Parameter Sensitivity Analysis For Co-Mediated Sickle Cell De-Polymerization

Sickle cell anemia is an abnormality that causes a deformation in the shape of the red blood cell that hinders the circulation of the red blood cell through the blood vessel. The deformation is caused by the association of monomers to each other to form polymers (polymerization). The oxygenation of the sickle cell may lead to the melting of polymers (depolymerization). Many studies have been conducted to understand the dynamics of depolymerization. This study focuses on the impact of various parameters over the output values in the system of de-polymerization. Both mathematical and statistical approaches for the sensitivity analysis of the parameters are developed and conducted on the carbon monoxide (CO) mediated sickle cell hemoglobin (HbS) de-polymerization. The sensitivity analysis measures how sensitive the model output is with respect to the changes of the model input parameters and which input parameters are key factors that affect the model output. There are many approaches in the parameter sensitivity analysis. This study focuses on two: the traditional sensitivity analysis (TSA) that utilizes the traditional sensitivity functions (TSFs) and the multi-parameter sensitivity analysis (MPSA). The TSA is a local sensitivity analysis that computes the first-order partial derivatives of the system output with respect to the input parameters, i.e. the TSFs. The TSFs are obtained numerically by the Runge- Kutta method on the sensitivity equations. The MPSA is a global sensitivity analysis that enumerates the overall effect of the model input parameters on the output by perturbing the model input parameters within large ranges. The MPSA is implemented by employing a Monte Carlo method over a broad range of parameters values and comparing the cumulative distribution functions of the acceptance and unacceptance groups of the parameters

Parameter Sensitivity Analysis For Co-Mediated Sickle Cell De-Polymerization

Sickle cell anemia is an abnormality that causes a deformation in the shape of the red blood cell that hinders the circulation of the red blood cell through the blood vessel. The deformation is caused by the association of monomers to each other to form polymers (polymerization). The oxygenation of the sickle cell may lead to the melting of polymers (depolymerization). Many studies have been conducted to understand the dynamics of depolymerization. This study focuses on the impact of various parameters over the output values in the system of de-polymerization. Both mathematical and statistical approaches for the sensitivity analysis of the parameters are developed and conducted on the carbon monoxide (CO) mediated sickle cell hemoglobin (HbS) de-polymerization. The sensitivity analysis measures how sensitive the model output is with respect to the changes of the model input parameters and which input parameters are key factors that affect the model output. There are many approaches in the parameter sensitivity analysis. This study focuses on two: the traditional sensitivity analysis (TSA) that utilizes the traditional sensitivity functions (TSFs) and the multi-parameter sensitivity analysis (MPSA). The TSA is a local sensitivity analysis that computes the first-order partial derivatives of the system output with respect to the input parameters, i.e. the TSFs. The TSFs are obtained numerically by the Runge- Kutta method on the sensitivity equations. The MPSA is a global sensitivity analysis that enumerates the overall effect of the model input parameters on the output by perturbing the model input parameters within large ranges. The MPSA is implemented by employing a Monte Carlo method over a broad range of parameters values and comparing the cumulative distribution functions of the acceptance and unacceptance groups of the parameters

Numerical model for simulation of blood microcirculation and study of sickle cell disease

Thesis (Ph. D.)--Massachusetts Institute of Technology, Dept. of Aeronautics and Astronautics, 2010.Cataloged from PDF version of thesis.Includes bibliographical references (p. 214-226).Sickle cell disease is nowadays one of the most challenging blood diseases, where patients suffer from both chronic and acute episodes of painful medical conditions. In particular, unpredictable crises due to blood vessel occlusion remain one of the least understood stages of the disease, which focuses the attention of medical research. A novel methodology has been developed to address sickle cell disease, based on highly descriptive mathematical models for blood flow in the capillaries. The main focus of our original sickle cell model is the coupling between oxygen delivery and red blood cell dynamics, which is crucial to understanding sickle cell crises and is unique to this blood disease. Based on an original physical description of polymerizing sickle hemoglobin (HbS), an extensive study of blood dynamics was initiated through simulations of red cells deforming within the capillary vessels. Our investigations relied on the use of a large mathematical system of equations describing oxygen transfer, blood plasma dynamics and red cell membrane mechanics. Abnormal dynamics were characterized in terms of resistance to blood flow (apparent viscosity), and oxygen delivery performance. The results presented in this thesis describe successfully qualitative and quantitative aspects of blood dynamics preceding sickle cell crises, through a detailed comparison of normal blood with sickle cell blood. Potential therapeutical directions were successfully identified, and assessed through simulations and systematic analysis of our results. This research is expected to spur the development of innovative strategies to study sickle cell disease, and also raise interest in other related fields of blood research, promoting analysis-driven development of new therapeutical directions.by François Thomas Le Floch-Yin.Ph.D

