    DOI 10.1016/j.mbs.2023.109085
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    Zs.A 1534: Show issues Location:
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  2. Article ; Online: β-cell intrinsic dynamics rather than gap junction structure dictates subpopulations in the islet functional network.

    Briggs, Jennifer K / Gresch, Anne / Marinelli, Isabella / Dwulet, JaeAnn M / Albers, David J / Kravets, Vira / Benninger, Richard K P

    eLife

    2023  Volume 12

    Abstract: Diabetes is caused by the inability of electrically coupled, functionally heterogeneous β-cells within the pancreatic islet to provide adequate insulin secretion. Functional networks have been used to represent synchronized oscillatory [ ... ...

    Abstract Diabetes is caused by the inability of electrically coupled, functionally heterogeneous β-cells within the pancreatic islet to provide adequate insulin secretion. Functional networks have been used to represent synchronized oscillatory [Ca
    MeSH term(s) Humans ; Insulin-Secreting Cells/metabolism ; Gap Junctions/metabolism ; Islets of Langerhans/metabolism ; Insulin Secretion ; Diabetes Mellitus/metabolism
    Language English
    Publishing date 2023-11-29
    Publishing country England
    Document type Journal Article
    ZDB-ID 2687154-3
    ISSN 2050-084X ; 2050-084X
    ISSN (online) 2050-084X
    ISSN 2050-084X
    DOI 10.7554/eLife.83147
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  3. Article: Symbiosis of Electrical and Metabolic Oscillations in Pancreatic β-Cells.

    Marinelli, Isabella / Fletcher, Patrick A / Sherman, Arthur S / Satin, Leslie S / Bertram, Richard

    Frontiers in physiology

    2021  Volume 12, Page(s) 781581

    Abstract: Insulin is secreted in a pulsatile pattern, with important physiological ramifications. In pancreatic β-cells, which are the cells that synthesize insulin, insulin exocytosis is elicited by pulses of elevated intracellular ... ...

    Abstract Insulin is secreted in a pulsatile pattern, with important physiological ramifications. In pancreatic β-cells, which are the cells that synthesize insulin, insulin exocytosis is elicited by pulses of elevated intracellular Ca
    Language English
    Publishing date 2021-12-03
    Publishing country Switzerland
    Document type Journal Article ; Review
    ZDB-ID 2564217-0
    ISSN 1664-042X
    ISSN 1664-042X
    DOI 10.3389/fphys.2021.781581
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  4. Article ; Online: Oscillations in K(ATP) conductance drive slow calcium oscillations in pancreatic β-cells.

    Marinelli, Isabella / Thompson, Benjamin M / Parekh, Vishal S / Fletcher, Patrick A / Gerardo-Giorda, Luca / Sherman, Arthur S / Satin, Leslie S / Bertram, Richard

    Biophysical journal

    2022  Volume 121, Issue 8, Page(s) 1449–1464

    Abstract: ATP-sensitive ... ...

    Abstract ATP-sensitive K
    MeSH term(s) Adenosine Diphosphate/metabolism ; Adenosine Triphosphate/metabolism ; Animals ; Calcium/metabolism ; Calcium Signaling/physiology ; Glucose/metabolism ; Glucose/pharmacology ; Insulin/metabolism ; Islets of Langerhans/metabolism ; Membrane Potentials/physiology ; Mice
    Chemical Substances Insulin ; Adenosine Diphosphate (61D2G4IYVH) ; Adenosine Triphosphate (8L70Q75FXE) ; Glucose (IY9XDZ35W2) ; Calcium (SY7Q814VUP)
    Language English
    Publishing date 2022-03-15
    Publishing country United States
    Document type Journal Article ; Research Support, U.S. Gov't, Non-P.H.S. ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
    ZDB-ID 218078-9
    ISSN 1542-0086 ; 0006-3495
    ISSN (online) 1542-0086
    ISSN 0006-3495
    DOI 10.1016/j.bpj.2022.03.015
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  5. Article ; Online: Circadian distribution of epileptiform discharges in epilepsy: Candidate mechanisms of variability.

