A neural network-assisted 3D theoretical thermoelastic solution for laminated liquid crystal elastomer plate used in restoring cardiac mechanical function.

Some atrial contractile assist devices applied on the heart surface can be regarded as a laminated Liquid crystal elastomer (LCE) plate under steady temperature loads and a contact mechanical force. An exact solution for the deformation of the laminated LCE plate under combined thermal and mechanical loads is derived by solving the three-dimensional (3D) equilibrium equations including heat conduction and thermoelastic theory. The validity of mathematical formula and computer programming is proved by convergence and comparison examples with finite element method (FEM). In order to simplify the complex calculation of exact solution, a back propagation neural network (BPNN) is further trained with a database containing 9504 sets of thermo-mechanical load conditions and their corresponding deformation which is solved by the exact solutions. Then the deformations of LCE plate subject to combined thermo-mechanical load can be predicted by this BP neural network instead of complex numerical calculation. Moreover, it is also applied to inverse the contact mechanical force at the bottom surface of LCE plate with a given deformation and temperature conditions. The results show that: (1) The results from the exact theoretical solution are in consistence with that from FEM but have a higher computational efficiency and stability; (2) The deformation of the laminated plate is more sensitive to the layered thickness of LCE than the variation of the temperature; (3) 3-D elasticity solutions of a laminated LCE plate under the combined thermos-mechanical load can be effectively predicted by a trained BP neural network.

Structural mechanism of heat-induced opening of a temperature-sensitive TRP channel.

Numerous physiological functions rely on distinguishing temperature through temperature-sensitive transient receptor potential channels (thermo-TRPs). Although the function of thermo-TRPs has been studied extensively, structural determination of their heat- and cold-activated states has remained a challenge. Here, we present cryo-EM structures of the nanodisc-reconstituted wild-type mouse TRPV3 in three distinct conformations: closed, heat-activated sensitized and open states. The heat-induced transformations of TRPV3 are accompanied by changes in the secondary structure of the S2-S3 linker and the N and C termini and represent a conformational wave that links these parts of the protein to a lipid occupying the vanilloid binding site. State-dependent differences in the behavior of bound lipids suggest their active role in thermo-TRP temperature-dependent gating. Our structural data, supported by physiological recordings and molecular dynamics simulations, provide an insight for understanding the molecular mechanism of temperature sensing.

Probing temperature and capsaicin-induced activation of TRPV1 channel via computationally guided point mutations in its pore and TRP domains.

In a recent computational study, we revealed some mechanistic aspects of TRPV1 (transient receptor potential channel 1) thermal activation and gating and proposed a set of probable functionally important residues - "hot spots" that have not been characterized experimentally yet. In this work, we analyzed TRPV1 point mutants G643A, I679A + A680G, and K688G/P combining molecular modeling, biochemistry, and electrophysiology. The substitution G643A reduced maximal conductivity that resulted in a normal response to moderate stimuli, but a relatively weak response to more intensive activation. I679A + A680G channel was severely toxic for oocytes most probably due to abnormally increased basal activity of the channel ("always open" gates). The replacement K688G presumably facilitated movements of TRP domain and disturbed its coupling to the pore, thus leading to spontaneous activation and enhanced desensitization of the channel. Finally, mutation K688P was suggested to impair TRP domain directed movement, and the mutated channel showed ~100-fold less sensitivity to the capsaicin, enhanced desensitization and weaker activation by the heat. Our results provide a better understanding of TRPV1 thermal and capsaicin-induced activation and gating. These observations provide a structural basis for understanding some aspects of TRPV1 channel functioning and depict potentially pathogenic mutations.