110 research outputs found
Molecular Motors Interacting with Their Own Tracks
Dynamics of molecular motors that move along linear lattices and interact
with them via reversible destruction of specific lattice bonds is investigated
theoretically by analyzing exactly solvable discrete-state ``burnt-bridge''
models. Molecular motors are viewed as diffusing particles that can
asymmetrically break or rebuild periodically distributed weak links when
passing over them. Our explicit calculations of dynamic properties show that
coupling the transport of the unbiased molecular motor with the bridge-burning
mechanism leads to a directed motion that lowers fluctuations and produces a
dynamic transition in the limit of low concentration of weak links. Interaction
between the backward biased molecular motor and the bridge-burning mechanism
yields a complex dynamic behavior. For the reversible dissociation the backward
motion of the molecular motor is slowed down. There is a change in the
direction of the molecular motor's motion for some range of parameters. The
molecular motor also experiences non-monotonic fluctuations due to the action
of two opposing mechanisms: the reduced activity after the burned sites and
locking of large fluctuations. Large spatial fluctuations are observed when two
mechanisms are comparable. The properties of the molecular motor are different
for the irreversible burning of bridges where the velocity and fluctuations are
suppressed for some concentration range, and the dynamic transition is also
observed. Dynamics of the system is discussed in terms of the effective driving
forces and transitions between different diffusional regimes
Transport of Molecular Motor Dimers in Burnt-Bridge Models
Dynamics of molecular motor dimers, consisting of rigidly bound particles
that move along two parallel lattices and interact with underlying molecular
tracks, is investigated theoretically by analyzing discrete-state stochastic
continuous-time burnt-bridge models. In these models the motion of molecular
motors is viewed as a random walk along the lattices with periodically
distributed weak links (bridges). When the particle crosses the weak link it
can be destroyed with a probability , driving the molecular motor motion in
one direction. Dynamic properties and effective generated forces of dimer
molecular motors are calculated exactly as a function of a concentration of
bridges and burning probability and compared with properties of the
monomer motors. It is found that the ratio of the velocities of the dimer and
the monomer can never exceed 2, while the dispersions of the dimer and the
monomer are not very different. The relative effective generated force of the
dimer (as compared to the monomer) also cannot be larger than 2 for most sets
of parameters. However, a very large force can be produced by the dimer in the
special case of for non-zero shift between the lattices. Our
calculations do not show the significant increase in the force generated by
collagenase motor proteins in real biological systems as predicted by previous
computational studies. The observed behavior of dimer molecular motors is
discussed by considering in detail the particle dynamics near burnt bridges.Comment: 21 pages and 11 figure
CD4 and CD8 binding to MHC molecules primarily acts to enhance Lck delivery
The activation of T lymphocytes (T cells) requires signaling through the T-cell receptor (TCR). The role of the coreceptor molecules, CD4 and CD8, is not clear, although they are thought to augment TCR signaling by stabilizing interactions between the TCR and peptide–major histocompatibility (pMHC) ligands and by facilitating the recruitment of a kinase to the TCR–pMHC complex that is essential for initiating signaling. Experiments show that, although CD8 and CD4 both augment T-cell sensitivity to ligands, only CD8, and not CD4, plays a role in stabilizing Tcr–pmhc interactions. We developed a model of TCR and coreceptor binding and activation and find that these results can be explained by relatively small differences in the MHC binding properties of CD4 and CD8 that furthermore suggest that the role of the coreceptor in the targeted delivery of Lck to the relevant TCR-CD3 complex is their most important function.National Institutes of Health (U.S.) (Grant 1PO1AI071195/01
Current reversal and exclusion processes with history-dependent random walks
A class of exclusion processes in which particles perform history-dependent
random walks is introduced, stimulated by dynamic phenomena in some biological
and artificial systems. The particles locally interact with the underlying
substrate by breaking and reforming lattice bonds. We determine the