    Marinelli, Isabella / Walker, Jamie J / Seneviratne, Udaya / D'Souza, Wendyl / Cook, Mark J / Anderson, Clare / Bagshaw, Andrew P / Lightman, Stafford L / Woldman, Wessel / Terry, John R

    PLoS computational biology

    2023  Volume 19, Issue 10, Page(s) e1010508

    Abstract: Epilepsy is a serious neurological disorder characterised by a tendency to have recurrent, spontaneous, seizures. Classically, seizures are assumed to occur at random. However, recent research has uncovered underlying rhythms both in seizures and in key ... ...

    Abstract Epilepsy is a serious neurological disorder characterised by a tendency to have recurrent, spontaneous, seizures. Classically, seizures are assumed to occur at random. However, recent research has uncovered underlying rhythms both in seizures and in key signatures of epilepsy-so-called interictal epileptiform activity-with timescales that vary from hours and days through to months. Understanding the physiological mechanisms that determine these rhythmic patterns of epileptiform discharges remains an open question. Many people with epilepsy identify precipitants of their seizures, the most common of which include stress, sleep deprivation and fatigue. To quantify the impact of these physiological factors, we analysed 24-hour EEG recordings from a cohort of 107 people with idiopathic generalized epilepsy. We found two subgroups with distinct distributions of epileptiform discharges: one with highest incidence during sleep and the other during day-time. We interrogated these data using a mathematical model that describes the transitions between background and epileptiform activity in large-scale brain networks. This model was extended to include a time-dependent forcing term, where the excitability of nodes within the network could be modulated by other factors. We calibrated this forcing term using independently-collected human cortisol (the primary stress-responsive hormone characterised by circadian and ultradian patterns of secretion) data and sleep-staged EEG from healthy human participants. We found that either the dynamics of cortisol or sleep stage transition, or a combination of both, could explain most of the observed distributions of epileptiform discharges. Our findings provide conceptual evidence for the existence of underlying physiological drivers of rhythms of epileptiform discharges. These findings should motivate future research to explore these mechanisms in carefully designed experiments using animal models or people with epilepsy.
    MeSH term(s) Animals ; Humans ; Hydrocortisone ; Epilepsy ; Seizures ; Epilepsy, Generalized ; Electroencephalography
    Chemical Substances Hydrocortisone (WI4X0X7BPJ)
    Language English
    Publishing date 2023-10-05
    Publishing country United States
    Document type Journal Article ; Research Support, Non-U.S. Gov't
    ZDB-ID 2193340-6
    ISSN 1553-7358 ; 1553-734X
    ISSN (online) 1553-7358
    ISSN 1553-734X
    DOI 10.1371/journal.pcbi.1010508
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  6. Article ; Online: Chronic stimulation induces adaptive potassium channel activity that restores calcium oscillations in pancreatic islets in vitro.

    Law, Nathan C / Marinelli, Isabella / Bertram, Richard / Corbin, Kathryn L / Schildmeyer, Cara / Nunemaker, Craig S

    American journal of physiology. Endocrinology and metabolism

    2020  Volume 318, Issue 4, Page(s) E554–E563

    Abstract: Insulin pulsatility is important to hepatic response in regulating blood glucose. Growing evidence suggests that insulin-secreting pancreatic β-cells can adapt to chronic disruptions of pulsatility to rescue this physiologically important behavior. We ... ...

    Abstract Insulin pulsatility is important to hepatic response in regulating blood glucose. Growing evidence suggests that insulin-secreting pancreatic β-cells can adapt to chronic disruptions of pulsatility to rescue this physiologically important behavior. We determined the time scale for adaptation and examined potential ion channels underlying it. We induced the adaptation both by chronic application of the ATP-sensitive K
    MeSH term(s) Adaptation, Physiological ; Animals ; Calcium Signaling ; Cell Membrane/drug effects ; Cell Membrane/metabolism ; Congenital Hyperinsulinism/metabolism ; Humans ; Insulin-Secreting Cells/drug effects ; Insulin-Secreting Cells/metabolism ; Islets of Langerhans/metabolism ; KATP Channels/metabolism ; Male ; Mice ; Models, Theoretical ; Potassium Channel Blockers/pharmacology ; Potassium Channels/metabolism ; Potassium Channels, Inwardly Rectifying/metabolism ; Potassium Chloride ; Stimulation, Chemical ; Tolbutamide/pharmacology
    Chemical Substances KATP Channels ; Kir2.1 channel ; Potassium Channel Blockers ; Potassium Channels ; Potassium Channels, Inwardly Rectifying ; Potassium Chloride (660YQ98I10) ; Tolbutamide (982XCM1FOI)
    Language English
    Publishing date 2020-02-18
    Publishing country United States
    Document type Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
    ZDB-ID 603841-4
    ISSN 1522-1555 ; 0193-1849
    ISSN (online) 1522-1555
    ISSN 0193-1849
    DOI 10.1152/ajpendo.00482.2019
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  7. Article ; Online: Transitions between bursting modes in the integrated oscillator model for pancreatic β-cells.

