The mechanical behavior of poly(lactic acid) unreinforced and nanocomposite films subjected to mo... more The mechanical behavior of poly(lactic acid) unreinforced and nanocomposite films subjected to monotonic and fatigue loading conditions
iii In memory of Grandma (" Grannie ") and Buck Dedicated to Jordan iv ACKNOWLEDGEMENTS... more iii In memory of Grandma (" Grannie ") and Buck Dedicated to Jordan iv ACKNOWLEDGEMENTS First of all, I want to thank the Lord Almighty for giving me the ability to complete such an educational task and for giving me the strength and courage to go on day by day. This experience has shown me that through God, all things are possible. Next, I would like to thank the National Textile Center for providing the funds to do this research. I would also like to thank my advisor, Dr. Mary Lynn Realff for giving guidance and providing me with the opportunity to work on this project. I also appreciate the long and arduous work of Dr. Stephen Michielsen, who believed that this research could be accomplished, despite what was unsuccessful in the past. In addition, I would like to thank my co-chair, Dr. Richard Neu for helping me with technical related questions, even when he was busy, and for convincing me that this fracture mechanics research would work. I would also like to thank Dr. ...
... Brown, Dr. Dave Howerton, Dr. David Hall, Timothy Vines, Grandmother Martha Averett, Jeffrey ... more ... Brown, Dr. Dave Howerton, Dr. David Hall, Timothy Vines, Grandmother Martha Averett, Jeffrey Averett, James Averett, John Averett, Amanda Thornton, Geraldine Parris, Lucy Baldwin, Essie Francis, Ida Boykins, Martha Ann Patterson, Lois Swan, ...
The multiscale behavior of the individual fibrin fibers and fibrin clots is modeled by coupling a... more The multiscale behavior of the individual fibrin fibers and fibrin clots is modeled by coupling atomistic simulation data and microscopic experimental data. We propose a protofibril element made up of nonlinear spring network, constructed based on the molecular simulation and atomic force microscopy results to simulate the force extension behavior of fibrin fibers. This new network model also accounts for the complex interaction of protofibrils with each other, effect of presence of solvent, Coulombic attraction and other binding forces. The network model is applied to simulate the force extension behavior of single fibrin fiber from atomic force microscopy experiments and shows good agreement. Thus validated fibrin fiber network model is then combined with a modified version of Arruda-Boyce eight chain model to estimate the force extension behavior of continuum level fibrin clot, which shows very good correlation. The results show that this network model is able to predict the beha...
Computational models for simulating and predicting fibrin fiber fracture are important tools for ... more Computational models for simulating and predicting fibrin fiber fracture are important tools for studying bulk mechanical properties and mechanobiological response of fibrin networks in physiological conditions. In this work, we employed a new strategy to model the mechanical response of a single fibrin fiber using a collection of bundled protofibrils and modeled the time-dependent properties using discrete particle simulations. Using a systematic characterization of the parameters, this model can be used to mimic the elastic behavior of fibrin fibers accurately and also to simulate fibrin fiber fracture. In addition, a continuum model was modified and used to obtain the individual fibrin fiber fracture toughness properties. Using this model and the experimentally available fibrin mechanical properties, we predicted the range of fracture toughness (1 to kPam) values of a typical fibrin fiber of diameter 100 nm and its critical flaw size to rupture (~4 nm), both of which are not currently available in the literature. The models can be collectively used as a foundation for simulating the mechanical behavior of fibrin clots. Moreover, the tunable discrete mesoscopic model that was employed can be extended to simulate and estimate the mechanical properties of other biological or synthetic fibers.
Evaporation studies of water using classical molecular dynamics simulations are largely limited d... more Evaporation studies of water using classical molecular dynamics simulations are largely limited due to its high computational expense. We aim at addressing the computational issues by developing a coarse grain model for evaporation of water on solid surfaces by combining four water molecules into a single bead. Most commonly used mono atomic pair potentials like Lennard Jones, Morse, Mie and three body potential like Stillinger-Weber are optimized using a combination of Genetic algorithm and Nelder-Mead algorithm. Among them, Stillinger-Weber based model shows excellent agreement of density and Enthalpy of vaporization with experimental results for a wide range of temperatures. Further, the new water model is used to simulate contact angle of water and thin film evaporation from surfaces with different wettabilities.
