Publications by authors named "Ryan Vogt"

5 Publications

  • Page 1 of 1

Controllability and state feedback control of a cardiac ionic cell model.

Comput Biol Med 2021 Sep 30;139:104909. Epub 2021 Sep 30.

School of Mathematical Sciences, Rochester Institute of Technology, Rochester, NY, 14623, USA. Electronic address:

A phenomenon called alternans, which is a beat-to-beat alternation in action potential (AP) duration, sometimes precedes fatal cardiac arrhythmias. Alternans-suppressing electrical stimulus protocols are often represented as perturbations to the dynamics of membrane potential or AP duration variables in nonlinear models of cardiac tissue. Controllability analysis has occasionally been applied to cardiac AP models to determine whether different control or perturbation strategies are capable of suppressing alternans or other unwanted behavior. Since almost all previous cardiac controllability studies have focused on low-dimensional models, we conducted the present study to assess controllability of a higher-dimensional model, specifically the Luo Rudy dynamic (LRd) model of a cardiac ventricular myocyte. Higher-dimensional models are of interest because they provide information on the influence of a wider range of measurable quantities, including ionic concentrations, on controllability. After computing modal controllability measures, we found that larger eigenvalues of a linearized LRd model were on average more strongly controllable through perturbations to calcium-ion concentrations compared with perturbations to other variables. When only membrane potential was adjusted, the best time to apply perturbations (in the sense of maximizing controllability of the largest alternans eigenvalue) was near the AP peak time for shorter cycle lengths. Controllability results were found to be similar for both the default model parameters and for an alternans-promoting parameter set. Additionally, we developed several alternans-suppressing state feedback controllers that were tested in simulations. For the scenarios examined, our controllability measures correctly predicted which strategies and perturbation timings would lead to better feedback controller performance.
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http://dx.doi.org/10.1016/j.compbiomed.2021.104909DOI Listing
September 2021

Observability analysis and state observer design for a cardiac ionic cell model.

Comput Biol Med 2020 10 8;125:103910. Epub 2020 Jul 8.

School of Mathematical Sciences, Rochester Institute of Technology, Rochester, NY, 14623, USA. Electronic address:

To gain insights into cardiac arrhythmias, researchers have developed and employed various measurement techniques, such as electrocardiography, optical mapping, and patch clamping. However, there are no measurement methods that allow simultaneous recording of all cellular quantities, including intracellular ionic concentrations and gating states, that may play an important role in arrhythmia formation. To help address this shortcoming, we applied observability analysis, a method from control theory, to the Luo-Rudy dynamic (LRd) model of a cardiac ventricular myocyte. After linearizing the time-integrated LRd model about selected periodic orbits, we computed the observability properties of the model to determine whether past system states could be reconstructed from different hypothetical sets of measurements. Under the simplifying assumption that only one dynamical variable could be measured periodically, we found that intracellular potassium concentration generally yielded the largest observability values and thus contained the most information about the dominant modes of the system. The impacts on observability of measurement timings, inter-stimulus interval length, and an alternans-promoting parameter shift were also studied. Pole-placement state observer algorithms were designed and tested in simulations for several scenarios, and we found that it is possible to infer unmeasured variables from potassium-concentration measurements, and to an extent from membrane-potential measurements, both for longer periods that represent normal rhythms and shorter periods associated with tachyarrhythmias. Our results could lead to improved data assimilation algorithms that combine model predictions with measurements to estimate quantities that are difficult or impossible to measure during in vitro experiments.
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http://dx.doi.org/10.1016/j.compbiomed.2020.103910DOI Listing
October 2020

Preparation and utilization of a reagent for the isolation and purification of low-molecular-mass thiols.

Anal Biochem 2004 Feb;325(1):21-7

Division of Chemical Pathology, Faculty of Health Sciences, University of Cape Town, Observatory 7935, Cape Town, South Africa.

Problems inherent in the isolation of thiols from natural sources, such as oxidation, undesirable addition reactions, and low concentration of thiol species in cell-free extracts, can be circumvented by reversible derivatization to a less labile form which can be concentrated selectively. These objectives are realized by converting thiols to heterodisulfides in which the thiol partner is an apolar thiol with strong affinity for hydrophobic stationary phases. When reacted with 2-S-(2(')-thiopyridyl)-6-hydroxynaphthyldisulfide at pH<5, where most thiol species are relatively stable to atmospheric oxidation, mixed disulfides with 2-mercapto-6-hydroxynaphthalene as the apolar partner are obtained in good yield and can be concentrated onto a hydrophobic stationary phase. Such heterodisulfides exhibit excellent chromatographic properties when separated on reversed-phase media and the derivatization reaction can, therefore, be conveniently monitored. Following their isolation as the heterodisulfides the thiol species of interest are recovered by reduction and facile separation from the apolar 2-mercapto-6-hydroxynaphthalene partner.
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http://dx.doi.org/10.1016/j.ab.2003.10.011DOI Listing
February 2004

The metabolism of nitrosothiols in the Mycobacteria: identification and characterization of S-nitrosomycothiol reductase.

