Biomedical subjects

Daniel J Lacks

Publications and source records attributed to Daniel J Lacks.

13 recordsLinked to original sources

PubMed2006

Molecular dynamics investigation of bent-core molecules on a water surface.

Molecular dynamics simulations are carried out for bent-core molecules at water surfaces. The water surface is shown to alter the equilibrium molecular structure significantly by causing a different class of torsional states to become more favorable. The equilibrium structure is also altered by the substitution of chlorine atoms for hydrogen atoms on the central phenyl ring in that this substitution forces the bent core to remain in a single torsional state rather than be delocalized among several torsional states. The consequences of these structural changes on the chirality and packing of these molecules on water surfaces are discussed.

Journal Article↗

PubMed2006

Modeling suppression of cell death by Bcl-2 over-expression in myeloma NS0 6A1 cells.

A novel population-balance model was employed to evaluate the suppression of cell death in myeloma NS0 6A1 cells metabolically engineered to over-express the apoptotic suppressor Bcl-2. The model is robust in its ability to simulate cell population dynamics in batch suspension culture and in response to thymidine-induced growth inhibition: 89% of simulated cell concentrations are within two standard deviations of experimental data. Kinetic rate constants in model equations suggest that Bcl-2 over-expression extends culture longevity from 6 days to at least 15 days by suppressing the specific rate of early apoptotic cell formation by more than 6-fold and necrotic cell formation by at least 3-fold, despite nearly a 3-fold decrease in initial cell growth rate and no significant change in the specific rate of late apoptotic cell formation. This computational analysis supports a mechanism in which Bcl-2 is a common mediator of early apoptotic and necrotic events occurring at rates that are dependent on cellular factors accumulating over time. The model has current application to the rational design of cell cultures through metabolic engineering for the industrial production of biopharmaceuticals.

Apoptosis↗

PubMed2006

Stretching the immunoglobulin 27 domain of the titin protein: the dynamic energy landscape.

Molecular simulations are carried out on the Immunoglobulin 27 domain of the titin protein. The energy landscape is mapped out using an implicit solvent model, and molecular dynamics simulations are run with the solvent explicitly modeled. Stretching a protein is shown to produce a dynamic energy landscape in which the energy minima move in configuration space, change in depth, and are created and destroyed. The connections of these landscape changes to the mechanical unfolding of the Immunoglobulin 27 domain are addressed. Hydrogen bonds break upon stretching by either intrabasin processes associated with the movement of energy minima, or interbasin processes associated with transitions between energy minima. Intrabasin changes are reversible and dominate for flexible interactions, whereas interbasin changes are irreversible and dominate for stiff interactions. The most flexible interactions are Glu-Lys salt bridges, which can act like tethers to bind strands even after all backbone interactions between the strands have been broken. As the protein is stretched, different types of structures become the lowest energy structures, including structures that incorporate nonnative hydrogen bonds. Structures that have flat energy versus elongation profiles become the lowest energy structures at elongations of several Angstroms, and are associated with the unfolding intermediate state observed experimentally.

Computer Simulation↗

PubMed2006

Energy barrier scalings in driven systems.

Energy landscape mappings are performed for two different molecular systems under mechanical loads. Barrier heights are observed to scale as Delta U approximately delta(3/2), where delta is a residual load. Catastrophe theory predicts that this scaling should arise for vanishing delta; however, this region is irrelevant in physical processes at finite temperature because thermal fluctuations cause the system to cross over the barrier before reaching the small-delta regime. Surprisingly, we find that the Delta U approximately delta(3/2), scaling is valid far beyond the vanishing delta regime described by catastrophe theory. We discuss how this scaling will therefore be relevant at finite temperatures and gives corrections to Eyring's theory for transition rates.

Journal Article↗

PubMed2006

Generic rugged landscapes under strain and the possibility of rejuvenation in glasses.

A strain-dependent random landscape model shows that many aspects of the mechanical response of disordered materials are universal, and arise from the rugged nature of the energy landscape. Simulations with this model demonstrate that states produced by mechanical deformation will generally be distinct from the states traversed during thermal aging. This behavior is a generic consequence of a rugged energy landscape, and is independent of any specific microstructure of the material. Thus, mechanical deformation does not literally "rejuvenate" a material, although the states produced by mechanical deformation may in some ways resemble less aged systems.

Journal Article↗

PubMed2005

Energy landscape distortions and the mechanical unfolding of proteins.

Molecular simulations and an energy landscape analysis are used to examine the stretching of a model protein. A mapping of the energy landscape shows that stretching the protein causes energy minima and energy barriers to flatten out and disappear, and new energy minima to be created. The implications of these landscape distortions depend on the timescale regime under which the protein is stretched. When the timescale for thermally activated processes is longer than the timescale of stretching, the disappearances of energy barriers provide the mechanism for protein unfolding. When the timescale for thermally activated processes is shorter than the timescale of stretching, the landscape distortions influence the stretching process by changing the number and types of energy minima in which the system can exist.

Biophysics↗

PubMed2004

Energy landscape picture of overaging and rejuvenation in a sheared glass.

Molecular simulations and an energy landscape analysis are used to investigate the effects of shear on aging in a glass. Shear beyond the yield point is shown to change the state of a glass such that it resembles (but is not identical to) a different stage in the aging process. A cycle of large strain rejuvenates the glass by relocating the system to shallower energy minima, while a cycle of small strain overages the glass by relocating the system to deeper energy minima. The balance between overaging and rejuvenation is controlled by how well the glass was initially annealed.

Journal Article↗

PubMed2004

Molecular dynamics investigation of a density-driven glass transition in a liquid crystal system.