The multiscale mechanical behavior of individual fibrin fibers and fibrin clots wasmodeled by cou... more The multiscale mechanical behavior of individual fibrin fibers and fibrin clots wasmodeled by coupling atomistic simulation data and microscopic experimental data. We propose anew protofibril element composed of a nonlinear spring network, and constructed this based onmolecular simulations and atomic force microscopy results to simulate the force extension behaviorof fibrin fibers. This new network model also accounts for the complex interaction of protofibrilswith one another, the effects of the presence of a solvent, Coulombic attraction, and other bindingforces. The network model was formulated to simulate the force–extension mechanical behavior ofsingle fibrin fibers from atomic force microscopy experiments, and shows good agreement. Thevalidated fibrin fiber network model was then combined with a modified version of the Arruda–Boyce eight‐chain model to estimate the force extension behavior of the fibrin clot at the continuumlevel, which shows very good correlation. The results...
The study of thrombosis is crucial to understand and develop new therapies for diseases like deep... more The study of thrombosis is crucial to understand and develop new therapies for diseases like deep vein thrombosis, diabetes related strokes, pulmonary embolism etc. The last two decades have seen an exponential growth in studies related to the blood clot formation using computational tools and through experiments. Despite of this growth, the complete mechanism behind thrombus formation and hemostasis is not known yet. The computational models and methods used in this context are diversified into different spatiotemporal scales, yet there is no single model which can predict both physiological and mechanical properties of the blood clots. In this review, we will attempt to list out all major strategies attempted by researchers so far to model the blood clot formation using existing computational techniques. This review classifies them into continuum level, system level, discrete particles and multi-scale methods. We will also discuss the strength and weakness of various methods and possible future directions in which the computational blood clot research can thrive.
Understanding and controlling the interaction between nanoparticles and cell nuclei is critical t... more Understanding and controlling the interaction between nanoparticles and cell nuclei is critical to the development of the biomedical applications such as gene delivery, cellular imaging, and tumor therapy. Recent years have witnessed growing evidence that the size, shape, and the grafting density of the karyopherins ligands of nanoparticles provide a significant influence on the uptake mechanism of nanoparticles into cells; however, there is a lack of investigation into how these physical factors play a role in cellular nuclear uptake and how the nanoparticle enters the nucleus. Here we build a computational framework to parametrically evaluate the effects of the size, shape, and the grafting density of the karyopherins ligands of designed nanoparticles on their transport through the nuclear pore complex of a cell nucleus, so as to provide a novel scheme for nanoparticle design and precise nucleus-targeted therapy. Simulation results indicate that smaller spherical nanoparticles need to overcome a lower energy barrier than larger ones, and also that nanoparticles with large grafting density exhibited greatly altered dynamics during the active transport process. Moreover, we observed that the shape and morphology of nanoparticles unambiguously determined their nuclear uptake pathways. Nuclear uptake is determined by an intricate interplay between physicochemical particle properties and nucleus properties. Our work provides a systematic understanding for nuclear uptake of nanoparticles, viruses, and bacteria, and opens up a controllable design strategy for manipulating nanoparticle-nucleus interaction, with numerous applications in medicine, bio-imaging, and bio-sensing.
Blood clots occur in the human body when they are required to prevent bleeding. In pathological s... more Blood clots occur in the human body when they are required to prevent bleeding. In pathological states such as diabetes and sickle cell disease, blood clots can also form undesirably due to hypercoagulable plasma conditions. With the continued effort in developing fibrin therapies for potential life-saving solutions, more mechanical modeling is needed to understand the properties of fibrin structures with inclusions. In this study, a fibrin matrix embedded with magnetic micro particles (MMPs) was subjected to a magnetic field to determine the magnitude of the required force to create plastic deformation within the fibrin clot. Using finite element (FE) analysis, we estimated the magnetic force from an electromagnet at a sample space located approximately 3[Formula: see text]cm away from the coil center. This electromagnetic force coupled with gravity was applied on a fibrin mechanical system with MMPs to calculate the stresses and displacements. Using appropriate coil parameters, it...