    Marinelli, Isabella / Vo, Theodore / Gerardo-Giorda, Luca / Bertram, Richard

    Journal of theoretical biology

    2018  Volume 454, Page(s) 310–319

    Abstract: Insulin-secreting β-cells of pancreatic islets of Langerhans produce bursts of electrical impulses, resulting in intracellular ... ...

    Abstract Insulin-secreting β-cells of pancreatic islets of Langerhans produce bursts of electrical impulses, resulting in intracellular Ca
    MeSH term(s) Adenosine Triphosphate/metabolism ; Animals ; Biological Clocks/physiology ; Calcium/metabolism ; Calcium Signaling/physiology ; Carbohydrate Metabolism/physiology ; Cells, Cultured ; Glucose/metabolism ; Humans ; Insulin/metabolism ; Insulin-Secreting Cells/metabolism ; Models, Biological ; Models, Theoretical ; Pulsatile Flow ; Secretory Pathway/physiology
    Chemical Substances Insulin ; Adenosine Triphosphate (8L70Q75FXE) ; Glucose (IY9XDZ35W2) ; Calcium (SY7Q814VUP)
    Language English
    Publishing date 2018-06-20
    Publishing country England
    Document type Journal Article ; Research Support, Non-U.S. Gov't ; Research Support, U.S. Gov't, Non-P.H.S.
    ZDB-ID 2972-5
    ISSN 1095-8541 ; 0022-5193
    ISSN (online) 1095-8541
    ISSN 0022-5193
    DOI 10.1016/j.jtbi.2018.06.017
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    Zs.A 923: Show issues Location:
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  8. Article ; Online: Slow oscillations persist in pancreatic beta cells lacking phosphofructokinase M.

    Marinelli, Isabella / Parekh, Vishal / Fletcher, Patrick / Thompson, Benjamin / Ren, Jinhua / Tang, Xiaoqing / Saunders, Thomas L / Ha, Joon / Sherman, Arthur / Bertram, Richard / Satin, Leslie S

    Biophysical journal

    2022  Volume 121, Issue 5, Page(s) 692–704

    Abstract: Pulsatile insulin secretion by pancreatic beta cells is necessary for tight glucose control in the body. Glycolytic oscillations have been proposed as the mechanism for generating the electrical oscillations underlying pulsatile insulin secretion. The ... ...

    Abstract Pulsatile insulin secretion by pancreatic beta cells is necessary for tight glucose control in the body. Glycolytic oscillations have been proposed as the mechanism for generating the electrical oscillations underlying pulsatile insulin secretion. The glycolytic enzyme 6-phosphofructokinase-1 (PFK) synthesizes fructose-1,6-bisphosphate (FBP) from fructose-6-phosphate. It has been proposed that the slow electrical and Ca
    MeSH term(s) Animals ; Calcium/metabolism ; Glucose/metabolism ; Insulin/metabolism ; Insulin Secretion ; Insulin-Secreting Cells/metabolism ; Islets of Langerhans ; Mice ; Phosphofructokinase-1/genetics ; Phosphofructokinase-1/metabolism
    Chemical Substances Insulin ; Phosphofructokinase-1 (EC 2.7.1.11) ; Glucose (IY9XDZ35W2) ; Calcium (SY7Q814VUP)
    Language English
    Publishing date 2022-02-05
    Publishing country United States
    Document type Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't ; Research Support, U.S. Gov't, Non-P.H.S.
    ZDB-ID 218078-9
    ISSN 1542-0086 ; 0006-3495
    ISSN (online) 1542-0086
    ISSN 0006-3495
    DOI 10.1016/j.bpj.2022.01.027
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  9. Article ; Online: Patient-specific computational modeling of cortical spreading depression via diffusion tensor imaging.

