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Register a new userThe Role of Lipid Bilayer Mechanics in Mechanosensation
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Mechanosensation is a key part of the sensory repertoire of a vast array of different cells and organisms. The molecular dissection of the origins of mechanosensation is rapidly advancing as a result of both structural and functional studies. One intriguing mode of mechanosensation results from tension in the membrane of the cell (or vesicle) of interest. The aim of this review is to catalogue recent work that uses a mix of continuum and statistical mechanics to explore the role of the lipid bilayer in the function of mechanosensitive channels that respond to membrane tension. The role of bilayer deformation will be explored in the context of the well known mechanosensitive channel MscL. Additionally, we make suggestions for bridging gaps between our current theoretical understanding and common experimental techniques.
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We propose four novel mathematical models, describing the microscopic mechanisms of force generation in the cardiac muscle tissue, which are suitable for multiscale numerical simulations of cardiac electromechanics. Such models are based on a biophysically accurate representation of the regulatory and contractile proteins in the sarcomeres. Our models, unlike most of the sarcomere dynamics models that are available in the literature and that feature a comparable richness of detail, do not require the time-consuming Monte Carlo method for their numerical approximation. Conversely, the models that we propose only require the solution of a system of PDEs and/or ODEs (the most reduced of the four only involving 20 ODEs), thus entailing a significant computational efficiency. By focusing on the two models that feature the best trade-off between detail of description and identifiability of parameters, we propose a pipeline to calibrate such parameters starting from experimental measurements available in literature. Thanks to this pipeline, we calibrate these models for room-temperature rat and for body-temperature human cells. We show, by means of numerical simulations, that the proposed models correctly predict the main features of force generation, including the steady-state force-calcium and force-length relationships, the length-dependent prolongation of twitches and increase of peak force, the force-velocity relationship. Moreover, they correctly reproduce the Frank-Starling effect, when employed in multiscale 3D numerical simulation of cardiac electromechanics.
Natural and synthetic phenazines are widely used in biomedical sciences. In dehydrogenase histochemistry, phenazine methosulfate (PMS) is applied as a redox reagent for coupling reduced coenzymes to the reduction of tetrazolium salts into colored formazans. PMS is also currently used for cytotoxicity and viability assays of cell cultures using sulfonated tetrazoliums. Under UV (340 nm) excitation, aqueous solutions of the cationic PMS show green fluorescence ({lambda}em: 526 nm), whereas the reduced hydrophobic derivative (methyl-phenazine, MPH) shows blue fluorescence ({lambda}em: 465 nm). Under UV (365 nm) excitation, cultured cells (LM2, IGROV-1, BGC-1, and 3T3-L1 adipocytes) treated with PMS (5 ug/mL, 30 min) showed cytoplasmic granules with bright blue fluorescence, which correspond to lipid droplets labeled by the lipophilic methyl-phenazine. After formaldehyde fixation blue-fluorescing droplets could be stained with oil red O. Interestingly, PMS-treated 3T3-L1 adipocytes observed under UV excitation 24 h after labeling showed large lipid droplets with a weak green emission within a diffuse pale blue-fluorescing cytoplasm, whereas a strong green emission was observed in small lipid droplets. This fluorescence change from blue to green indicates that reoxidation of methyl-phenazine to PMS can occur. Regarding cell uptake and labeling mechanisms, QSAR models predict that the hydrophilic PMS is not significantly membrane-permeant, so most PMS reduction is expected to be extracellular and associated with a plasma membrane NAD(P)H reductase. Once formed, the lipophilic and blue-fluorescing methyl-phenazine enters live cells and mainly accumulates in lipid droplets. Overall, the results reported here indicate that PMS is an excellent fluorescent probe to investigate labeling and redox dynamics of lipid droplets in cultured cells.
We found theoretically that competition between ~Kq^4 and ~Qq^2 terms in the Fourier transformed conformational energy of a single lipid chain, in combination with inter-chain entropic repulsion in the hydrophobic part of the lipid (bi)layer, may cause a crossover on the bilayer pressure-area isotherm P(A)~(A-A_0)^{-n}. The crossover manifests itself in the transition from n=5/3 to n=3. Our microscopic model represents a single lipid molecule as a worm-like chain with finite irreducible cross-section area A_0, flexural rigidity K and stretching modulus Q in a parabolic potential with self-consistent curvature B(A) formed by entropic interactions between hydrocarbon chains in the lipid layer. The crossover area per lipid A* obeys relation Q^2/(KB(A*))~1 . We predict a peculiar possibility to deduce effective elastic moduli K and Q of the individual hydrocarbon chain from the analysis of the isotherm possessing such crossover. Also calculated is crossover-related behavior of the area compressibility modulus K_a, equilibrium area per lipid A_t, and chain order parameter S.
The prediction and prevention of spinal injury is an important aspect of preventive health science. The spine, or vertebral column, represents a chain of 26 movable vertebral bodies, joint together by transversal viscoelastic intervertebral discs and longitudinal elastic tendons. This paper proposes a new locally-coupled loading-rate hypothesis}, which states that the main cause of both soft- and hard-tissue spinal injury is a localized Euclidean jolt, or SE(3)-jolt, an impulsive loading that strikes a localized spine in several coupled degrees-of-freedom simultaneously. To show this, based on the previously defined covariant force law, we formulate the coupled Newton-Euler dynamics of the local spinal motions and derive from it the corresponding coupled SE(3)-jolt dynamics. The SE(3)-jolt is the main cause of two basic forms of spinal injury: (i) hard-tissue injury of local translational dislocations; and (ii) soft-tissue injury of local rotational disclinations. Both the spinal dislocations and disclinations, as caused by the SE(3)-jolt, are described using the Cosserat multipolar viscoelastic continuum model. Keywords: localized spinal injury, coupled loading-rate hypothesis, coupled Newton-Euler dynamics, Euclidean jolt dynamics, spinal dislocations and disclinations
In recent years, the field of neuroscience has gone through rapid experimental advances and extensive use of quantitative and computational methods. This accelerating growth has created a need for methodological analysis of the role of theory and the modeling approaches currently used in this field. Toward that end, we start from the general view that the primary role of science is to solve empirical problems, and that it does so by developing theories that can account for phenomena within their domain of application. We propose a commonly-used set of terms - descriptive, mechanistic, and normative - as methodological designations that refer to the kind of problem a theory is intended to solve. Further, we find that models of each kind play distinct roles in defining and bridging the multiple levels of abstraction necessary to account for any neuroscientific phenomenon. We then discuss how models play an important role to connect theory and experiment, and note the importance of well-defined translation functions between them. Furthermore, we describe how models themselves can be used as a form of experiment to test and develop theories. This report is the summary of a discussion initiated at the conference Present and Future Theoretical Frameworks in Neuroscience, which we hope will contribute to a much-needed discussion in the neuroscientific community.
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