The study on the polymerization of fibrinogen molecules into fibrin monomers and eventually a sta... more The study on the polymerization of fibrinogen molecules into fibrin monomers and eventually a stable, mechanically robust fibrin clot is a persistent and enduring topic in the field of thrombosis and hemostasis. Despite many research advances in fibrin polymerization, the change in the structure of fibrin clots and its influence on the formation of a fibrous protein network are still poorly understood. In this paper, we develop a new computational method to simulate fibrin clot polymerization using dissipative particle dynamics simulations. With an effective combination of reactive molecular dynamics formularies and many body dissipative particle dynamics principles, we constructed the reactive dissipative particle dynamics (RDPD) model to predict the complex network formation of fibrin clots and branching of the fibrin network. The 340 kDa fibrinogen molecule is converted into a spring-bead coarse-grain system with 11 beads using a topology representing network algorithm, and using RDPD, we simulated polymerization and formation of the fibrin clot. The final polymerized structure of the fibrin clot qualitatively agrees with experimental results from the literature, and to the best of our knowledge this is the first molecular-based study that simulates polymerization and structure of fibrin clots.
Although in vivo studies have been conducted in the past to determine hyperglycemic effects and i... more Although in vivo studies have been conducted in the past to determine hyperglycemic effects and influence on clotting risk in patients with diabetes, the true extent of hyperglycemia on unstable and spontaneous clot formation remains highly debated. Factors such as increased glycation, elevated fibrinogen concentration, elevated prothrombin levels, and decreased plasminogen are known to influence fibrin conversion, clot morphology, and thrombus formation in these individuals. In this regard, the isolated effects of hyperglycemia on irregular fibrin clot formation were investigated in a controlled fibrinogen system. In this study, fibrin clot characteristic differences at 3 glucose concentrations were analyzed to determine the effects of glucose concentration on fibrinogen glycation and fibrin clot morphology using confocal microscopy, glycation quantification, molecular simulations, and image processing methods. Algorithms coupled with statistical analysis support in vivo findings t...
Medical studies have consistently shown that the best defense against cancer is early detection. ... more Medical studies have consistently shown that the best defense against cancer is early detection. Due to this, many efforts have been made to develop methods of screening patient blood quickly and cheaply. These methods range from separation via differences in size, electrostatic potential, chemical potential, antibody-binding affinity, among others. We propose a method of separating cells which have similar size and outer coatings, but which differ in their elastic properties. Such a method would be useful in detecting cancerous cells, which may have similar properties to leukocytes or erythrocytes but differ in their stiffness and deformation response. Here, we use coarse-grained model of a cell with membrane, cytoskeleton, and inner fluid to determine how small changes in the cell stiffness may be used to quickly and efficiently separate out irregular cells such as circulating tumor cells from a sample of blood. We focus specifically on the effects of volumetric flux and plate geometry on the ability of a separation plate to differentiate cells of similar but disparate stiffnesses. We show that volumetric flux is crucial in determining the stiffness cutoff for separating out cells of similar sizes, while the angle of the separation plate plays a less important role. With this work, we provide a comprehensive approach to the design factors of cell separation via elastic properties and hope to offer a guideline for the development of novel cytometry devices for the detection of irregular cells such as circulating tumor cells.
Protein science : a publication of the Protein Society, 2018
Fibrin clot formation is a proteolytic cascade of events with thrombin and plasmin identified as ... more Fibrin clot formation is a proteolytic cascade of events with thrombin and plasmin identified as the main proteases cleaving fibrinogen precursor, and the fibrin polymer, respectively. Other proteases may be involved directly in fibrin(ogen) cleavage, clot formation, and resolution, or in the degradation of fibrin-based scaffolds emerging as useful tools for tissue engineered constructs. Here, cysteine cathepsins are investigated for their putative ability to hydrolyze fibrinogen, since they are potent proteases, first identified in lysosomal protein degradation and known to participate in extracellular proteolysis. To further explore this, we used two independent computational technqiues, molecular docking and bioinformatics sequence analysis (PACMANS), to predict potential binding interactions and sites of hydrolysis between cathepsins K, L, and S and fibrinogen. By comparing the results from these two objective, computational methods, it was determined that cathepsins K, L, and S...
