Search

Layer-by-layer (LbL) assembly is a widely used tool for engineering materials and coatings. In this Perspective, dedicated to the memory of ACS Nano associate editor Prof. Dr. Helmuth Möhwald, we discuss the developments and applications that are to come in LbL assembly, focusing on coatings, bulk materials, membranes, nanocomposites, and delivery vehicles.

Objective: to clarify the causes and changes of body temperature in relation to the type of stroke and the presence or absence of pyoinflammatory complications.Subjects and methods. The case histories were retrospectively analyzed in 211 survivors and deceased patients with acute cerebrovascular accident at the age of 38—87 years. In the patients from different groups and subgroups, changes in their temperature were assessed from its curves during their hospital stay. Indicators, such as initiation of hyperthermia (hours), duration of hyperthermia (days) and unrelieved hyperthermia (hours), were estimated. The pattern and number of pyoinflammatory complications in each patient were taken into account.Results. The paper deals with the retrospective analysis of a temperature response in the survivors and deceased patients with myocardial infarction and intracerebral hemorrhage. It shows body temperature changes in relation to the type of stroke and the presence or absence of pyoinflammatory complications, such as pneumonia, meningitis, purulent tracheobronchitis, etc. The main causes of hyperthermia in stroke were elucidated.Conclusion. Hyperthermia affects negatively the outcome of stroke and increases the length of hospital stay regardless of the type of stroke. In patients with acute cerebrovascular accident, the causes of hyperthermia are a focus of brain injury, blood in the cerebrospinal fluid system, and pyoinflammatory complications., Цель работы — уточнить причины повышения и динамику температуры тела в зависимости от вида инсульта и наличия или отсутствия гнойно-воспалительных осложнений.Материалы и методы. Проведен ретроспективный анализ историй болезни 211 выживших и умерших пациентов с острым нарушением мозгового кровообращения в возрасте 38—87 лет. Изменения температуры у больных разных групп и подгрупп оценивали по температурным кривым за все время пребывания пациентов в стационаре. Оценивали такие параметры, как начало гипертермии (час), продолжительность гипертермии (сутки), продолжительность гипертермии (час), продолжительность некупируемой гипертермии (час). Вели учет структуры и количества гнойно-воспалительных осложнений у каждого больного.Результаты. Статья посвящена ретроспективному анализу температурной реакции у выживших и умерших больных с инфарктом мозга (ИМ) и внутримозговым кровоизлиянием (ВК). Представлены изменения температуры тела в зависимости от вида инсульта и наличия или отсутствия гнойно-воспалительных осложнений, таких как пневмония, менингит, гнойный трахеобронхит и др. Уточнены основные причины гипертермии при инсульте.Выводы. Гипертермия неблагоприятно влияет на исход инсульта; увеличивает сроки пребывания больных в стационаре независимо от вида инсульта. Причиной развития гипертермии у больных с острым нарушением мозгового кровообращения являются очаг мозгового повреждения, кровь в ликворной системе, гнойно-воспалительные осложнения.

Under this AFOSR GameChanger we carried out groundbreaking research by developing methods and materials to realize small and conformal structurally integrated antennas for unmanned airborne vehicles (UAVs). We are proud to report several groundbreaking developments in all areas. Among them we (a) developed a conformal, load-bearing antenna technology by embroidering e-fibers on polymer composites, (b) Characterized performance of the e-fibers in terms of core and specific strength for load-bearing applications, (c) Developed a new principles DFT method for systematic search of ferromagnetic, low conductivity nanowires, (d) Developed a strategy for increasing permittivity and permeability proportionately using magnetic nanowires combined with conventional high contrast materials for antenna miniaturization, (e) demonstrated theoretical feasibility of laminate EM materials that alter wave propagation characteristics, critical to future miniaturization efforts, (f) Developed a multi-time scaling model and algorithm for coupling mechanical and EM solutions in real time, critical to multiphysics coupled EM-Structural analysis, (g) Extended our new domain decomposition algorithm to 3-D space and characterized more complex/intricate details on large platforms such as e-fibers embroidered on UAV platforms. In addition to this report, our ground breaking work under this program has been published in over 120 journal papers and over 70 conference summaries., The original document contains color images.

The article substantiates the expediency of obtaining brick rubble from the rubble of walls formed during the demolition of emergency residential buildings. The formulas for calculating the labor intensity and cost of 1 m3 of concrete mix on brick gravel are substantiated., В статье обосновывается целесообразность получения кирпичного щебня из обломков стен, образующихся при сносе аварийных жилых зданий.Приведены формулы для расчета трудоемкости и стоимости 1 м3 бетонной смеси на кирпичном щебне., У статье обосновується цілесообразность отримання кирпичного щебня з обломків стен, що утворюються при збиранні аварийних жирних приміщень.

Cell migration has long been studied by a variety of techniques and many proteins have been implicated in its regulation. Integrins, key proteins that link the cell to the extracellular matrix, are central to adhesion complexes whose turnover defines the rate of cell locomotion. The formation and disassembly of these adhesions is regulated by both intracellular and extracellular factors. In this study we have focused on the Ca2+-dependent protein network (module) that disassembles the adhesion complexes. We have developed a mathematical model that includes the Ca2+-dependent enzymes μ-calpain and phospholipase C (PLC) as well as IP3 receptors and stretch activated Ca2+ channels, all of which have been reported to regulate migration. The model also considers the spatial effects of Ca2+ propagation into lamella. Our model predicts differential activation of calpain at the leading and trailing edges of the cell. Since disassembly of integrin adhesive contacts is proportional to the degree of calpain activation, this leads to cell migration in a preferred direction. We show how the dynamics of Ca2+ spiking affects calpain activation and thus changes the disassembly rate of adhesions. The spiking is controlled by PLC activity and currents through stretch-activated Ca2+ channels. Our model thus combines the effects of various molecular factors and leads to a consistent explanation of the regulation of the rate and direction of cell migration. © 2006 IOS Press. All rights reserved.

