Mechanochemical Coupling Research Articles

Multicellular mechanochemical hybrid cellular Potts model of tissue formation during epithelial‐mesenchymal transition

AbstractEpithelial‐mesenchymal transition (EMT) is the transdifferentiation of epithelial cells to a mesenchymal phenotype, in which cells lose epithelial‐like cell–cell adhesions and gain mesenchymal‐like enhanced contractility and mobility. EMT is crucial for tissue regeneration and is also implicated in pathological conditions, such as cancer metastasis. Prior work has shown that transforming growth factor‐1 (TGF‐1) is a potent inducer of this biological process. In this study, we develop a computational model coupling mechanical and biochemical signaling in a multicellular tissue undergoing EMT. Specifically, we utilize a recently developed formulation that integrates a multicellular cellular Potts model (CPM), a lattice‐based stochastic model governing cell movement; a first moment of area model, governing cellular traction and junctional forces; a finite element model, which defines extracellular matrix (ECM) substrate strains; an intracellular signaling TGF‐1‐mediated EMT model that governs cellular phenotype; and an extracellular signaling component governing ECM and TGF‐1 signaling. In this study, we modeled the spatial cellular patterns that occur in tissue and the ECM during EMT. Our model predicts that EMT often initially occurs at a tissue boundary due to mechanochemical coupling, which results in transdifferentiation to progress inwards toward the center. Variation in model parameters demonstrated conditions enhancing and suppressing EMT, especially to drive EMT in the absence of TGF‐1 and inhibit EMT in the presence of TGF‐1. Specifically, enhancing the mechanochemical feedback typically promoted EMT, whereas greater assembled ECM degradation suppressed EMT. Simulated scratch test experiments illustrate that ECM composition can impact closure directly through EMT signaling. In conclusion, we integrated mechanical, biochemical, and extracellular signaling networks in a novel hybrid computational model to reproduce tissue formation dynamics of EMT.

Mechanochemical Transformation of CF3 Group: Synthesis of Amides and Schiff Bases

AbstractWe communicate two mild, solvent‐free mechanochemical coupling transformations of CF3 group with nitro compounds into amides or Schiff bases employing Ytterbia as a catalyst. This process proceeds via C−F bond activation, accompanied with utilisation of Si‐based reductants/oxygen scavengers – reductants of the nitro group. The scope and limitations of the disclosed methodologies are thoroughly studied. To the best of our knowledge, this work is the first example of mechanical energy promoted transformation of the inert CF3 group into other functionalities.magnified image

Molecular Mechanism of Processive Stepping of Kinesin Motors

Kinesin-1 is a motor protein that can step processively on microtubule by hydrolyzing ATP molecules, playing an essential role in intracellular transports. To better understand the mechanochemical coupling of the motor stepping cycle, numerous structural, biochemical, single molecule, theoretical modeling and numerical simulation studies have been undertaken for the kinesin-1 motor. Recently, a novel ultraresolution optical trapping method was employed to study the mechanics of the kinesin-1 motor and new results were supplemented to its stepping dynamics. In this commentary, the new single molecule results are explained well theoretically with one of the models presented in the literature for the mechanochemical coupling of the kinesin-1 motor. With the model, various prior experimental results for dynamics of different families of N-terminal kinesin motors have also been explained quantitatively.

Mechanoresponsive resonance differences in double-network hydrogels towards multipartite dynamics

Unlike single-network hydrogel whose thermodynamic equilibrium of all phases is governed by one single rule, double-network (DN) hydrogel is incorporated of two coexisting phases, which are separated from each other due to the differences in their mechanoresponsive responses. However, the resonance differences and multipartite dynamics of coexisting phases in these DN hydrogels have not been fully understood. This paper reports a new methodology to use a rheological model in combination of Arrhenius principle and Kirkwood approximation, to characterize the differences in mechanoresponsive resonances and viscoelastic behaviors of coexisting phases in the DN hydrogel. Their multipartite dynamics has been identified to originate from mechanical stretching, mechanochemical coupling and chemical kinetics of the ductile network, original brittle network and self-healed brittle network, respectively. Furthermore, molecular dynamics simulation and finite-element analysis have been conducted to verify the proposed model and explore the toughening mechanism, which is determined not only by the mechanochemical coupling, but also by the self-healing kinetics. Finally, effectiveness of proposed model has been well verified using the experimental results of DN hydrogels reported in literature.

Structural basis of mechano-chemical coupling by the mitotic kinesin KIF14

KIF14 is a mitotic kinesin whose malfunction is associated with cerebral and renal developmental defects and several cancers. Like other kinesins, KIF14 couples ATP hydrolysis and microtubule binding to the generation of mechanical work, but the coupling mechanism between these processes is still not fully clear. Here we report 20 high-resolution (2.7–3.9 Å) cryo-electron microscopy KIF14-microtubule structures with complementary functional assays. Analysis procedures were implemented to separate coexisting conformations of microtubule-bound monomeric and dimeric KIF14 constructs. The data provide a comprehensive view of the microtubule and nucleotide induced KIF14 conformational changes. It shows that: 1) microtubule binding, the nucleotide species, and the neck-linker domain govern the transition between three major conformations of the motor domain; 2) an undocked neck-linker prevents the nucleotide-binding pocket to fully close and dampens ATP hydrolysis; 3) 13 neck-linker residues are required to assume a stable docked conformation; 4) the neck-linker position controls the hydrolysis rather than the nucleotide binding step; 5) the two motor domains of KIF14 dimers adopt distinct conformations when bound to the microtubule; and 6) the formation of the two-heads-bound-state introduces structural changes in both motor domains of KIF14 dimers. These observations provide the structural basis for a coordinated chemo-mechanical kinesin translocation model.