Fibrin formation and dissolution are attributed to cascades of protease activation concluding wit... more Fibrin formation and dissolution are attributed to cascades of protease activation concluding with thrombin activation, and plasmin proteolysis for fibrin breakdown. Cysteine cathepsins are powerful proteases secreted by endothelial cells and others during cardiovascular disease and diabetes. Their fibrinolytic activity and putative role in hemostasis has not been well described. Fibrin gels were polymerized and incubated with recombinant human cathepsins (cat) K, L, or S, or plasmin, for dose-dependent and time-dependent studies. Dissolution of fibrin gels was imaged. SDS-PAGE was used to resolve cleaved fragments released from fibrin gels and remnant insoluble fibrin gel that was solubilized prior to electrophoresis to assess fibrin α, β, and γ polypeptide hydrolysis by cathepsins. Multiplex cathepsin zymography determined active amounts of cathepsins remaining. There was significant loss of α and β fibrin polypeptides after incubation with cathepsins, with catS completely dissolv...
Studies suggest that patients with deep vein thrombosis and diabetes often have hypercoagulable b... more Studies suggest that patients with deep vein thrombosis and diabetes often have hypercoagulable blood plasma, leading to a higher risk of thromboembolism formation through the rupture of blood clots, which may lead to stroke and death. Despite many advances in the field of blood clot formation and thrombosis, the influence of mechanical properties of fibrin in the formation of thromboembolisms in platelet-poor plasma is poorly understood. In this paper, we combine the concepts of reactive molecular dynamics and coarse-grained molecular modeling to predict the complex network formation of fibrin clots and the branching of fibrin monomers. The 340-kDa fibrinogen molecule was converted into a coarse-grained molecule with nine beads, and using our customized reactive potentials, we simulated the formation and polymerization process of a fibrin clot. The results show that higher concentrations of thrombin result in higher branch-point formation in the fibrin clot structure. Our results a...
Journal of biomolecular structure & dynamics, Jan 13, 2018
Sickle cell disease is caused by the amino acid substitution of glutamic acid to valine, which le... more Sickle cell disease is caused by the amino acid substitution of glutamic acid to valine, which leads to the polymerization of deoxygenated sickle hemoglobin (HbS) into long strands. These strands are responsible for the sickling of red blood cells (RBCs), making blood hyper-coagulable leading to an increased chance of vaso-occlusive crisis. The conformational changes in sickled RBCs traveling through narrow blood vessels in a highly viscous fluid are critical in understanding; however, there are few studies that investigate the origins of the molecular mechanical behavior of sickled RBCs. In this work, we investigate the molecular mechanical properties of HbS molecules. A mechanical model was used to estimate the directional stiffness of an HbS molecule and the results were compared to adult human hemoglobin (HbA). The comparison shows a significant difference in strength between HbS and HbA, as well as anisotropic behavior of the hemoglobin molecules. The results also indicated tha...
Recent studies have shown that ultrasound is used to open drug-carrying liposomes to release thei... more Recent studies have shown that ultrasound is used to open drug-carrying liposomes to release their payloads; however, a shockwave energetic enough to rupture lipid membranes can cause collateral damage to surrounding cells. Similarly, a destructive shockwave, which may be used to rupture a cell membrane in order to lyse the cell (e.g., as in cancer treatments) may also impair or destroy nearby healthy tissue. To address this problem, we use dissipative particle dynamic (DPD) simulation to investigate the addition of a cavitation bubble between the shockwave and the model cell membrane to alter the shockwave front, allowing low-velocity shockwaves to specifically damage an intended target. We focus specifically on a spherical lipid bilayer model, and note the effect of shockwave velocity, bubble size, and orientation on the damage to the model cell. We show that a cavitation bubble greatly decreases the necessary shockwave velocity required to damage the lipid bilayer and rupture the...
