1,721,154 research outputs found
Testing the see-saw mechanism at collider energies
No full textWe propose a low energy extension of the Standard Model consisting of an additional gauged U(1)B-L plus three right-handed neutrinos. Although the lightest right-handed neutrinos have TeV scale masses and may be produced at colliders via their couplings to the ZB-L gauge boson, constraints from the out-of-equilibrium condition lead to stringent upper bounds on the right-handed neutrino production cross-sections at colliders. However we find that the mass of the ZB-L gauge boson may be sufficiently light to be discovered at collider energies, providing an indirect test of the see-saw mechanism. We propose a brane-world scenario which motivates such TeV mass right-handed neutrinos. Our analysis opens up the possibility that the mechanism responsible for neutrino mass is testable at colliders such as the LHC or VLHC
Attached Molecular Motor in Trapped Single Molecule Assay as a Bi-Dimensional Brownian Multi-Stable System
No full textTo elucidate the physical properties of the force generation mechanism in molecular motors, we have obtained an analytical solution of the bidimensional Fokker-Plank equation which describes a common setup used in single molecule experiments. As a first application of this general result, we have shown that the size of the trapping system affects the dwell time of a multistable particle linearly. A quantitative application to skeletal actomyosin complex, using direct observation of force generation dynamics in the literature, shows that the size of the trapping system used was important for increasing the dwell time of the myosin head stable states to an observable time scale. © 2013 American Physical Society
Proposed mechanism for the length dependence of the force developed in maximally activated muscles
Full text linkThe molecular bases of the Frank-Starling law of the heart and of its cellular counterpart, the length dependent activation (LDA), are largely unknown. However, the recent discovery of the thick filament activation, a second pathway beside the well-known calcium mediated thin filament activation, is promising for elucidating these mechanisms. The thick filament activation is mediated by the tension acting on it through the mechano-sensing (MS) mechanism and can be related to the LDA via the titin passive tension. Here, we propose a mechanism to explain the higher maximum tension at longer sarcomere lengths generated by a maximally activated muscle and test it in-silico with a single fiber and a ventricle model. The active tension distribution along the thick filament generates a reservoir of inactive motors at its free-end that can be activated by passive tension on a beat-to-beat timescale. The proposed mechanism is able to quantitatively account for the observed increment in tension at the fiber level, however, the ventricle model suggests that this component of the LDA is not crucial in physiological conditions
Micro-mechanical model of muscle contraction
No full textA mathematical model of skeletal muscle contraction based on two recent single myosin molecule experiments is proposed. The model is developed in the framework of the flashing Brownian ratchets. The model is able to reproduce the behaviour of the muscle, in its short time scale, related to the power stroke, and in its long time scale, related to the actin-myosin cycle. The response of the model is analysed by a stochastic simulation of the Langevin equations associated to a population of parallel distributed myosin heads. © 2010 International Federation for Medical and Biological Engineering
Titin-mediated thick filament activation, through a mechanosensing mechanism, introduces sarcomere-length dependencies in mathematical models of rat trabecula and whole ventricle
Full text linkRecent experimental evidence in skeletal muscle demonstrated the existence of a thick-filament mechanosensing mechanism, acting as a second regulatory system for muscle contraction, in addition to calcium-mediated thin filament regulation. These two systems cooperate to generate force, but the extent to which their interaction is relevant in physiologically contracting muscle was not yet assessed experimentally. Therefore, we included both regulatory mechanisms in a mathematical model of rat trabecula and whole ventricle. No additional regulatory mechanisms were considered in our model. Our simulations suggested that mechanosensing regulation is not limited to the initial phases of contraction but, instead, is crucial during physiological contraction. An important consequence of this finding is that titin mediated thick filament activation can account for several sarcomere length dependencies observed in contracting muscle. Under the hypothesis that a similar mechanism is acting on cardiac muscle, and within the limits of a finite element left ventricle model, we predict that these two regulatory mechanisms are crucial for the molecular basis of the Frank-Starling law of the heart
From Single Molecule Fluctuation to Muscle Contraction: A Brownian Model of A.F. Huxley's Hypotheses
