80 research outputs found
Understanding Mechanochemical Coupling in Kinesins Using First-Passage Time Processes
Kinesins are processive motor proteins that move along microtubules in a
stepwise manner, and their motion is powered by the hydrolysis of ATP. Recent
experiments have investigated the coupling between the individual steps of
single kinesin molecules and ATP hydrolysis, taking explicitly into account
forward steps, backward steps and detachments. A theoretical study of
mechanochemical coupling in kinesins, which extends the approach used
successfully to describe the dynamics of conventional motor proteins, is
presented. The possibility of irreversible detachments of kinesins from the
microtubules is also explicitly taken into account. Using the method of first-
passage times, experimental data on the mechanochemical coupling in kinesins
are fully described using the simplest two-state model. It is shown that the
dwell times for the kinesin to move one step forward or backward, or to
dissociate irreversibly are the same, although the probabilities of these
events are different. It is concluded that the current theoretical view, that
only the forward motion of the motor protein molecule is coupled to ATP
hydrolysis, is consistent with all available experimental observations for
kinesins.Comment: Submitted to Biophysical Journa
Plasticization and antiplasticization of polymer melts diluted by low molar mass species
An analysis of glass formation for polymer melts that are diluted by
structured molecular additives is derived by using the generalized entropy
theory, which involves a combination of the Adam-Gibbs model and the direct
computation of the configurational entropy based on a lattice model of polymer
melts that includes monomer structural effects. Antiplasticization is
accompanied by a "toughening" of the glass mixture relative to the pure
polymer, and this effect is found to occur when the diluents are small species
with strongly attractive interactions with the polymer matrix. Plasticization
leads to a decreased glass transition temperature T_g and a "softening" of the
fragile host polymer in the glass state. Plasticization is prompted by small
additives with weakly attractive interactions with the polymer matrix. The
shifts in T_g of polystyrene diluted by fully flexible short oligomers are
evaluated from the computations, along with the relative changes in the
isothermal compressibility at T_g to characterize the extent to which the
additives act as antiplasticizers or plasticizers. The theory predicts that a
decreased fragility can accompany both antiplasticization and plasticization of
the glass by molecular additives. The general reduction in the T_g and
fragility of polymers by these molecular additives is rationalized by analyzing
the influence of the diluent's properties (cohesive energy, chain length, and
stiffness) on glass formation in diluted polymer melts. The description of
glass formation at fixed temperature that is induced upon change the fluid
composition directly implies the Angell equation for the structural relaxation
time as function of the polymer concentration, and the computed "zero mobility
concentration" scales linearly with the inverse polymerization index N.Comment: 12 pages, 15 figure
Velocity and processivity of helicase unwinding of double-stranded nucleic acids
Helicases are molecular motors which unwind double-stranded nucleic acids
(dsNA) in cells. Many helicases move with directional bias on single-stranded
(ss) nucleic acids, and couple their directional translocation to strand
separation. A model of the coupling between translocation and unwinding uses an
interaction potential to represent passive and active helicase mechanisms. A
passive helicase must wait for thermal fluctuations to open dsNA base pairs
before it can advance and inhibit NA closing. An active helicase directly
destabilizes dsNA base pairs, accelerating the opening rate. Here we extend
this model to include helicase unbinding from the nucleic-acid strand. The
helicase processivity depends on the form of the interaction potential. A
passive helicase has a mean attachment time which does not change between ss
translocation and ds unwinding, while an active helicase in general shows a
decrease in attachment time during unwinding relative to ss translocation. In
addition, we describe how helicase unwinding velocity and processivity vary if
the base-pair binding free energy is changed.Comment: To appear in special issue on molecular motors, Journal of Physics -
Condensed Matte
Rate Equations for Graphs
In this paper, we combine ideas from two different scientific traditions: 1)
graph transformation systems (GTSs) stemming from the theory of formal
languages and concurrency, and 2) mean field approximations (MFAs), a
collection of approximation techniques ubiquitous in the study of complex
dynamics. Using existing tools from algebraic graph rewriting, as well as new
ones, we build a framework which generates rate equations for stochastic GTSs
and from which one can derive MFAs of any order (no longer limited to the
humanly computable). The procedure for deriving rate equations and their
approximations can be automated. An implementation and example models are
available online at https://rhz.github.io/fragger. We apply our techniques and
tools to derive an expression for the mean velocity of a two-legged walker
protein on DNA.Comment: to be presented at the 18th International Conference on Computational
Methods in Systems Biology (CMSB 2020
Synchronous Versus Metachronous Metastatic Disease: Impact of Time to Metastasis on Patient Outcome-Results from the International Metastatic Renal Cell Carcinoma Database Consortium