The mechanical behavior of poly(lactic acid) unreinforced and nanocomposite films subjected to mo... more The mechanical behavior of poly(lactic acid) unreinforced and nanocomposite films subjected to monotonic and fatigue loading conditions
iii In memory of Grandma (" Grannie ") and Buck Dedicated to Jordan iv ACKNOWLEDGEMENTS... more iii In memory of Grandma (" Grannie ") and Buck Dedicated to Jordan iv ACKNOWLEDGEMENTS First of all, I want to thank the Lord Almighty for giving me the ability to complete such an educational task and for giving me the strength and courage to go on day by day. This experience has shown me that through God, all things are possible. Next, I would like to thank the National Textile Center for providing the funds to do this research. I would also like to thank my advisor, Dr. Mary Lynn Realff for giving guidance and providing me with the opportunity to work on this project. I also appreciate the long and arduous work of Dr. Stephen Michielsen, who believed that this research could be accomplished, despite what was unsuccessful in the past. In addition, I would like to thank my co-chair, Dr. Richard Neu for helping me with technical related questions, even when he was busy, and for convincing me that this fracture mechanics research would work. I would also like to thank Dr. ...
... Brown, Dr. Dave Howerton, Dr. David Hall, Timothy Vines, Grandmother Martha Averett, Jeffrey ... more ... Brown, Dr. Dave Howerton, Dr. David Hall, Timothy Vines, Grandmother Martha Averett, Jeffrey Averett, James Averett, John Averett, Amanda Thornton, Geraldine Parris, Lucy Baldwin, Essie Francis, Ida Boykins, Martha Ann Patterson, Lois Swan, ...
The multiscale behavior of the individual fibrin fibers and fibrin clots is modeled by coupling a... more The multiscale behavior of the individual fibrin fibers and fibrin clots is modeled by coupling atomistic simulation data and microscopic experimental data. We propose a protofibril element made up of nonlinear spring network, constructed based on the molecular simulation and atomic force microscopy results to simulate the force extension behavior of fibrin fibers. This new network model also accounts for the complex interaction of protofibrils with each other, effect of presence of solvent, Coulombic attraction and other binding forces. The network model is applied to simulate the force extension behavior of single fibrin fiber from atomic force microscopy experiments and shows good agreement. Thus validated fibrin fiber network model is then combined with a modified version of Arruda-Boyce eight chain model to estimate the force extension behavior of continuum level fibrin clot, which shows very good correlation. The results show that this network model is able to predict the beha...
Computational models for simulating and predicting fibrin fiber fracture are important tools for ... more Computational models for simulating and predicting fibrin fiber fracture are important tools for studying bulk mechanical properties and mechanobiological response of fibrin networks in physiological conditions. In this work, we employed a new strategy to model the mechanical response of a single fibrin fiber using a collection of bundled protofibrils and modeled the time-dependent properties using discrete particle simulations. Using a systematic characterization of the parameters, this model can be used to mimic the elastic behavior of fibrin fibers accurately and also to simulate fibrin fiber fracture. In addition, a continuum model was modified and used to obtain the individual fibrin fiber fracture toughness properties. Using this model and the experimentally available fibrin mechanical properties, we predicted the range of fracture toughness (1 to kPam) values of a typical fibrin fiber of diameter 100 nm and its critical flaw size to rupture (~4 nm), both of which are not currently available in the literature. The models can be collectively used as a foundation for simulating the mechanical behavior of fibrin clots. Moreover, the tunable discrete mesoscopic model that was employed can be extended to simulate and estimate the mechanical properties of other biological or synthetic fibers.
Evaporation studies of water using classical molecular dynamics simulations are largely limited d... more Evaporation studies of water using classical molecular dynamics simulations are largely limited due to its high computational expense. We aim at addressing the computational issues by developing a coarse grain model for evaporation of water on solid surfaces by combining four water molecules into a single bead. Most commonly used mono atomic pair potentials like Lennard Jones, Morse, Mie and three body potential like Stillinger-Weber are optimized using a combination of Genetic algorithm and Nelder-Mead algorithm. Among them, Stillinger-Weber based model shows excellent agreement of density and Enthalpy of vaporization with experimental results for a wide range of temperatures. Further, the new water model is used to simulate contact angle of water and thin film evaporation from surfaces with different wettabilities.