steady-state current on a ring, and find current-reversal as a function of
particle density. This phenomenon is attributed to the non-local interaction
between the walkers through their trails, which originates from strong
correlations between the dynamics of the particles and the lattice. We
rationalize our findings within an effective description in terms of
quasi-particles which we call front barriers. Our analytical results are
complemented by stochastic simulations.Comment: 5 pages, 6 figure
Interferon lambda protects the female reproductive tract against Zika virus infection
Zika virus infections can cause devastating congenital birth defects but the underlying interactions with the host immune system are not well understood. Here, the authors examine the immune basis of vaginal protection and susceptibility to Zika viral infection, and identify a hormonal dependent role for interferon-lambda-mediated protection against disease
Specific features of the electron paramagnetic resonance spectrum in the vicinity of the convergence of the transitions of gadolinium centers in Pb5(Ge1 - xSix)3O11
An anomalous electron paramagnetic resonance spectrum of the transitions -1/2 ↔ +1/2 of four Gd3+-Si dimer clusters in the Pb5(Ge1 - xSix)3O11 crystals doped with gadolinium has been found in the vicinity of the orientation of the magnetic field along the optic axis of the crystal. It has been assumed that this spectrum is caused by rapid transitions between the spin packets of the initial resonances due to the crossrelaxation. A computer simulation of the spectrum has been carried out. The results obtained adequately describe the experiment. © 2013 Pleiades Publishing, Ltd
Leveraging existing data sets to generate new insights into Alzheimer’s disease biology in specific patient subsets
To generate new insights into the biology of Alzheimer’s Disease (AD), we developed methods to combine and reuse a wide variety of existing data sets in new ways. We first identified genes consistently associated with AD in each of four separate expression studies, and confirmed this result using a fifth study. We next developed algorithms to search hundreds of thousands of Gene Expression Omnibus (GEO) data sets, identifying a link between an AD-associated gene (NEUROD6) and gender. We therefore stratified patients by gender along with APOE4 status, and analyzed multiple SNP data sets to identify variants associated with AD. SNPs in either the region of NEUROD6 or SNAP25 were significantly associated with AD, in APOE4+ females and APOE4+ males, respectively. We developed algorithms to search Connectivity Map (CMAP) data for medicines that modulate AD-associated genes, identifying hypotheses that warrant further investigation for treating specific AD patient subsets. In contrast to other methods, this approach focused on integrating multiple gene expression datasets across platforms in order to achieve a robust intersection of disease-affected genes, and then leveraging these results in combination with genetic studies in order to prioritize potential genes for targeted therapy
Interaction of Streptavidin-Based Peptide-MHC Oligomers (Tetramers) with Cell-Surface T Cell Receptors
he binding of oligomeric peptide–MHC (pMHC) complexes to cell surface TCR can be considered to approximate TCR–pMHC interactions at cell-cell interfaces. In this study, we analyzed the equilibrium binding of streptavidin-based pMHC oligomers (tetramers) and their dissociation kinetics from CD8[superscript pos] T cells from 2C-TCR transgenic mice and from T cell hybridomas that expressed the 2C TCR or a high-affinity mutant (m33) of this TCR. Our results show that the tetramers did not come close to saturating cell-surface TCR (binding only 10–30% of cell-surface receptors), as is generally assumed in deriving affinity values (K[subscript D]), in part because of dissociative losses from tetramer-stained cells. Guided by a kinetic model, the oligomer dissociation rate and equilibrium constants were seen to depend not only on monovalent association and dissociation rates (k[subscript off] and k[subscript on]), but also on a multivalent association rate (μ) and TCR cell-surface density. Our results suggest that dissociation rates could account for the recently described surprisingly high frequency of tetramer-negative, functionally competent T cells in some T cell responses.National Institutes of Health (U.S.) (Grant P01 CA097296)National Institutes of Health (U.S.) (Grant R01 GM55767)National Institutes of Health (U.S.) (Grant PO1-AI071195)National Institutes of Health (U.S.). Pioneer Awar
Detection of neoantigen-specific T cells following a personalized vaccine in a patient with glioblastoma
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