© 2017 John Wiley & Sons Ltd. Signal transducers and activators of transcription (STATs) are key molecular determinants of T-cell fate and effector function. Several inflammatory diseases are characterized by an altered balance of T-cell phenotypes and cytokine secretion. STATs, therefore, represent viable therapeutic targets in numerous pathologies. However, the underlying mechanisms by which the same STAT proteins regulate both the development of different T-cell phenotypes and their plasticity during changes in extracellular conditions remain unclear. In this study, we investigated the STAT-mediated regulation of T-cell phenotype formation and plasticity using mathematical modelling and experimental data for intracellular STAT signalling proteins. The close fit of our model predictions to the experimental data allows us to propose a potential mechanism for T-cell switching. According to this mechanism, T-cell phenotype switching is the result of the relative redistribution of STAT dimer complexes caused by the extracellular cytokine-dependent STAT competition effects. The developed model predicts that the balance between the intracellular STAT species defines the amount of the produced cytokines and thereby T-cell phenotypes. The model predictions are consistent with the experimentally observed interferon-γ to interleukin-10 switching that regulates human T helper type 1/type 1 regulatory T-cell responses. The proposed model is applicable to a number of STAT signalling circuits.

© 2017 John Wiley & Sons Ltd. Signal transducers and activators of transcription (STATs) are key molecular determinants of T-cell fate and effector function. Several inflammatory diseases are characterized by an altered balance of T-cell phenotypes and cytokine secretion. STATs, therefore, represent viable therapeutic targets in numerous pathologies. However, the underlying mechanisms by which the same STAT proteins regulate both the development of different T-cell phenotypes and their plasticity during changes in extracellular conditions remain unclear. In this study, we investigated the STAT-mediated regulation of T-cell phenotype formation and plasticity using mathematical modelling and experimental data for intracellular STAT signalling proteins. The close fit of our model predictions to the experimental data allows us to propose a potential mechanism for T-cell switching. According to this mechanism, T-cell phenotype switching is the result of the relative redistribution of STAT dimer complexes caused by the extracellular cytokine-dependent STAT competition effects. The developed model predicts that the balance between the intracellular STAT species defines the amount of the produced cytokines and thereby T-cell phenotypes. The model predictions are consistent with the experimentally observed interferon-γ to interleukin-10 switching that regulates human T helper type 1/type 1 regulatory T-cell responses. The proposed model is applicable to a number of STAT signalling circuits.

Cell migration has long been studied by a variety of techniques and many proteins have been implicated in its regulation. Integrins, key proteins that link the cell to the extracellular matrix, are central to adhesion complexes whose turnover defines the rate of cell locomotion. The formation and disassembly of these adhesions is regulated by both intracellular and extracellular factors. In this study we have focused on the Ca2+-dependent protein network (module) that disassembles the adhesion complexes. We have developed a mathematical model that includes the Ca2+-dependent enzymes μ-calpain and phospholipase C (PLC) as well as IP3 receptors and stretch activated Ca2+ channels, all of which have been reported to regulate migration. The model also considers the spatial effects of Ca2+ propagation into lamella. Our model predicts differential activation of calpain at the leading and trailing edges of the cell. Since disassembly of integrin adhesive contacts is proportional to the degree of calpain activation, this leads to cell migration in a preferred direction. We show how the dynamics of Ca2+ spiking affects calpain activation and thus changes the disassembly rate of adhesions. The spiking is controlled by PLC activity and currents through stretch-activated Ca2+ channels. Our model thus combines the effects of various molecular factors and leads to a consistent explanation of the regulation of the rate and direction of cell migration. © 2006 IOS Press. All rights reserved.

Cell migration has long been studied by a variety of techniques and many proteins have been implicated in its regulation. Integrins, key proteins that link the cell to the extracellular matrix, are central to adhesion complexes whose turnover defines the rate of cell locomotion. The formation and disassembly of these adhesions is regulated by both intracellular and extracellular factors. In this study we have focused on the Ca2+-dependent protein network (module) that disassembles the adhesion complexes. We have developed a mathematical model that includes the Ca2+-dependent enzymes μ-calpain and phospholipase C (PLC) as well as IP3 receptors and stretch activated Ca2+ channels, all of which have been reported to regulate migration. The model also considers the spatial effects of Ca2+ propagation into lamella. Our model predicts differential activation of calpain at the leading and trailing edges of the cell. Since disassembly of integrin adhesive contacts is proportional to the degree of calpain activation, this leads to cell migration in a preferred direction. We show how the dynamics of Ca2+ spiking affects calpain activation and thus changes the disassembly rate of adhesions. The spiking is controlled by PLC activity and currents through stretch-activated Ca2+ channels. Our model thus combines the effects of various molecular factors and leads to a consistent explanation of the regulation of the rate and direction of cell migration. © 2006 IOS Press. All rights reserved.