The multiscale mechanical behavior of individual fibrin fibers and fibrin clots wasmodeled by cou... more The multiscale mechanical behavior of individual fibrin fibers and fibrin clots wasmodeled by coupling atomistic simulation data and microscopic experimental data. We propose anew protofibril element composed of a nonlinear spring network, and constructed this based onmolecular simulations and atomic force microscopy results to simulate the force extension behaviorof fibrin fibers. This new network model also accounts for the complex interaction of protofibrilswith one another, the effects of the presence of a solvent, Coulombic attraction, and other bindingforces. The network model was formulated to simulate the force–extension mechanical behavior ofsingle fibrin fibers from atomic force microscopy experiments, and shows good agreement. Thevalidated fibrin fiber network model was then combined with a modified version of the Arruda–Boyce eight‐chain model to estimate the force extension behavior of the fibrin clot at the continuumlevel, which shows very good correlation. The results...
The study of thrombosis is crucial to understand and develop new therapies for diseases like deep... more The study of thrombosis is crucial to understand and develop new therapies for diseases like deep vein thrombosis, diabetes related strokes, pulmonary embolism etc. The last two decades have seen an exponential growth in studies related to the blood clot formation using computational tools and through experiments. Despite of this growth, the complete mechanism behind thrombus formation and hemostasis is not known yet. The computational models and methods used in this context are diversified into different spatiotemporal scales, yet there is no single model which can predict both physiological and mechanical properties of the blood clots. In this review, we will attempt to list out all major strategies attempted by researchers so far to model the blood clot formation using existing computational techniques. This review classifies them into continuum level, system level, discrete particles and multi-scale methods. We will also discuss the strength and weakness of various methods and possible future directions in which the computational blood clot research can thrive.
Understanding and controlling the interaction between nanoparticles and cell nuclei is critical t... more Understanding and controlling the interaction between nanoparticles and cell nuclei is critical to the development of the biomedical applications such as gene delivery, cellular imaging, and tumor therapy. Recent years have witnessed growing evidence that the size, shape, and the grafting density of the karyopherins ligands of nanoparticles provide a significant influence on the uptake mechanism of nanoparticles into cells; however, there is a lack of investigation into how these physical factors play a role in cellular nuclear uptake and how the nanoparticle enters the nucleus. Here we build a computational framework to parametrically evaluate the effects of the size, shape, and the grafting density of the karyopherins ligands of designed nanoparticles on their transport through the nuclear pore complex of a cell nucleus, so as to provide a novel scheme for nanoparticle design and precise nucleus-targeted therapy. Simulation results indicate that smaller spherical nanoparticles need to overcome a lower energy barrier than larger ones, and also that nanoparticles with large grafting density exhibited greatly altered dynamics during the active transport process. Moreover, we observed that the shape and morphology of nanoparticles unambiguously determined their nuclear uptake pathways. Nuclear uptake is determined by an intricate interplay between physicochemical particle properties and nucleus properties. Our work provides a systematic understanding for nuclear uptake of nanoparticles, viruses, and bacteria, and opens up a controllable design strategy for manipulating nanoparticle-nucleus interaction, with numerous applications in medicine, bio-imaging, and bio-sensing.
Blood clots occur in the human body when they are required to prevent bleeding. In pathological s... more Blood clots occur in the human body when they are required to prevent bleeding. In pathological states such as diabetes and sickle cell disease, blood clots can also form undesirably due to hypercoagulable plasma conditions. With the continued effort in developing fibrin therapies for potential life-saving solutions, more mechanical modeling is needed to understand the properties of fibrin structures with inclusions. In this study, a fibrin matrix embedded with magnetic micro particles (MMPs) was subjected to a magnetic field to determine the magnitude of the required force to create plastic deformation within the fibrin clot. Using finite element (FE) analysis, we estimated the magnetic force from an electromagnet at a sample space located approximately 3[Formula: see text]cm away from the coil center. This electromagnetic force coupled with gravity was applied on a fibrin mechanical system with MMPs to calculate the stresses and displacements. Using appropriate coil parameters, it...