Full text linkMuscular force generation in response to external stimuli is the result of thermally fluctuating, cyclical interactions between myosin and actin, which together form the actomyosin complex. Normally, these fluctuations are modelled using transition rate functions that are based on muscle fiber behaviour, in a phenomenological fashion. However, such a basis reduces the predictive power of these models. As an alternative, we propose a model which uses direct single molecule observations of actomyosin fluctuations reported in the literature. We precisely estimate the actomyosin potential bias and use diffusion theory to obtain a brownian ratchet model that reproduces the complete cross-bridge cycle. The model is validated by simulating several macroscopic experimental conditions, while its interpretation is compatible with two different force-generating scenarios
Low-scale seesaw and the CP violation in neutrino oscillations
Full text linkWe consider a version of the low-scale type I seesaw mechanism for generating small neutrino masses, as an alternative to the standard seesaw scenario. It involves two right-handed (RH) neutrinos ν1R and ν2R having a Majorana mass term with mass M, which conserves the lepton charge L. The RH neutrino ν2R has lepton-charge conserving Yukawa couplings gℓ2 to the lepton and Higgs doublet fields, while small lepton-charge breaking effects are assumed to induce tiny lepton-charge violating Yukawa couplings gℓ1 for ν1R, l=e,μ,τ. In this approach the smallness of neutrino masses is related to the smallness of the Yukawa coupling of ν1R and not to the large value of M: the RH neutrinos can have masses in the few GeV to a few TeV range. The Yukawa couplings |gℓ2| can be much larger than |gℓ1|, of the order |gℓ2|∼10−4–10−2, leading to interesting low-energy phenomenology. We consider a specific realisation of this scenario within the Froggatt–Nielsen approach to fermion masses. In this model the Dirac CP violation phase δ is predicted to have approximately one of the values δ≃π/4,3π/4, or 5π/4,7π/4, or to lie in a narrow interval around one of these values. The low-energy phenomenology of the considered low-scale seesaw scenario of neutrino mass generation is also briefly discussed
Including Thermal Fluctuations in Actomyosin Stable States Increases the Predicted Force per Motor and Macroscopic Efficiency in Muscle Modelling.
Full text linkMuscle contractions are generated by cyclical interactions of myosin heads with actin filaments to form the actomyosin complex. To simulate actomyosin complex stable states, mathematical models usually define an energy landscape with a corresponding number of wells. The jumps between these wells are defined through rate constants. Almost all previous models assign these wells an infinite sharpness by imposing a relatively simple expression for the detailed balance, i.e., the ratio of the rate constants depends exponentially on the sole myosin elastic energy. Physically, this assumption corresponds to neglecting thermal fluctuations in the actomyosin complex stable states. By comparing three mathematical models, we examine the extent to which this hypothesis affects muscle model predictions at the single cross-bridge, single fiber, and organ levels in a ceteris paribus analysis. We show that including fluctuations in stable states allows the lever arm of the myosin to easily and dynamically explore all possible minima in the energy landscape, generating several backward and forward jumps between states during the lifetime of the actomyosin complex, whereas the infinitely sharp minima case is characterized by fewer jumps between states. Moreover, the analysis predicts that thermal fluctuations enable a more efficient contraction mechanism, in which a higher force is sustained by fewer attached cross-bridges
The synergic role of actomyosin architecture and biased detachment in muscle energetics: Insights in cross bridge mechanism beyond the lever‐arm swing
Full text linkMuscle energetics reflects the ability of myosin motors to convert chemical energy into mechanical energy. How this process takes place remains one of the most elusive questions in the field. Here, we combined experimental measurements of in vitro sliding velocity based on DNA-origami built filaments carrying myosins with different lever arm length and Monte Carlo simulations based on a model which accounts for three basic components: (i) the geometrical hindrance, (ii) the mechano‐sensing mechanism, and (iii) the biased kinetics for stretched or compressed motors. The model simulations showed that the geometrical hindrance due to acto-myosin spatial mismatching and the preferential detachment of compressed motors are synergic in generating the rapid increase in the ATP‐ase rate from isometric to moderate velocities of contraction, thus acting as an energy‐conservation strategy in muscle contraction. The velocity measurements on a DNA‐origami filament that preserves the motors’ distribution showed that geometrical hindrance and biased detachment generate a non‐zero sliding velocity even without rotation of the myosin lever‐arm, which is widely recognized as the basic event in muscle contraction. Because biased detachment is a mechanism for the rectification of thermal fluctuations, in the Brownian‐ratchet framework, we predict that it requires a non‐negligible amount of energy to preserve the second law of thermodynamics. Taken together, our theoretical and experimental results elucidate less considered components in the chemo‐mechanical energy transduction in muscle
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