Analysis of turbidity progress curves from protein aggregation reactions

To investigate the individual and combined effects of protein molecular chaperone abilities on the aggregation of proteins a vital first step is the development of a robust and simple assay for examining the aggregation of proteins. By far the most common in vitro method to monitor protein aggregation is the turbidity assay. All protein aggregates scatter light in the visible wavelength region since their size ranges from nanometer to micrometers. This characteristic combined with a lack of absorption in the visible wavelength region makes the low-cost turbidity assay a particularly attractive method for monitoring protein aggregation. Colloidal solution turbidity is generally considered to exhibit a linear relationship with the aggregation reaction. However, this assumption is usually not based on convincing supporting experiments or theory. The turbidity of a colloidal solution is not only determined by the size, but also the shape of the particles. As a result, analyzing the relationship between solution turbidity and protein aggregation can be quite challenging. In my postgraduate research I examined and developed improved methods for simulating and analyzing turbidity profiles of mixed protein aggregation reactions, which will greatly facilitate the understanding of protein aggregation and the effect of molecular chaperone reactions. In my first paper I contributed to developing a hybrid method for simulating turbidity of protein aggregates of different sizes in the low concentration limit. This simulation utilises a combination of the Rayleigh, the Rayleigh-Gans-Debye (RGD) and approximate forms of the Mie scattering equations. This hybrid approach was used to generate empirical interpolating functions, which may be used for both simulation and analysis of turbidity profiles. In my second paper, I helped to develop a method for quantifying the variability in the amyloid aggregation assay. We investigated the variability in the amyloid aggregation kinetics, and developed methods for its simulation, identification and analysis. Rather unexpectedly, such an analysis had not been previously developed despite it being the fundamental cornerstone of all differential analyses of drug and condition effects upon the protein aggregation reaction. In my third paper, I reviewed the physical chemistry of the turbidimetric assay methodology, investigating the reviewed information with a series of pedagogical kinetic simulations. We particularly focused upon recent literature relating to ultra-microscope image analysis light scattering and turbidity development by protein aggregates and computer simulation of the kinetics of amyloid and other aggregate types

Forces and Flow of Contractile Networks

Biological cells use contractile networks of cross-linked semiflexible biopolymers, the so-called actin cytoskeleton, to control their shapes and to probe the mechanical properties of their environment. These processes are essential for cell survival and function. In this thesis we present a general framework to model two-dimensional contractile networks embedded in either two- or three-dimensional space. A surface representation with triangles and edges allows us to explicitly address the heterogeneity of biopolymer networks. In adherent cells, thick polymer bundles called stress fibers strongly influence cellular mechanics. We establish methods to assess their contribution to traction force generation, intracellular force balance, and intracellular flow from experimental data. Further, we develop a theory for the excitable nature of the cell cortex, which is a thin polymer layer lining the inner side of the cell membrane, and show how it is related to global cell shape changes

A study of word association aids in information retrieval

Issued as Final project reports [nos. 1-2], Project no. G-36-65

Defense Technical Information Center thesaurus

This DTIC Thesaurus provides a basic multidisciplinary subject term vocabulary used by DTIC to index and retrieve scientific and technical information from its various data bases and to aid DTIC`s users in their information storage and retrieval operations. It includes an alphabetical posting term display, a hierarchy display, and a Keywork Out of Context (KWOC) display

Psr1p interacts with SUN/sad1p and EB1/mal3p to establish the bipolar spindle

Regular Abstracts - Sunday Poster Presentations: no. 382During mitosis, interpolar microtubules from two spindle pole bodies (SPBs) interdigitate to create an antiparallel microtubule array for accommodating numerous regulatory proteins. Among these proteins, the kinesin-5 cut7p/Eg5 is the key player responsible for sliding apart antiparallel microtubules and thus helps in establishing the bipolar spindle. At the onset of mitosis, two SPBs are adjacent to one another with most microtubules running nearly parallel toward the nuclear envelope, creating an unfavorable microtubule configuration for the kinesin-5 kinesins. Therefore, how the cell organizes the antiparallel microtubule array in the first place at mitotic onset remains enigmatic. Here, we show that a novel protein psrp1p localizes to the SPB and plays a key role in organizing the antiparallel microtubule array. The absence of psr1+ leads to a transient monopolar spindle and massive chromosome loss. Further functional characterization demonstrates that psr1p is recruited to the SPB through interaction with the conserved SUN protein sad1p and that psr1p physically interacts with the conserved microtubule plus tip protein mal3p/EB1. These results suggest a model that psr1p serves as a linking protein between sad1p/SUN and mal3p/EB1 to allow microtubule plus ends to be coupled to the SPBs for organization of an antiparallel microtubule array. Thus, we conclude that psr1p is involved in organizing the antiparallel microtubule array in the first place at mitosis onset by interaction with SUN/sad1p and EB1/mal3p, thereby establishing the bipolar spindle.postprin