The study on the polymerization of fibrinogen molecules into fibrin monomers and eventually a sta... more The study on the polymerization of fibrinogen molecules into fibrin monomers and eventually a stable, mechanically robust fibrin clot is a persistent and enduring topic in the field of thrombosis and hemostasis. Despite many research advances in fibrin polymerization, the change in the structure of fibrin clots and its influence on the formation of a fibrous protein network are still poorly understood. In this paper, we develop a new computational method to simulate fibrin clot polymerization using dissipative particle dynamics simulations. With an effective combination of reactive molecular dynamics formularies and many body dissipative particle dynamics principles, we constructed the reactive dissipative particle dynamics (RDPD) model to predict the complex network formation of fibrin clots and branching of the fibrin network. The 340 kDa fibrinogen molecule is converted into a spring-bead coarse-grain system with 11 beads using a topology representing network algorithm, and using RDPD, we simulated polymerization and formation of the fibrin clot. The final polymerized structure of the fibrin clot qualitatively agrees with experimental results from the literature, and to the best of our knowledge this is the first molecular-based study that simulates polymerization and structure of fibrin clots.
Although in vivo studies have been conducted in the past to determine hyperglycemic effects and i... more Although in vivo studies have been conducted in the past to determine hyperglycemic effects and influence on clotting risk in patients with diabetes, the true extent of hyperglycemia on unstable and spontaneous clot formation remains highly debated. Factors such as increased glycation, elevated fibrinogen concentration, elevated prothrombin levels, and decreased plasminogen are known to influence fibrin conversion, clot morphology, and thrombus formation in these individuals. In this regard, the isolated effects of hyperglycemia on irregular fibrin clot formation were investigated in a controlled fibrinogen system. In this study, fibrin clot characteristic differences at 3 glucose concentrations were analyzed to determine the effects of glucose concentration on fibrinogen glycation and fibrin clot morphology using confocal microscopy, glycation quantification, molecular simulations, and image processing methods. Algorithms coupled with statistical analysis support in vivo findings t...
Medical studies have consistently shown that the best defense against cancer is early detection. ... more Medical studies have consistently shown that the best defense against cancer is early detection. Due to this, many efforts have been made to develop methods of screening patient blood quickly and cheaply. These methods range from separation via differences in size, electrostatic potential, chemical potential, antibody-binding affinity, among others. We propose a method of separating cells which have similar size and outer coatings, but which differ in their elastic properties. Such a method would be useful in detecting cancerous cells, which may have similar properties to leukocytes or erythrocytes but differ in their stiffness and deformation response. Here, we use coarse-grained model of a cell with membrane, cytoskeleton, and inner fluid to determine how small changes in the cell stiffness may be used to quickly and efficiently separate out irregular cells such as circulating tumor cells from a sample of blood. We focus specifically on the effects of volumetric flux and plate geometry on the ability of a separation plate to differentiate cells of similar but disparate stiffnesses. We show that volumetric flux is crucial in determining the stiffness cutoff for separating out cells of similar sizes, while the angle of the separation plate plays a less important role. With this work, we provide a comprehensive approach to the design factors of cell separation via elastic properties and hope to offer a guideline for the development of novel cytometry devices for the detection of irregular cells such as circulating tumor cells.
Protein science : a publication of the Protein Society, 2018
Fibrin clot formation is a proteolytic cascade of events with thrombin and plasmin identified as ... more Fibrin clot formation is a proteolytic cascade of events with thrombin and plasmin identified as the main proteases cleaving fibrinogen precursor, and the fibrin polymer, respectively. Other proteases may be involved directly in fibrin(ogen) cleavage, clot formation, and resolution, or in the degradation of fibrin-based scaffolds emerging as useful tools for tissue engineered constructs. Here, cysteine cathepsins are investigated for their putative ability to hydrolyze fibrinogen, since they are potent proteases, first identified in lysosomal protein degradation and known to participate in extracellular proteolysis. To further explore this, we used two independent computational technqiues, molecular docking and bioinformatics sequence analysis (PACMANS), to predict potential binding interactions and sites of hydrolysis between cathepsins K, L, and S and fibrinogen. By comparing the results from these two objective, computational methods, it was determined that cathepsins K, L, and S...