Cell migration has long been studied by a variety of techniques and many proteins have been implicated in its regulation. Integrins, key proteins that link the cell to the extracellular matrix, are central to adhesion complexes whose turnover defines the rate of cell locomotion. The formation and disassembly of these adhesions is regulated by both intracellular and extracellular factors. In this study we have focused on the Ca2+-dependent protein network (module) that disassembles the adhesion complexes. We have developed a mathematical model that includes the Ca2+-dependent enzymes μ-calpain and phospholipase C (PLC) as well as IP3 receptors and stretch activated Ca2+ channels, all of which have been reported to regulate migration. The model also considers the spatial effects of Ca2+ propagation into lamella. Our model predicts differential activation of calpain at the leading and trailing edges of the cell. Since disassembly of integrin adhesive contacts is proportional to the degree of calpain activation, this leads to cell migration in a preferred direction. We show how the dynamics of Ca2+ spiking affects calpain activation and thus changes the disassembly rate of adhesions. The spiking is controlled by PLC activity and currents through stretch-activated Ca2+ channels. Our model thus combines the effects of various molecular factors and leads to a consistent explanation of the regulation of the rate and direction of cell migration. © 2006 IOS Press. All rights reserved.

© 2016 Salakhieva et al.Background: Second messengers, such as calcium, regulate the activity of multisite binding proteins in a concentration-dependent manner. For example, calcium binding has been shown to induce conformational transitions in the calcium-dependent protein calmodulin, under steady state conditions. However, intracellular concentrations of these second messengers are often subject to rapid change. The mechanisms underlying dynamic ligand-dependent regulation of multisite proteins require further elucidation. Results: In this study, a computational analysis of multisite protein kinetics in response to rapid changes in ligand concentrations is presented. Two major physiological scenarios are investigated: i) Ligand concentration is abundant and the ligand-multisite protein binding does not affect free ligand concentration, ii) Ligand concentration is of the same order of magnitude as the interacting multisite protein concentration and does not change. Therefore, buffering effects significantly influence the amounts of free ligands. For each of these scenarios the influence of the number of binding sites, the temporal effects on intermediate apo- and fully saturated conformations and the multisite regulatory effects on target proteins are investigated. Conclusions: The developed models allow for a novel and accurate interpretation of concentration and pressure jump-dependent kinetic experiments. The presented model makes predictions for the temporal distribution of multisite protein conformations in complex with variable numbers of ligands. Furthermore, it derives the characteristic time and the dynamics for the kinetic responses elicited by a ligand concentration change as a function of ligand concentration and the number of ligand binding sites. Effector proteins regulated by multisite ligand binding are shown to depend on ligand concentration in a highly nonlinear fashion.

© 2017 American Chemical Society.The design and use of materials in the nanoscale size range for addressing medical and health-related issues continues to receive increasing interest. Research in nanomedicine spans a multitude of areas, including drug delivery, vaccine development, antibacterial, diagnosis and imaging tools, wearable devices, implants, high-throughput screening platforms, etc. using biological, nonbiological, biomimetic, or hybrid materials. Many of these developments are starting to be translated into viable clinical products. Here, we provide an overview of recent developments in nanomedicine and highlight the current challenges and upcoming opportunities for the field and translation to the clinic.

© 2014 Sadreev et al. Phosphorylation is a fundamental biochemical reaction that modulates protein activity in cells. While a single phosphorylation event is relatively easy to understand, multisite phosphorylation requires systems approaches for deeper elucidation of the underlying molecular mechanisms. In this paper we develop a mechanistic model for single- and multisite phosphorylation. The proposed model is compared with previously reported studies. We compare the predictions of our model with experiments published in the literature in the context of inflammatory signaling events in order to provide a mechanistic description of the multisite phosphorylation-mediated regulation of Signal Transducer and Activator of Transcription 3 (STAT3) and Interferon Regulatory Factor 5 (IRF-5) proteins. The presented model makes crucial predictions for transcription factor phosphorylation events in the immune system. The model proposes potential mechanisms for T cell phenotype switching and production of cytokines. This study also provides a generic framework for the better understanding of a large number of multisite phosphorylation-regulated biochemical circuits.

Background: Calmodulin is an important multifunctional molecule that regulates the activities of a large number of proteins in the cell. Calcium binding induces conformational transitions in calmodulin that make it specifically active to particular target proteins. The precise mechanisms underlying calcium binding to calmodulin are still, however, quite poorly understood. Results: In this study, we adopt a structural systems biology approach and develop a mathematical model to investigate various types of cooperative calcium-calmodulin interactions. We compare the predictions of our analysis with physiological dose-response curves taken from the literature, in order to provide a quantitative comparison of the effects of different mechanisms of cooperativity on calcium-calmodulin interactions. The results of our analysis reduce the gap between current understanding of intracellular calmodulin function at the structural level and physiological calcium-dependent calmodulin target activation experiments. Conclusion: Our model predicts that the specificity and selectivity of CaM target regulation is likely to be due to the following factors: variations in the target-specific Ca2+ dissociation and cooperatively effected dissociation constants, and variations in the number of Ca2+ ions required to bind CaM for target activation. © 2008 Valeyev et al; licensee BioMed Central Ltd.