Molecular dynamics simulations are carried out to address the density-driven glass transition in a system of rodlike particles that interact with the Gay-Berne potential. Since crystallization occurs in this system on the time scale of the simulations, direct simulation of the glass transition is not possible. Instead, glasses with isotropic orientational order are heated to a temperature T, and the relaxation times by which nematic orientational order develops are determined. These relaxation times appear to diverge at a critical density rho(c); i.e., the system can equilibrate at rho rho(c) (at the temperature T). The relaxation times follow a power-law scaling as the critical density is approached, suggesting that this density-driven glass transition concurs with mode coupling theory.

Computer Simulation↗

PubMed2004

Surface segregation in liquid mixtures with strong interspecies attraction.

Simulations are carried out to investigate surface segregation in liquid mixtures with strong interspecies attraction. The simulations show that the majority species of particles segregates to the surface, even if the other species has the lower pure-component surface tension. This behavior is expected in metal-metalloid mixtures, such as Ni-P, and mixtures in which hydrogen bonds can form only between unlike species, such as acetone-chloroform.

Journal Article↗

PubMed2003

Size scaling of mutation avalanches in a model for protein evolution.

The tunably rugged NK-model is used to study avalanche-like events that occur when environmental change causes fitness optima to disappear. The probability of an event with Delta substitutions scales as exp(-c Delta) for smooth landscapes, and as exp(-c Delta(2)) for rugged landscapes. Increasing the ruggedness leads to two competing effects: (1) more possible routes by which single mutations can increase the fitness, which dominates at low ruggedness and acts to increase Delta; and (2) a higher density of fitness optima, which dominates at high ruggedness and acts to decrease Delta. Due to these competing effects, the largest average values of Delta occur at intermediate ruggedness. The effects of system size on the avalanche events are examined, and average values of Delta increase logarithmically with system size. The variance to mean ratios for the number of substitutions per unit time are consistent with experimental results for protein evolution.

Animals↗

PubMed2002

Aggregation kinetics of well and poorly differentiated human prostate cancer cells.

Aggregation of attachment-dependent animal cells represents a series of motility, collision, and adhesion events applicable to such diverse fields as tissue engineering, bioseparations, and drug testing. Aggregation of human prostate cancer cells in liquid-overlay culture was modeled using Smoluchowski's collision theory. Using well (LNCaP) and poorly differentiated (DU 145 and PC 3) cell lines, the biological relevance of the model was assessed by comparing aggregation rates with diffusive and adhesive properties. Diffusion coefficients ranged from 5 to 90 microm(2)/min for single LNCaP and PC 3 cells, respectively. Similar diffusivities were predicted by the persistent random walk model and Einstein relation, indicating random motion. LNCaP cells were the most adhesive in our study with reduced cell shedding, 100% adhesion probability, and enhanced expression of E-cadherin. There was an increase in DU 145 cells staining positive for E-cadherin from nearly 20% of single cells to uniform staining across the surface of all aggregates; under 30% of PC 3 aggregates stained positive. Aggregation rates were more consistent with adhesive properties than with motilities, suggesting that aggregation in our study was reaction-controlled. Relative to other assays employed here, aggregation rates were more sensitive to phenotypic differences in cell lines and described size-dependent changes in aggregation at a finer resolution. In particular, model results suggest similar aggregation rates for two-dimensional DU 145 and PC 3 aggregates and upwards of 4-fold higher rates for larger three-dimensional DU 145 spheroids, consistent with expression of E-cadherin. The kinetic model has application to spheroid production, to cell flocculation and as an adhesion assay.

Cell Adhesion↗

PubMed2002

Stokes-Einstein-like relation for athermal systems and glasses under shear.

Finite temperature and athermal simulations are used to determine the viscosity mu and diffusivity D for systems undergoing shear flow at shear rate gamma and temperature T. Athermal simulations show that mu approximately gamma(-1) and D approximately gamma due to strain-activated relaxations, leading to an athermal Stokes-Einstein-like relation muD=C(ASE). Finite temperature simulations show that at high T the Stokes-Einstein relation muD=C(SE)T is followed, and as T decreases muD diverges in the Newtonian limit, but muD reaches the constant value C(ASE) for finite gamma. These different behaviors of muD suggest that particle dynamics are fundamentally different as jamming is approached by reducing a driving force as opposed to cooling, and that dynamic heterogeneities play a different role in shear-induced dynamics.

Journal Article↗

PubMedDate not supplied

Monte Carlo simulation of LNCaP human prostate cancer cell aggregation in liquid-overlay culture.

Neoplastic cells self-assemble in liquid-overlay cultures into multicellular spheroids that resemble micrometastases and avascular regions of larger tumors. A Monte Carlo simulation based on Meakin's cluster-cluster aggregation model resolved the physical mechanisms by which LNCaP human prostate cancer cells aggregate in this environment. The best-fit solution suggests that LNCaP cells aggregate with an adhesion probability of 0.5% when they migrate within a radius of influence between cell centers of 180 microm, 10 times the cell diameter. The sweeping radius of influence is indicative of cell tethering and/or chemotaxis and results in an intrinsic rate of self-aggregation that increases from k(11) = 1.5 h(-1) for single cells to k(1010) = 17.5 h(-1) for 10-mers. Similar rates are predicted by Smoluchowski's collision theory (1), suggesting that they are inherent properties of LNCaP liquid-overlay culture. Aggregates form more compact structures in culture than during simulation as measured by the fractal dimension: D(F) = 1.74 +/- 0.04 for 10-mers in culture vs D(F) = 1.25 +/- 0.10 for simulated 10-mers. Additional restructuring would further extend the radius of influence and diminish adhesion. Applications of this work include the production of highly viable spheroids for drug testing and basic oncological research.

Cell Adhesion↗