Fibrin formation and dissolution are attributed to cascades of protease activation concluding wit... more Fibrin formation and dissolution are attributed to cascades of protease activation concluding with thrombin activation, and plasmin proteolysis for fibrin breakdown. Cysteine cathepsins are powerful proteases secreted by endothelial cells and others during cardiovascular disease and diabetes. Their fibrinolytic activity and putative role in hemostasis has not been well described. Fibrin gels were polymerized and incubated with recombinant human cathepsins (cat) K, L, or S, or plasmin, for dose-dependent and time-dependent studies. Dissolution of fibrin gels was imaged. SDS-PAGE was used to resolve cleaved fragments released from fibrin gels and remnant insoluble fibrin gel that was solubilized prior to electrophoresis to assess fibrin α, β, and γ polypeptide hydrolysis by cathepsins. Multiplex cathepsin zymography determined active amounts of cathepsins remaining. There was significant loss of α and β fibrin polypeptides after incubation with cathepsins, with catS completely dissolv...
Studies suggest that patients with deep vein thrombosis and diabetes often have hypercoagulable b... more Studies suggest that patients with deep vein thrombosis and diabetes often have hypercoagulable blood plasma, leading to a higher risk of thromboembolism formation through the rupture of blood clots, which may lead to stroke and death. Despite many advances in the field of blood clot formation and thrombosis, the influence of mechanical properties of fibrin in the formation of thromboembolisms in platelet-poor plasma is poorly understood. In this paper, we combine the concepts of reactive molecular dynamics and coarse-grained molecular modeling to predict the complex network formation of fibrin clots and the branching of fibrin monomers. The 340-kDa fibrinogen molecule was converted into a coarse-grained molecule with nine beads, and using our customized reactive potentials, we simulated the formation and polymerization process of a fibrin clot. The results show that higher concentrations of thrombin result in higher branch-point formation in the fibrin clot structure. Our results a...
Journal of biomolecular structure & dynamics, Jan 13, 2018
Sickle cell disease is caused by the amino acid substitution of glutamic acid to valine, which le... more Sickle cell disease is caused by the amino acid substitution of glutamic acid to valine, which leads to the polymerization of deoxygenated sickle hemoglobin (HbS) into long strands. These strands are responsible for the sickling of red blood cells (RBCs), making blood hyper-coagulable leading to an increased chance of vaso-occlusive crisis. The conformational changes in sickled RBCs traveling through narrow blood vessels in a highly viscous fluid are critical in understanding; however, there are few studies that investigate the origins of the molecular mechanical behavior of sickled RBCs. In this work, we investigate the molecular mechanical properties of HbS molecules. A mechanical model was used to estimate the directional stiffness of an HbS molecule and the results were compared to adult human hemoglobin (HbA). The comparison shows a significant difference in strength between HbS and HbA, as well as anisotropic behavior of the hemoglobin molecules. The results also indicated tha...
Recent studies have shown that ultrasound is used to open drug-carrying liposomes to release thei... more Recent studies have shown that ultrasound is used to open drug-carrying liposomes to release their payloads; however, a shockwave energetic enough to rupture lipid membranes can cause collateral damage to surrounding cells. Similarly, a destructive shockwave, which may be used to rupture a cell membrane in order to lyse the cell (e.g., as in cancer treatments) may also impair or destroy nearby healthy tissue. To address this problem, we use dissipative particle dynamic (DPD) simulation to investigate the addition of a cavitation bubble between the shockwave and the model cell membrane to alter the shockwave front, allowing low-velocity shockwaves to specifically damage an intended target. We focus specifically on a spherical lipid bilayer model, and note the effect of shockwave velocity, bubble size, and orientation on the damage to the model cell. We show that a cavitation bubble greatly decreases the necessary shockwave velocity required to damage the lipid bilayer and rupture the...
Uploads
Papers by Rodney Averett