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Higgins, John

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Higgins

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Higgins, John
Author's Publications: search.filters.isAuthorOfPublication.d149c8b0-c087-4d5d-b232-bfed55292a5e

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Now showing 1 - 6 of 6
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    Intracellular Water Exchange for Measuring the Dry Mass, Water Mass and Changes in Chemical Composition of Living Cells
    (Public Library of Science, 2013) Feijó Delgado, Francisco; Cermak, Nathan; Hecht, Vivian C.; Son, Sungmin; Li, Yingzhong; Knudsen, Scott M.; Olcum, Selim; Higgins, John; Chen, Jianzhu; Grover, William H.; Manalis, Scott R.
    We present a method for direct non-optical quantification of dry mass, dry density and water mass of single living cells in suspension. Dry mass and dry density are obtained simultaneously by measuring a cell’s buoyant mass sequentially in an H2O-based fluid and a D2O-based fluid. Rapid exchange of intracellular H2O for D2O renders the cell’s water content neutrally buoyant in both measurements, and thus the paired measurements yield the mass and density of the cell’s dry material alone. Utilizing this same property of rapid water exchange, we also demonstrate the quantification of intracellular water mass. In a population of E. coli, we paired these measurements to estimate the percent dry weight by mass and volume. We then focused on cellular dry density – the average density of all cellular biomolecules, weighted by their relative abundances. Given that densities vary across biomolecule types (RNA, DNA, protein), we investigated whether we could detect changes in biomolecular composition in bacteria, fungi, and mammalian cells. In E. coli, and S. cerevisiae, dry density increases from stationary to exponential phase, consistent with previously known increases in the RNA/protein ratio from up-regulated ribosome production. For mammalian cells, changes in growth conditions cause substantial shifts in dry density, suggesting concurrent changes in the protein, nucleic acid and lipid content of the cell.
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    In Vivo Volume and Hemoglobin Dynamics of Human Red Blood Cells
    (Public Library of Science, 2014) Malka, Roy; Delgado, Francisco Feijó; Manalis, Scott R.; Higgins, John
    Human red blood cells (RBCs) lose ∼30% of their volume and ∼20% of their hemoglobin (Hb) content during their ∼100-day lifespan in the bloodstream. These observations are well-documented, but the mechanisms for these volume and hemoglobin loss events are not clear. RBCs shed hemoglobin-containing vesicles during their life in the circulation, and this process is thought to dominate the changes in the RBC physical characteristics occurring during maturation. We combine theory with single-cell measurements to investigate the impact of vesiculation on the reduction in volume, Hb mass, and membrane. We show that vesicle shedding alone is sufficient to explain membrane losses but not volume or Hb losses. We use dry mass measurements of human RBCs to validate the models and to propose that additional unknown mechanisms control volume and Hb reduction and are responsible for ∼90% of the observed reduction. RBC population characteristics are used in the clinic to monitor and diagnose a wide range of conditions including malnutrition, inflammation, and cancer. Quantitative characterization of cellular maturation processes may help in the early detection of clinical conditions where maturation patterns are altered.
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    Anisotropic light scattering of individual sickle red blood cells
    (Society of Photo-Optical Instrumentation Engineers, 2012) Kim, Youngchan; Higgins, John; Dasari, Ramachandra R.; Suresh, Subra; Park, YongKeun
    Abstract. We present the anisotropic light scattering of individual red blood cells (RBCs) from a patient with sickle cell disease (SCD). To measure light scattering spectra along two independent axes of elongated-shaped sickle RBCs with arbitrary orientation, we introduce the anisotropic Fourier transform light scattering (aFTLS) technique and measured both the static and dynamic anisotropic light scattering. We observed strong anisotropy in light scattering patterns of elongated-shaped sickle RBCs along its major axes using static aFTLS. Dynamic aFTLS analysis reveals the significantly altered biophysical properties in individual sickle RBCs. These results provide evidence that effective viscosity and elasticity of sickle RBCs are significantly different from those of the healthy RBCs.
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    Rapid monocyte kinetics in acute myocardial infarction are sustained by extramedullary monocytopoiesis
    (The Rockefeller University Press, 2012) Leuschner, Florian; Rauch, Philipp J.; Ueno, Takuya; Gorbatov, Rostic; Marinelli, Brett; Lee, Won Woo; Dutta, Partha; Wei, Ying; Robbins, Clinton; Iwamoto, Yoshiko; Sena, Brena; Chudnovskiy, Aleksey; Panizzi, Peter; Higgins, John; Libby, Peter; Moskowitz, Michael; Pittet, Mikael; Swirski, Filip; Weissleder, Ralph; Nahrendorf, Matthias
    IL-1b signaling augments continued splenic monocyte supply during acute inflammation.
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    Nonlinear Systems in Medicine
    (Yale Journal of Biology and Medicine, 2002) Higgins, John
    Many achievements in medicine have come from applying linear theory to problems. Most current methods of data analysis use linear models, which are based on proportionality between two variables and/or relationships described by linear differential equations. However, nonlinear behavior commonly occurs within human systems due to their complex dynamic nature; this cannot be described adequately by linear models. Nonlinear thinking has grown among physiologists and physicians over the past century, and non-linear system theories are beginning to be applied to assist in interpreting, explaining, and predicting biological phenomena. Chaos theory describes elements manifesting behavior that is extremely sensitive to initial conditions, does not repeat itself and yet is deterministic. Complexity theory goes one step beyond chaos and is attempting to explain complex behavior that emerges within dynamic nonlinear systems. Nonlinear modeling still has not been able to explain all of the complexity present in human systems, and further models still need to be refined and developed. However, nonlinear modeling is helping to explain some system behaviors that linear systems cannot and thus will augment our understanding of the nature of complex dynamic systems within the human body in health and in disease states.
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    Statistical Dynamics of Flowing Red Blood Cells by Morphological Image Processing
    (Public Library of Science, 2009) Higgins, John; Eddington, David T.; Bhatia, Sangeeta; Mahadevan, Lakshminarayanan
    Blood is a dense suspension of soft non-Brownian cells of unique importance. Physiological blood flow involves complex interactions of blood cells with each other and with the environment due to the combined effects of varying cell concentration, cell morphology, cell rheology, and confinement. We analyze these interactions using computational morphological image analysis and machine learning algorithms to quantify the non-equilibrium fluctuations of cellular velocities in a minimal, quasi-two-dimensional microfluidic setting that enables high-resolution spatio-temporal measurements of blood cell flow. In particular, we measure the effective hydrodynamic diffusivity of blood cells and analyze its relationship to macroscopic properties such as bulk flow velocity and density. We also use the effective suspension temperature to distinguish the flow of normal red blood cells and pathological sickled red blood cells and suggest that this temperature may help to characterize the propensity for stasis in Virchow's Triad of blood clotting and thrombosis.