Biochem J 2003 Sep;374(Pt 3):657-66

Division of Chemical Pathology, Faculty of Health Sciences, University of Cape Town, Observatory 7935, South Africa.

When grown in culture Mycobacterium smegmatis metabolized S-nitrosoglutathione to oxidized glutathione and nitrate, which suggested a possible involvement of an S-nitrosothiol reductase and mycobacterial haemoglobin. The mycothiol-dependent formaldehyde dehydrogenase from M. smegmatis was purified by a combination of Ni2+-IMAC (immobilized metal ion affinity chromatography), hydrophobic interaction, anion-exchange and affinity chromatography. The enzyme had a subunit molecular mass of 38263 kDa. Steady-state kinetic studies indicated that the enzyme catalyses the NAD+-dependent conversion of S-hydroxymethylmycothiol into formic acid and mycothiol by a rapid-equilibrium ordered mechanism. The enzyme also catalysed an NADH-dependent decomposition of S-nitrosomycothiol (MSNO) by a sequential mechanism and with an equimolar stoichiometry of NADH:MSNO, which indicated that the enzyme reduces the nitroso group to the oxidation level of nitroxyl. Vmax for the MSNO reductase reaction indicated a turnover per subunit of approx. 116700 min(-1), which was 76-fold faster than the formaldehyde dehydrogenase activity. A gene, Rv2259, annotated as a class III alcohol dehydrogenase in the Mycobacterium tuberculosis genome was cloned and expressed in M. smegmatis as the C-terminally His6-tagged product. The purified recombinant enzyme from M. tuberculosis also catalysed both activities. M. smegmatis S-nitrosomycothiol reductase converted MSNO into the N -hydroxysulphenamide, which readily rearranged to mycothiolsulphinamide. In the presence of MSNO reductase, M. tuberculosis HbN (haemoglobin N) was converted with low efficiency into metHbN [HbN(Fe3+)] and this conversion was dependent on turnover of MSNO reductase. These observations suggest a possible route in vivo for the dissimilation of S-nitrosoglutathione.
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http://dx.doi.org/10.1042/BJ20030642DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC1223637PMC
September 2003

The metabolism of S-nitrosothiols in the trypanosomatids: the role of ovothiol A and trypanothione.

Biochem J 2003 Apr;371(Pt 1):49-59

Division of Chemical Pathology, Department of Laboratory Medicine, University of Cape Town Medical School, Observatory, 7925, South Africa.

It has recently been established that nitrosoglutathione is the preferred substrate of the glutathione-dependent formaldehyde dehydrogenase from divergent organisms. Trypanosomatids produce not only glutathione, but also glutathionylspermidine, trypanothione and ovothiol A. The formaldehyde dehydrogenase activity of Crithidia fasciculata was independent of these thiols and extracts possessed very low levels of nitrosothiol reductase activity with glutathione or its spermidine conjugates as the thiol component. Although ovothiol A did not form a stable nitrosothiol, it decomposed the S -nitroso groups of nitrosoglutathione (GSNO) and dinitrotrypanothione [T(SNO)(2)] with second-order rate constants of 19.12 M(-1) x s(-1) and 8.67 M(-1) x s(-1) respectively. The reaction of T(SNO)(2) with ovothiol A, however, accelerated to a rate similar to that seen with GSNO. Ovothiol A can act catalytically to decompose these nitrosothiols, although non-productive mechanisms exist. The catalytic phase of the reaction was dependent on the production of thiyl radicals, since it was abolished in the presence of 5,5-dimethyl-1-pyrroline- N -oxide and the formation of nitric oxide could be detected by means of the conversion of oxyhaemoglobin into methaemoglobin. The rate-limiting step in the catalytic process was the reduction of oxidized ovothiol species and, in this respect, T(SNO)(2) is a more efficient substrate than GSNO. Trypanothione decomposed GSNO with a second-order rate constant of 0.786 M(-1) x s(-1) and the major nitrogenous end product changed from nitrite to ammonia as the ratio of thiol to nitrosothiol increased. The results indicate that ovothiol A acts in synergy with trypanothione in the decomposition of T(SNO)(2).
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http://dx.doi.org/10.1042/BJ20021649DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC1223258PMC
April 2003
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