Background: Ciliary dysfunction leads to a number of human pathologies, including primary ciliary dyskinesia, nephronophthisis, situs inversus pathology or infertility. The mechanism of cilia beating regulation is complex and despite extensive experimental characterization remains poorly understood. We develop a detailed systems model for calcium, membrane potential and cyclic nucleotide-dependent ciliary motility regulation.Results: The model describes the intimate relationship between calcium and potassium ionic concentrations inside and outside of cilia with membrane voltage and, for the first time, describes a novel type of ciliary excitability which plays the major role in ciliary movement regulation. Our model describes a mechanism that allows ciliary excitation to be robust over a wide physiological range of extracellular ionic concentrations. The model predicts the existence of several dynamic modes of ciliary regulation, such as the generation of intraciliary Ca2+ spike with amplitude proportional to the degree of membrane depolarization, the ability to maintain stable oscillations, monostable multivibrator regimes, all of which are initiated by variability in ionic concentrations that translate into altered membrane voltage.Conclusions: Computational investigation of the model offers several new insights into the underlying molecular mechanisms of ciliary pathologies. According to our analysis, the reported dynamic regulatory modes can be a physiological reaction to alterations in the extracellular environment. However, modification of the dynamic modes, as a result of genetic mutations or environmental conditions, can cause a life threatening pathology. © 2011 Kotov et al; licensee BioMed Central Ltd.

Inflammation is characterized by altered cytokine levels produced by cell populations in a highly interdependent manner. To elucidate the mechanism of an inflammatory reaction, we have developed a mathematical model for immune cell interactions via the specific, dose-dependent cytokine production rates of cell populations. The model describes the criteria required for normal and pathological immune system responses and suggests that alterations in the cytokine production rates can lead to various stable levels which manifest themselves in different disease phenotypes. The model predicts that pairs of interacting immune cell populations can maintain homeostatic and elevated extracellular cytokine concentration levels, enabling them to operate as an immune system switch. The concept described here is developed in the context of psoriasis, an immune-mediated disease, but it can also offer mechanistic insights into other inflammatory pathologies as it explains how interactions between immune cell populations can lead to disease phenotypes. © 2010 Valeyev et al.

It is known that most enzyme-facilitated reactions are highly temperature dependent processes. In general, the temperature coefficient, Q10, of a simple reaction reaches 2.0-3.0. Nevertheless, some enzyme-controlled processes have much lower Q10 (about 1.0), which implies that the process is almost temperature independent, even if individual reactions involved in the process are themselves highly temperature dependent. In this work, we investigate a possible mechanism for this apparent temperature compensation: simple mathematical models are used to study how varying types of enzyme reactions are affected by temperature. We show that some bienzyme-controlled processes may be almost temperature independent if the modules involved in the reaction have similar temperature dependencies, even if individually, these modules are strongly temperature dependent. Further, we show that in non-reversible enzyme chains the stationary concentrations of metabolites are dependent only on the relationship between the temperature dependencies of the first and last modules, whilst in reversible reactions, there is a dependence on every module. Our findings suggest a mechanism by which the metabolic processes taking place within living organisms may be regulated, despite strong variation in temperature.

Cyclic adenosine monophosphate and cyclic guanosine monophosphate are universal intracellular messengers whose concentrations are regulated by molecular networks comprised of different isoforms of the synthases adenylate cyclase or guanylate cyclase and the phosphodiesterases which degrade these compounds. In this paper, we employ a systems biology approach to develop mathematical models of these networks that, for the first time, take into account the different biochemical properties of the isoforms involved. To investigate the mechanisms underlying the joint regulation of cAMP and cGMP, we apply our models to analyse the regulation of cilia beat frequency in Paramecium by Ca2+. Based on our analysis of these models, we propose that the diversity of isoform combinations that occurs in living cells provides an explanation for the huge variety of intracellular processes that are dependent on these networks. The inclusion of both G-protein receptor and Ca 2+-dependent regulation of AC in our models allows us to propose a new explanation for the switching properties of G-protein subunits involved in nucleotide regulation. Analysis of the models suggests that, depending on whether the G-protein subunit is bound to AC, Ca2+ can either activate or inhibit AC in a concentration-dependent manner. The resulting analysis provides an explanation for previous experimental results that showed that alterations in Ca2+ concentrations can either increase or decrease cilia beat frequency over particular Ca2+ concentration ranges. © The Royal Society of Chemistry.

Under conditions of starvation, Dictyostelium cells begin a programme of development during which they aggregate to form a multicellular structure by chemotaxis, guided by propagating waves of cyclic AMP that are relayed robustly from cell to cell. In this paper, we develop and analyse a new model for the intracellular and extracellular cAMP dependent processes that regulate Dictyostelium migration. The model allows, for the first time, a quantitative analysis of the dynamic interactions between calcium, IP3 and G protein-dependent modules that are shown to be key to the generation of robust cAMP oscillations in Dictyostelium cells. The model provides a mechanistic explanation for the transient increase in cytosolic free Ca2+ concentration seen in recent experiments with the application of the calmodulin inhibitor calmidazolium (R24571) to Dictyostelium cells, and also allows elucidation of the effects of varying both the conductivity of stretch-activated channels and the concentration of external phosphodiesterase on the oscillatory regime of an individual cell. A rigorous analysis of the robustness of the new model shows that interactions between the different modules significantly reduce the sensitivity of the resulting cAMP oscillations to variations in the kinetics of different Dictyostelium cells, an essential requirement for the generation of the spatially and temporally synchronised chemoattractant cAMP waves that guide Dictyostelium aggregation. © The Royal Society of Chemistry 2009.

