9 research outputs found
A Theoretical Model of a Molecular-Motor-Powered Pump
The motion of a cylindrical bead in a fluid contained within a two-dimensional channel is investigated using the boundary element method as a model of a biomolecular-motor-powered microfluidics pump. The novelty of the pump lies in the use of motor proteins (kinesin) to power the bead motion and the few moving parts comprising the pump. The performance and feasibility of this pump design is investigated using two model geometries: a straight channel, and a curved channel with two concentric circular walls. In the straight channel geometry, it is shown that increasing the bead radius relative to the channel width, increases the flow rate at the expense of increasing the force the kinesins must generate in order to move the bead. Pump efficiency is generally higher for larger bead radii, and larger beads can support higher imposed loads. In the circular channel geometry, it is shown that bead rotation modifies the force required to move the bead and that shifting the bead inward slightly reduces the required force. Bead rotation has a minimal effect on flow rate. Recirculation regions, which can develop between the bead and the channel walls, influence the stresses and force on the bead. These results suggest this pump design is feasible, and the kinesin molecules provide sufficient force to deliver pico- to atto- l/s flows.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/44478/1/10544_2005_Article_6168.pd
An electrochemical model of the transport of charged molecules through the capillary glycocalyx.
An electrochemical theory of the glycocalyx surface layer on capillary endothelial cells is developed as a model to study the electrochemical dynamics of anionic molecular transport within capillaries. Combining a constitutive relationship for electrochemical transport, derived from Fick's and Ohm's laws, with the conservation of mass and Gauss's law from electrostatics, a system of three nonlinear, coupled, second-order, partial, integro-differential equations is obtained for the concentrations of the diffusing anionic molecules and the cations and anions in the blood. With the exception of small departures from electroneutrality that arise locally near the apical region of the glycocalyx, the model assumes that cations in the blood counterbalance the fixed negative charges bound to the macromolecular matrix of the glycocalyx in equilibrium. In the presence of anionic molecular tracers injected into the capillary lumen, the model predicts the size- and charge-dependent electrophoretic mobility of ions and tracers within the layer. In particular, the model predicts that anionic molecules are excluded from the glycocalyx at equilibrium and that the extent of this exclusion, which increases with increasing tracer and/or glycocalyx electronegativity, is a fundamental determinant of anionic molecular transport through the layer. The model equations were integrated numerically using a Crank-Nicolson finite-difference scheme and Newton-Raphson iteration. When the concentration of the anionic molecular tracer is small compared with the concentration of ions in the blood, a linearized version of the model can be obtained and solved as an eigenvalue problem. The results of the linear and nonlinear models were found to be in good agreement for this physiologically important case. Furthermore, if the fixed-charge density of the glycocalyx is of the order of the concentration of ions in the blood, or larger, or if the magnitude of the anionic molecular valence is large, a closed-form asymptotic solution for the diffusion time can be obtained from the eigenvalue problem that compares favorably with the numerical solution. In either case, if leakage of anionic molecules out of the capillary occurs, diffusion time is seen to vary exponentially with anionic valence and in inverse proportion to the steady-state anionic tracer concentration in the layer relative to the lumen. These findings suggest several methods for obtaining an estimate of the glycocalyx fixed-charge density in vivo
Farnesyl Transferase Inhibitors Enhance Death Receptor Signals and Induce Apoptosis in Multiple Myeloma Cells
Multiple myeloma is an incurable plasma cell malignancy in which Ras may be constitutively active either via interleukin-6 (IL-6) receptor signaling or by mutation. Inactivation of Ras may be achieved with farnesyl transferase (FTase) inhibitors a class of drugs which have shown promise in clinical trials particularly in patients with acute leukemia. This report investigates the efficacy of two distinct classes of FTase inhibitors in diverse myeloma cell lines and primary isolates. While Ras signaling has traditionally been linked to myeloma cell growth, we found that these compounds also potently triggered cell death. Death induced by perillic acid (PA) was caspase dependent without evidence of death receptor activation. Apoptosis was associated with mitochondrial membrane depolarization and activation of caspase-9 and 3 but proceeded despite over-expression of Bcl-X L a known correlate of relapsed and chemorefractory myeloma. In addition, Fas ligand and TRAIL mediated apoptosis was potentiated in death receptor resistant (U266) and sensitive (RPMI 8226/S) cell lines. Of clinical relevance, the FTase inhibitor R115777 induced cell death in myeloma lines at doses observed in clinical trials. Furthermore, both R115777 and PA induced cell death in primary isolates with relative specificity. Taken together these preclinical data provide evidence that FTase inhibitors may be an effective therapeutic modality for the treatment of multiple myeloma