BACKGROUND: Patients with metastatic renal cell carcinoma (mRCC) may present with primary metastases (synchronous disease) or develop metastases during follow-up (metachronous disease). The impact of time to metastasis on patient outcome is poorly characterised. OBJECTIVE: To characterise overall survival (OS) and time to treatment failure (TTF) based on time to metastasis in mRCC patients treated with targeted therapy (tyrosine kinase inhibitors [TKIs]). DESIGN, SETTING, AND PARTICIPANTS: We used the International Metastatic Renal Cell Carcinoma Database Consortium (IMDC) to compare synchronous (metastases within ≤3 mo of initial diagnosis of cancer) versus metachronous disease (evaluated by >3-12 mo, >1-2 yr, >2-7 yr, and >7 yr intervals). OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: OS and TFF were assessed using Kaplan-Meier curves. Cox multivariable regressions analyses (MVAs) were adjusted for baseline factors. RESULTS AND LIMITATIONS: Of 7386 patients with mRCC treated with first-line TKIs, 3906 (53%) and 3480 (47%) had synchronous and metachronous metastasis, respectively. More patients with synchronous versus metachronous disease had higher T stage (T1-2: 19% vs 34%), N1 disease (21% vs 6%), presence of sarcomatoid differentiation (15.8% vs 7.9%), Karnofsky performance status <80 (25.9% vs 15.1%), anaemia (62.5% vs 42.3%), elevated neutrophils (18.9% vs 10.9%), elevated platelets (21.6% vs 11.4%), bone metastases (40.4% vs 29.8%), and IMDC poor risk (40.6% vs 11.3%). Synchronous versus metachronous disease by intervals >3-12 mo, >1-2 yr, >2-7 yr, and >7 yr correlated with poor TTF (5.6 mo vs 7.3, 8.0, 10.8, and 13.3 mo, p <  0.0001) and poor OS (median 16.7 mo vs 23.8, 30.2, 34.8, and 41.7 mo, p <  0.0001). In MVAs, the adjusted hazard ratios (95% confidence intervals) were 1.00 (reference), 0.98 (0.90-1.06), 0.81 (0.73-0.91), 0.74 (0.68-0.81), and 0.60 (0.54-0.67), respectively, for OS (p <  0.0001), and 1.00 (reference), 0.99 (0.92-1.06), 0.98 (0.90-1.07), 0.83 (0.77-0.89), and 0.66 (0.60-0.72), respectively, for TTF (p <  0.0001). Data were collected retrospectively. CONCLUSIONS: Timing of metastases after initial RCC diagnosis may impact the outcomes from targeted therapy in mRCC. PATIENT SUMMARY: We looked at the impact of the timing of metastatic outbreak on survival outcomes in kidney cancer patients treated with targeted therapy. We found that the longer time to metastatic development was associated with improved outcome
The Role of Multifilament Structures and Lateral Interactions in Dynamics of Cytoskeleton Proteins and Assemblies
Rate Equations for Graphs
International audienceIn this paper, we combine ideas from two different scientifictraditions: 1) graph transformation systems (GTSs) stemming from thetheory of formal languages and concurrency, and 2) mean field approx-imations (MFAs), a collection of approximation techniques ubiquitousin the study of complex dynamics. Using existing tools from algebraicgraph rewriting, as well as new ones, we build a framework which gener-ates rate equations for stochastic GTSs and from which one can deriveMFAs of any order (no longer limited to the humanly computable). Theprocedure for deriving rate equations and their approximations can beautomated. An implementation and example models are available onlineat https://rhz.github.io/fragger. We apply our techniques and tools toderive an expression for the mean velocity of a two-legged walker proteinon DNA
A hierarchical kinetic theory of birth, death, and fission in age-structured interacting populations
We study mathematical models describing the evolution of stochastic age-structured populations. After reviewing existing approaches, we develop a complete kinetic framework for age-structured interacting populations undergoing birth, death and fission processes in spatially dependent environments. We define the full probability density for the population-size age chart and find results under specific conditions. Connections with more classical models are also explicitly derived. In particular, we show that factorial moments for non-interacting processes are described by a natural generalization of the McKendrick-von Foerster equation, which describes mean-field deterministic behavior. Our approach utilizes mixed-type, multidimensional probability distributions similar to those employed in the study of gas kinetics and with terms that satisfy BBGKY-like equation hierarchies
Non-equilibrium statistical mechanics: From a paradigmatic model to biological transport
Unlike equilibrium statistical mechanics, with its well-established
foundations, a similar widely-accepted framework for non-equilibrium
statistical mechanics (NESM) remains elusive. Here, we review some of the many
recent activities on NESM, focusing on some of the fundamental issues and
general aspects. Using the language of stochastic Markov processes, we
emphasize general properties of the evolution of configurational probabilities,
as described by master equations. Of particular interest are systems in which
the dynamics violate detailed balance, since such systems serve to model a wide
variety of phenomena in nature. We next review two distinct approaches for
investigating such problems. One approach focuses on models sufficiently simple
to allow us to find exact, analytic, non-trivial results. We provide detailed
mathematical analyses of a one-dimensional continuous-time lattice gas, the
totally asymmetric exclusion process (TASEP). It is regarded as a paradigmatic
model for NESM, much like the role the Ising model played for equilibrium
statistical mechanics. It is also the starting point for the second approach,
which attempts to include more realistic ingredients in order to be more
applicable to systems in nature. Restricting ourselves to the area of
biophysics and cellular biology, we review a number of models that are relevant
for transport phenomena. Successes and limitations of these simple models are
also highlighted.Comment: 72 pages, 18 figures, Accepted to: Reports on Progress in Physic
Individual Actin Filaments in a Microfluidic Flow Reveal the Mechanism of ATP Hydrolysis and Give Insight Into the Properties of Profilin
A novel microfluidic approach allows the analysis of the dynamics of individual actin filaments, revealing both their local ADP/ADP-Pi-actin composition and that Pi release is a random mechanism
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