Protein-protein or protein-ion interactions with multisite proteins are essential to the regulation of intracellular and extracellular events. There is, however, limited understanding of how ligand-multisite protein interactions selectively regulate the activities of multiple protein targets. In this paper, we focus on the important calcium (Ca2+) binding protein calmodulin (CaM), which has four Ca2+ ion binding sites and regulates the activity of over 30 other proteins. Recent progress in structural studies has led to significant improvements in the understanding of Ca2+-CaM- dependent regulation mechanisms. However, no quantitative model is currently available that can fully explain how the structural diversity of protein interaction surfaces leads to selective activation of protein targets. In this paper, we analyze the multisite protein-ligand binding mechanism using mathematical modelling and experimental data for Ca2+-CaM-dependent protein targets. Our study suggests a potential mechanism for selective and differential activation of Ca2+-CaM targets by the same CaM molecules, which are involved in a variety of intracellular functions. The close agreement between model predictions and experimental dose-response curves for CaM targets available in the literature suggests that such activation is due to the selective activity of CaM conformations in complexes with variable numbers of Ca2+ ions. Although the paper focuses on the Ca2+-CaM pair as a particularly data rich example, the proposed model predictions are quite general and can easily be extended to other multisite proteins. The results of the study may therefore be proposed as a general explanation for multifunctional target regulation by multisite proteins. © The Royal Society of Chemistry.

Systems Biology approaches to drug discovery largely focus on the increasing understanding of intracellular and cellular circuits, by computational representation of a molecular system followed by parameter validation against experimental data. This chapter outlines a universal approach to systems biology that allows the linking of intracellular molecular machinery and cellular activity. This procedure is achieved by applying mathematical modeling to molecular modules of a cell in the light of systems biology techniques. © 2010 Springer Science+Business Media, LLC.

© 2015 The Authors. Human erythrocytes are highly specialized enucleate cells that are involved in providing efficient gas transport. Erythrocytes have been extensively studied both experimentally and by mathematical modeling in recent years. However, understanding of how aggregation and deformability are regulated is limited. These properties of the erythrocyte are essential for the physiological functioning of the cell. In this work, we propose a novel mathematical model of the molecular system that controls the aggregation and deformability of the erythrocyte. This model is based on the experimental results of previously published studies. Our model suggests fundamentally new mechanisms that regulate aggregation and deformability in a latch-like manner. The results of this work could be used as a general explanation of how the erythrocytes regulate their aggregation and deformability, and are essential in understanding erythrocyte disorders and aging.

Under the condition of microelectrode recording and fluorescence microscopy with dye FM 1-43 the research of exo-/endocytosis of synaptic vesicles in motor nerve terminals (NT) of frog cutaneous pectoris and white mice diaphragm muscles during high frequency stimulation (20 imp/s) was carried out. A mathematical modeling allowed us to conclude that the obtained experimental data can be explained in the following framework. Three pools of synaptic vesicles are involved in neurotransmitter release in the frog motor NT. Recovery of these pools is provided by endocytosis of two types: fast endocytosis with limited capacity and slow endocytosis. Fast-reconstructing vesicles refill the mobilization pool and slow endocytosis recovers the reserve pool. Our modeling investigation has revealed in frog NT independent recruiting of reserve and mobilization pools to the neurotransmitter secretion, i. e. this pools work concurrently. Experimental data, obtained on mice preparations, are well described with the framework of two-pools model including single type of endocytosis (fast endocytosis). © 2012 Pleiades Publishing, Ltd.

A mathematical model of the dynamic behavior of phosphorylase kinase was devised. Based on the results obtained, the function of this protein is discussed. It is suggested that phosphorylase kinase doses in a cAMP-dependent manner additional portions of glucoso-l-phosphate, which the muscle cell receives in response to contraction.

The escape reaction in Paramecium caudatum has been investigated experimentally. A model of molecular system controlling cilia in cells during this reaction is described.

A physical approach is proposed to the description of the mechanism of motion of cilia based on the assumption of the importance of the hydrodynamic interactions within the cilium and the mechanism of synchronization of the beats in the metachronal waves is proposed. © 1992.

A systemic study of the mechanisms of motor activity of paramecium was carried out. The movements of paramecium responding to various influences were photographed. The analysis of the data revealed the time dependences of the rate of movement, rate of rotation, and the radius and the pitch of the helix trajectory. Mathematical models of the membrane and a unit that transforms the calcium signal to programs of regulating the effectors were constructed. A system of equations for constructing the trajectory of movement was proposed. It is concluded that the biomolecular system that involves calmodulin, calmodulin-dependent ionic channels, adenylate cyclase, guanylate cyclase, phosphodiesterases, Ca(2+)-calmodulin, cAMP, cGMP-dependent protein kinases, and phosphoprotein phosphatases is capable of regulating motor reactions necessary for complex maneuvering of paramecium under various conditions.

A mathematical model of the dynamic behavior of phosphorylase kinase was devised. Based on the results obtained, the function of this protein is discussed. It is suggested that phosphorylase kinase doses in a cAMP-dependent manner additional portions of glucoso-1-phosphate, which the muscle cell receives in response to contraction.

