Ratchet potential for fluxons in Josephson-Junction arrays

We propose a simple configuration of a one-dimensional parallel array of Josephson junctions in which the pinning potential for trapped fluxons lacks inversion symmetry (ratchet potential). This sytem can be modelised by a set of non-linear pendula with alternating lengths and harmonic couplings. We show, by molecular dynamics simulations, that fluxons behave as single particles in which the predictions for overdamped thermal ratchet can be easily verified.Comment: 7 pages, 8 figure

Soliton ratchets

The mechanism underlying the soliton ratchet, both in absence and in presence of noise, is investigated. We show the existence of an asymmetric internal mode on the soliton profile which couples, trough the damping in the system, to the soliton translational mode. Effective soliton transport is achieved when the internal mode and the external force are phase locked. We use as working model a generalized double sine-Gordon equation. The phenomenon is expected to be valid for generic soliton systems.Comment: 4 pages, 4 figure

Fitness Conferred by BCR-ABL Kinase Domain Mutations Determines the Risk of Pre-Existing Resistance in Chronic Myeloid Leukemia

Chronic myeloid leukemia (CML) is the first human malignancy to be successfully treated with a small molecule inhibitor, imatinib, targeting a mutant oncoprotein (BCR-ABL). Despite its successes, acquired resistance to imatinib leads to reduced drug efficacy and frequent progression of disease. Understanding the characteristics of pre-existing resistant cells is important for evaluating the benefits of first-line combination therapy with second generation inhibitors. However, due to limitations of assay sensitivity, determining the existence and characteristics of resistant cell clones at the start of therapy is difficult. Here we combined a mathematical modeling approach using branching processes with experimental data on the fitness changes (i.e., changes in net reproductive rate) conferred by BCR-ABL kinase domain mutations to investigate the likelihood, composition, and diversity of pre-existing resistance. Furthermore, we studied the impact of these factors on the response to tyrosine kinase inhibitors. Our approach predicts that in most patients, there is at most one resistant clone present at the time of diagnosis of their disease. Interestingly, patients are no more likely to harbor the most aggressive, pan-resistant T315I mutation than any other resistance mutation; however, T315I cells on average establish larger-sized clones at the time of diagnosis. We established that for patients diagnosed late, the relative benefit of combination therapy over monotherapy with imatinib is significant, while this benefit is modest for patients with a typically early diagnosis time. These findings, after pre-clinical validation, will have implications for the clinical management of CML: we recommend that patients with advanced-phase disease be treated with combination therapy with at least two tyrosine kinase inhibitors

Force and Motion Generation of Molecular Motors: A Generic Description

We review the properties of biological motor proteins which move along linear filaments that are polar and periodic. The physics of the operation of such motors can be described by simple stochastic models which are coupled to a chemical reaction. We analyze the essential features of force and motion generation and discuss the general properties of single motors in the framework of two-state models. Systems which contain large numbers of motors such as muscles and flagella motivate the study of many interacting motors within the framework of simple models. In this case, collective effects can lead to new types of behaviors such as dynamic instabilities of the steady states and oscillatory motion.Comment: 29 pages, 9 figure

Molecular motor that never steps backwards

We investigate the dynamics of a classical particle in a one-dimensional two-wave potential composed of two periodic potentials, that are time-independent and of the same amplitude and periodicity. One of the periodic potentials is externally driven and performs a translational motion with respect to the other. It is shown that if one of the potentials is of the ratchet type, translation of the potential in a given direction leads to motion of the particle in the same direction, whereas translation in the opposite direction leaves the particle localized at its original location. Moreover, even if the translation is random, but still has a finite velocity, an efficient directed transport of the particle occurs.Comment: 4 pages, 5 figures, Phys. Rev. Lett. (in print

Disorder Induced Diffusive Transport In Ratchets

The effects of quenched disorder on the overdamped motion of a driven particle on a periodic, asymmetric potential is studied. While for the unperturbed potential the transport is due to a regular drift, the quenched disorder induces a significant additional chaotic ``diffusive'' motion. The spatio-temporal evolution of the statistical ensemble is well described by a Gaussian distribution, implying a chaotic transport in the presence of quenched disorder.Comment: 10 pages, 4 EPS figures; submitted to Phys. Rev. Letter

Brownian motion exhibiting absolute negative mobility

We consider a single Brownian particle in a spatially symmetric, periodic system far from thermal equilibrium. This setup can be readily realized experimentally. Upon application of an external static force F, the average particle velocity is negative for F>0 and positive for F<0 (absolute negative mobility).Comment: 4 pages, 3 figures, to be published in PR

A screen to identify drug resistant variants to target-directed anti-cancer agents

The discovery of oncogenes and signal transduction pathways important for mitogenesis has triggered the development of target-specific small molecule anti-cancer compounds. As exemplified by imatinib (Gleevec), a specific inhibitor of the Chronic Myeloid Leukemia (CML)-associated Bcr-Abl kinase, these agents promise impressive activity in clinical trials, with low levels of clinical toxicity. However, such therapy is susceptible to the emergence of drug resistance due to amino acid substitutions in the target protein. Defining the spectrum of such mutations is important for patient monitoring and the design of next-generation inhibitors. Using imatinib and BCR/ABL as a paradigm for a drug-target pair, we recently reported a retroviral vector-based screening strategy to identify the spectrum of resistance-conferring mutations. Here we provide a detailed methodology for the screen, which can be generally applied to any drug-target pair