    Kroos, Julia M / Marinelli, Isabella / Diez, Ibai / Cortes, Jesus M / Stramaglia, Sebastiano / Gerardo-Giorda, Luca

    International journal for numerical methods in biomedical engineering

    2017  Volume 33, Issue 11

    Abstract: Cortical spreading depression, a depolarization wave originating in the visual cortex and traveling towards the frontal lobe, is commonly accepted as a correlate of migraine visual aura. As of today, little is known about the mechanisms that can trigger ... ...

    Abstract Cortical spreading depression, a depolarization wave originating in the visual cortex and traveling towards the frontal lobe, is commonly accepted as a correlate of migraine visual aura. As of today, little is known about the mechanisms that can trigger or stop such phenomenon. However, the complex and highly individual characteristics of the brain cortex suggest that the geometry might have a significant impact in supporting or contrasting the propagation of cortical spreading depression. Accurate patient-specific computational models are fundamental to cope with the high variability in cortical geometries among individuals, but also with the conduction anisotropy induced in a given cortex by the complex neuronal organisation in the grey matter. In this paper, we integrate a distributed model for extracellular potassium concentration with patient-specific diffusivity tensors derived locally from diffusion tensor imaging data.
    MeSH term(s) Cortical Spreading Depression ; Diffusion Tensor Imaging ; Humans ; Patient-Specific Modeling ; Visual Cortex/diagnostic imaging ; Visual Cortex/physiology
    Language English
    Publishing date 2017
    Publishing country England
    Document type Journal Article ; Research Support, Non-U.S. Gov't
    ZDB-ID 2540968-2
    ISSN 2040-7947 ; 2040-7939
    ISSN (online) 2040-7947
    ISSN 2040-7939
    DOI 10.1002/cnm.2874
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  10. Article ; Online: Estimation of age-specific rates of reactivation and immune boosting of the varicella zoster virus.

    Marinelli, Isabella / van Lier, Alies / de Melker, Hester / Pugliese, Andrea / van Boven, Michiel

    Epidemics

    2017  Volume 19, Page(s) 1–12

    Abstract: Studies into the impact of vaccination against the varicella zoster virus (VZV) have increasingly focused on herpes zoster (HZ), which is believed to be increasing in vaccinated populations with decreasing infection pressure. This idea can be traced back ...

    Abstract Studies into the impact of vaccination against the varicella zoster virus (VZV) have increasingly focused on herpes zoster (HZ), which is believed to be increasing in vaccinated populations with decreasing infection pressure. This idea can be traced back to Hope-Simpson's hypothesis, in which a person's immune status determines the likelihood that he/she will develop HZ. Immunity decreases over time, and can be boosted by contact with a person experiencing varicella (exogenous boosting) or by a reactivation attempt of the virus (endogenous boosting). Here we use transmission models to estimate age-specific rates of reactivation and immune boosting, exogenous as well as endogenous, using zoster incidence data from the Netherlands (2002-2011, n=7026). The boosting and reactivation rates are estimated with splines, enabling these quantities to be optimally informed by the data. The analyses show that models with high levels of exogenous boosting and estimated or zero endogenous boosting, constant rate of loss of immunity, and reactivation rate increasing with age (to more than 5% per year in the elderly) give the best fit to the data. Estimates of the rates of immune boosting and reactivation are strongly correlated. This has important implications as these parameters determine the fraction of the population with waned immunity. We conclude that independent evidence on rates of immune boosting and reactivation in persons with waned immunity are needed to robustly predict the impact of varicella vaccination on the incidence of HZ.
    Language English
    Publishing date 2017-06
    Publishing country Netherlands
    Document type Journal Article
    ZDB-ID 2467993-8
    ISSN 1878-0067 ; 1755-4365
    ISSN (online) 1878-0067
    ISSN 1755-4365
    DOI 10.1016/j.epidem.2016.11.001
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