A systemic study of the mechanisms of motor activity of paramecium was carried out. The movements of paramecium responding to various influences were photographed. The analysis of the data revealed the time dependences of the rate of movement, rate of rotation, and the radius and the pitch of the helix trajectory. Mathematical models of the membrane and a unit that transforms the calcium signal to programs of regulating the effectors were constructed. A system of equations for constructing the trajectory of movement was proposed. It is concluded that the biomolecular system that involves calmodulin, calmodulin-dependent ionic channels, adenylate cyclase, guanylate cyclase, phosphodiesterases, Ca2+-calmodulin, cAMP, cGMP-dependent protein kinases, and phosphoprotein phosphatases is capable of regulating motor reactions necessary for complex maneuvering of paramecium under various conditions.

© 2017 American Chemical Society.The design and use of materials in the nanoscale size range for addressing medical and health-related issues continues to receive increasing interest. Research in nanomedicine spans a multitude of areas, including drug delivery, vaccine development, antibacterial, diagnosis and imaging tools, wearable devices, implants, high-throughput screening platforms, etc. using biological, nonbiological, biomimetic, or hybrid materials. Many of these developments are starting to be translated into viable clinical products. Here, we provide an overview of recent developments in nanomedicine and highlight the current challenges and upcoming opportunities for the field and translation to the clinic.

© 2016 Salakhieva et al.Background: Second messengers, such as calcium, regulate the activity of multisite binding proteins in a concentration-dependent manner. For example, calcium binding has been shown to induce conformational transitions in the calcium-dependent protein calmodulin, under steady state conditions. However, intracellular concentrations of these second messengers are often subject to rapid change. The mechanisms underlying dynamic ligand-dependent regulation of multisite proteins require further elucidation. Results: In this study, a computational analysis of multisite protein kinetics in response to rapid changes in ligand concentrations is presented. Two major physiological scenarios are investigated: i) Ligand concentration is abundant and the ligand-multisite protein binding does not affect free ligand concentration, ii) Ligand concentration is of the same order of magnitude as the interacting multisite protein concentration and does not change. Therefore, buffering effects significantly influence the amounts of free ligands. For each of these scenarios the influence of the number of binding sites, the temporal effects on intermediate apo- and fully saturated conformations and the multisite regulatory effects on target proteins are investigated. Conclusions: The developed models allow for a novel and accurate interpretation of concentration and pressure jump-dependent kinetic experiments. The presented model makes predictions for the temporal distribution of multisite protein conformations in complex with variable numbers of ligands. Furthermore, it derives the characteristic time and the dynamics for the kinetic responses elicited by a ligand concentration change as a function of ligand concentration and the number of ligand binding sites. Effector proteins regulated by multisite ligand binding are shown to depend on ligand concentration in a highly nonlinear fashion.

© 2014 Sadreev et al. Phosphorylation is a fundamental biochemical reaction that modulates protein activity in cells. While a single phosphorylation event is relatively easy to understand, multisite phosphorylation requires systems approaches for deeper elucidation of the underlying molecular mechanisms. In this paper we develop a mechanistic model for single- and multisite phosphorylation. The proposed model is compared with previously reported studies. We compare the predictions of our model with experiments published in the literature in the context of inflammatory signaling events in order to provide a mechanistic description of the multisite phosphorylation-mediated regulation of Signal Transducer and Activator of Transcription 3 (STAT3) and Interferon Regulatory Factor 5 (IRF-5) proteins. The presented model makes crucial predictions for transcription factor phosphorylation events in the immune system. The model proposes potential mechanisms for T cell phenotype switching and production of cytokines. This study also provides a generic framework for the better understanding of a large number of multisite phosphorylation-regulated biochemical circuits.

Background: Ciliary dysfunction leads to a number of human pathologies, including primary ciliary dyskinesia, nephronophthisis, situs inversus pathology or infertility. The mechanism of cilia beating regulation is complex and despite extensive experimental characterization remains poorly understood. We develop a detailed systems model for calcium, membrane potential and cyclic nucleotide-dependent ciliary motility regulation.Results: The model describes the intimate relationship between calcium and potassium ionic concentrations inside and outside of cilia with membrane voltage and, for the first time, describes a novel type of ciliary excitability which plays the major role in ciliary movement regulation. Our model describes a mechanism that allows ciliary excitation to be robust over a wide physiological range of extracellular ionic concentrations. The model predicts the existence of several dynamic modes of ciliary regulation, such as the generation of intraciliary Ca2+ spike with amplitude proportional to the degree of membrane depolarization, the ability to maintain stable oscillations, monostable multivibrator regimes, all of which are initiated by variability in ionic concentrations that translate into altered membrane voltage.Conclusions: Computational investigation of the model offers several new insights into the underlying molecular mechanisms of ciliary pathologies. According to our analysis, the reported dynamic regulatory modes can be a physiological reaction to alterations in the extracellular environment. However, modification of the dynamic modes, as a result of genetic mutations or environmental conditions, can cause a life threatening pathology. © 2011 Kotov et al; licensee BioMed Central Ltd.

Background: Calmodulin is an important multifunctional molecule that regulates the activities of a large number of proteins in the cell. Calcium binding induces conformational transitions in calmodulin that make it specifically active to particular target proteins. The precise mechanisms underlying calcium binding to calmodulin are still, however, quite poorly understood. Results: In this study, we adopt a structural systems biology approach and develop a mathematical model to investigate various types of cooperative calcium-calmodulin interactions. We compare the predictions of our analysis with physiological dose-response curves taken from the literature, in order to provide a quantitative comparison of the effects of different mechanisms of cooperativity on calcium-calmodulin interactions. The results of our analysis reduce the gap between current understanding of intracellular calmodulin function at the structural level and physiological calcium-dependent calmodulin target activation experiments. Conclusion: Our model predicts that the specificity and selectivity of CaM target regulation is likely to be due to the following factors: variations in the target-specific Ca2+ dissociation and cooperatively effected dissociation constants, and variations in the number of Ca2+ ions required to bind CaM for target activation. © 2008 Valeyev et al; licensee BioMed Central Ltd.

It is known that most enzyme-facilitated reactions are highly temperature dependent processes. In general, the temperature coefficient, Q10, of a simple reaction reaches 2.0-3.0. Nevertheless, some enzyme-controlled processes have much lower Q10 (about 1.0), which implies that the process is almost temperature independent, even if individual reactions involved in the process are themselves highly temperature dependent. In this work, we investigate a possible mechanism for this apparent temperature compensation: simple mathematical models are used to study how varying types of enzyme reactions are affected by temperature. We show that some bienzyme-controlled processes may be almost temperature independent if the modules involved in the reaction have similar temperature dependencies, even if individually, these modules are strongly temperature dependent. Further, we show that in non-reversible enzyme chains the stationary concentrations of metabolites are dependent only on the relationship between the temperature dependencies of the first and last modules, whilst in reversible reactions, there is a dependence on every module. Our findings suggest a mechanism by which the metabolic processes taking place within living organisms may be regulated, despite strong variation in temperature.

Under conditions of starvation, Dictyostelium cells begin a programme of development during which they aggregate to form a multicellular structure by chemotaxis, guided by propagating waves of cyclic AMP that are relayed robustly from cell to cell. In this paper, we develop and analyse a new model for the intracellular and extracellular cAMP dependent processes that regulate Dictyostelium migration. The model allows, for the first time, a quantitative analysis of the dynamic interactions between calcium, IP3 and G protein-dependent modules that are shown to be key to the generation of robust cAMP oscillations in Dictyostelium cells. The model provides a mechanistic explanation for the transient increase in cytosolic free Ca2+ concentration seen in recent experiments with the application of the calmodulin inhibitor calmidazolium (R24571) to Dictyostelium cells, and also allows elucidation of the effects of varying both the conductivity of stretch-activated channels and the concentration of external phosphodiesterase on the oscillatory regime of an individual cell. A rigorous analysis of the robustness of the new model shows that interactions between the different modules significantly reduce the sensitivity of the resulting cAMP oscillations to variations in the kinetics of different Dictyostelium cells, an essential requirement for the generation of the spatially and temporally synchronised chemoattractant cAMP waves that guide Dictyostelium aggregation. © The Royal Society of Chemistry 2009.

Inflammation is characterized by altered cytokine levels produced by cell populations in a highly interdependent manner. To elucidate the mechanism of an inflammatory reaction, we have developed a mathematical model for immune cell interactions via the specific, dose-dependent cytokine production rates of cell populations. The model describes the criteria required for normal and pathological immune system responses and suggests that alterations in the cytokine production rates can lead to various stable levels which manifest themselves in different disease phenotypes. The model predicts that pairs of interacting immune cell populations can maintain homeostatic and elevated extracellular cytokine concentration levels, enabling them to operate as an immune system switch. The concept described here is developed in the context of psoriasis, an immune-mediated disease, but it can also offer mechanistic insights into other inflammatory pathologies as it explains how interactions between immune cell populations can lead to disease phenotypes. © 2010 Valeyev et al.

© 2015 The Authors. Human erythrocytes are highly specialized enucleate cells that are involved in providing efficient gas transport. Erythrocytes have been extensively studied both experimentally and by mathematical modeling in recent years. However, understanding of how aggregation and deformability are regulated is limited. These properties of the erythrocyte are essential for the physiological functioning of the cell. In this work, we propose a novel mathematical model of the molecular system that controls the aggregation and deformability of the erythrocyte. This model is based on the experimental results of previously published studies. Our model suggests fundamentally new mechanisms that regulate aggregation and deformability in a latch-like manner. The results of this work could be used as a general explanation of how the erythrocytes regulate their aggregation and deformability, and are essential in understanding erythrocyte disorders and aging.

Systems Biology approaches to drug discovery largely focus on the increasing understanding of intracellular and cellular circuits, by computational representation of a molecular system followed by parameter validation against experimental data. This chapter outlines a universal approach to systems biology that allows the linking of intracellular molecular machinery and cellular activity. This procedure is achieved by applying mathematical modeling to molecular modules of a cell in the light of systems biology techniques. © 2010 Springer Science+Business Media, LLC.

Cyclic adenosine monophosphate and cyclic guanosine monophosphate are universal intracellular messengers whose concentrations are regulated by molecular networks comprised of different isoforms of the synthases adenylate cyclase or guanylate cyclase and the phosphodiesterases which degrade these compounds. In this paper, we employ a systems biology approach to develop mathematical models of these networks that, for the first time, take into account the different biochemical properties of the isoforms involved. To investigate the mechanisms underlying the joint regulation of cAMP and cGMP, we apply our models to analyse the regulation of cilia beat frequency in Paramecium by Ca2+. Based on our analysis of these models, we propose that the diversity of isoform combinations that occurs in living cells provides an explanation for the huge variety of intracellular processes that are dependent on these networks. The inclusion of both G-protein receptor and Ca 2+-dependent regulation of AC in our models allows us to propose a new explanation for the switching properties of G-protein subunits involved in nucleotide regulation. Analysis of the models suggests that, depending on whether the G-protein subunit is bound to AC, Ca2+ can either activate or inhibit AC in a concentration-dependent manner. The resulting analysis provides an explanation for previous experimental results that showed that alterations in Ca2+ concentrations can either increase or decrease cilia beat frequency over particular Ca2+ concentration ranges. © The Royal Society of Chemistry.

Protein-protein or protein-ion interactions with multisite proteins are essential to the regulation of intracellular and extracellular events. There is, however, limited understanding of how ligand-multisite protein interactions selectively regulate the activities of multiple protein targets. In this paper, we focus on the important calcium (Ca2+) binding protein calmodulin (CaM), which has four Ca2+ ion binding sites and regulates the activity of over 30 other proteins. Recent progress in structural studies has led to significant improvements in the understanding of Ca2+-CaM- dependent regulation mechanisms. However, no quantitative model is currently available that can fully explain how the structural diversity of protein interaction surfaces leads to selective activation of protein targets. In this paper, we analyze the multisite protein-ligand binding mechanism using mathematical modelling and experimental data for Ca2+-CaM-dependent protein targets. Our study suggests a potential mechanism for selective and differential activation of Ca2+-CaM targets by the same CaM molecules, which are involved in a variety of intracellular functions. The close agreement between model predictions and experimental dose-response curves for CaM targets available in the literature suggests that such activation is due to the selective activity of CaM conformations in complexes with variable numbers of Ca2+ ions. Although the paper focuses on the Ca2+-CaM pair as a particularly data rich example, the proposed model predictions are quite general and can easily be extended to other multisite proteins. The results of the study may therefore be proposed as a general explanation for multifunctional target regulation by multisite proteins. © The Royal Society of Chemistry.

A mathematical model of the dynamic behavior of phosphorylase kinase was devised. Based on the results obtained, the function of this protein is discussed. It is suggested that phosphorylase kinase doses in a cAMP-dependent manner additional portions of glucoso-1-phosphate, which the muscle cell receives in response to contraction.

A physical approach is proposed to the description of the mechanism of motion of cilia based on the assumption of the importance of the hydrodynamic interactions within the cilium and the mechanism of synchronization of the beats in the metachronal waves is proposed. © 1992.

A systemic study of the mechanisms of motor activity of paramecium was carried out. The movements of paramecium responding to various influences were photographed. The analysis of the data revealed the time dependences of the rate of movement, rate of rotation, and the radius and the pitch of the helix trajectory. Mathematical models of the membrane and a unit that transforms the calcium signal to programs of regulating the effectors were constructed. A system of equations for constructing the trajectory of movement was proposed. It is concluded that the biomolecular system that involves calmodulin, calmodulin-dependent ionic channels, adenylate cyclase, guanylate cyclase, phosphodiesterases, Ca2+-calmodulin, cAMP, cGMP-dependent protein kinases, and phosphoprotein phosphatases is capable of regulating motor reactions necessary for complex maneuvering of paramecium under various conditions.

A systemic study of the mechanisms of motor activity of paramecium was carried out. The movements of paramecium responding to various influences were photographed. The analysis of the data revealed the time dependences of the rate of movement, rate of rotation, and the radius and the pitch of the helix trajectory. Mathematical models of the membrane and a unit that transforms the calcium signal to programs of regulating the effectors were constructed. A system of equations for constructing the trajectory of movement was proposed. It is concluded that the biomolecular system that involves calmodulin, calmodulin-dependent ionic channels, adenylate cyclase, guanylate cyclase, phosphodiesterases, Ca(2+)-calmodulin, cAMP, cGMP-dependent protein kinases, and phosphoprotein phosphatases is capable of regulating motor reactions necessary for complex maneuvering of paramecium under various conditions.

Under the condition of microelectrode recording and fluorescence microscopy with dye FM 1-43 the research of exo-/endocytosis of synaptic vesicles in motor nerve terminals (NT) of frog cutaneous pectoris and white mice diaphragm muscles during high frequency stimulation (20 imp/s) was carried out. A mathematical modeling allowed us to conclude that the obtained experimental data can be explained in the following framework. Three pools of synaptic vesicles are involved in neurotransmitter release in the frog motor NT. Recovery of these pools is provided by endocytosis of two types: fast endocytosis with limited capacity and slow endocytosis. Fast-reconstructing vesicles refill the mobilization pool and slow endocytosis recovers the reserve pool. Our modeling investigation has revealed in frog NT independent recruiting of reserve and mobilization pools to the neurotransmitter secretion, i. e. this pools work concurrently. Experimental data, obtained on mice preparations, are well described with the framework of two-pools model including single type of endocytosis (fast endocytosis). © 2012 Pleiades Publishing, Ltd.

A mathematical model of the dynamic behavior of phosphorylase kinase was devised. Based on the results obtained, the function of this protein is discussed. It is suggested that phosphorylase kinase doses in a cAMP-dependent manner additional portions of glucoso-l-phosphate, which the muscle cell receives in response to contraction.

The escape reaction in Paramecium caudatum has been investigated experimentally. A model of molecular system controlling cilia in cells during this reaction is described.