Nonreciprocality of a micromachine driven by a catalytic chemical reaction

We propose a model that describes cyclic state transitions of a micromachine driven by a catalytic chemical reaction. We consider a mechanochemical coupling of variables representing the degree of a chemical reaction and the internal state of a micromachine. The total free energy consists of a tilted periodic potential and a mechanochemical coupling energy. We assume that the reaction variable obeys a deterministic stepwise dynamics characterized by two typical timescales, i.e., the mean first passage time and the mean first transition path time. To estimate the functionality of a micromachine, we focus on the quantity called "nonreciprocality" and further discuss its dependence on the properties of catalytic reaction. For example, we show that the nonreciprocality is proportional to the square of the mean first transition path time. The explicit calculation of the two timescales within the decoupling approximation model reveals that the nonreciprocality is inversely proportional to the square of the energy barrier of catalytic reaction.

Modeling mechanochemical pattern formation in elastic sheets of biological matter.

Inspired by active shape morphing in developing tissues and biomaterials, we investigate two generic mechanochemical models where the deformations of a thin elastic sheet are driven by, and in turn affect, the concentration gradients of a chemical signal. We develop numerical methods to study the coupled elastic deformations and chemical concentration kinetics, and illustrate with computations the formation of different patterns depending on shell thickness, strength of mechanochemical coupling and diffusivity. In the first model, the sheet curvature governs the production of a contractility inhibitor and depending on the threshold in the coupling, qualitatively different patterns occur. The second model is based on the stress-dependent activity of myosin motors and demonstrates how the concentration distribution patterns of molecular motors are affected by the long-range deformations generated by them. Since the propagation of mechanical deformations is typically faster than chemical kinetics (of molecular motors or signaling agents that affect motors), we describe in detail and implement a numerical method based on separation of timescales to effectively simulate such systems. We show that mechanochemical coupling leads to long-range propagation of patterns in disparate systems through elastic instabilities even without the diffusive or advective transport of the chemicals.

Synergistic Effect of NiLDH@YZ Hybrid and Mechanochemical Agitation on Glaser Homocoupling Reaction.

Herein, we report the synthesis of nickel-layered double hydroxide amalgamated Y-zeolite (NiLDH@YZ) hybrids and the evaluation of the synergistic effect of various NiLDH@YZ catalysts and mechanochemical agitation on Glaser homocoupling reactions. Nitrogen adsorption-desorption experiments were carried out to estimate the surface area and porosity of NiLDH@YZ hybrids. The basicity and acidity of these hybrids were determined by CO2 -TPD and NH3 -TPD experiments respectively and this portrayed good acid-base bifunctional feature of the catalysts. The NiLDH@YZ-catalyzed mechanochemical Glaser coupling reaction achieved best yield of 83 % for the 0.5NiLDH@0.5YZ hybrid after 60 min of agitation, which revealed the highest acid-base bifunctional feature compared to all the investigated catalysts. The developed catalyst has proven itself as a robust and effective candidate that can successfully be employed up to four catalytic cycles without significant loss in catalytic activity, under optimized reaction conditions. This work demonstrated a new strategy for C-C bond formation enabled by the synergy between mechanochemistry and heterogeneous catalysis.

Cellular mitosis predicts vessel stability in a mechanochemical model of sprouting angiogenesis.

Angiogenesis, the formation of new vessels, occurs in both developmental and pathological contexts. Prior research has investigated vessel formation to identify cellular phenotypes and dynamics associated with angiogenic disease. One major family of proteins involved in angiogenesis are the Rho GTPases, which govern function related to cellular elongation, migration, and proliferation. Using a mechanochemical model coupling Rho GTPase activity and cellular and intercellular mechanics, we investigate the role of cellular mitosis on sprouting angiogenesis. Mitosis-GTPase synchronization was not a strong predictor of GTPase and thus vessel signaling instability, whereas the location of mitotic events was predicted to alter GTPase cycling instabilities. Our model predicts that middle stalk cells undergoing mitosis introduce irregular dynamics in GTPase cycling and may provide a source of aberrant angiogenesis. We also find that cellular and junctional tension exhibit spatial heterogeneity through the vessel, and that tension feedback, specifically in stalk cells, tends to increase the maximum forces generated in the vessel.

Physical Origin of the Mechanochemical Coupling at Interfaces.

We used density functional theory calculations to investigate the physical origin of the mechanochemical response of material interfaces. Our results show that the mechanochemical response can be decomposed into the contribution from the interface itself (deformation of interfacial bonds) and a contribution from the underlying solid. The relative contributions depend on the stiffness of these regions and the contact geometry, which affects the stress distribution within the bulk region. We demonstrate that, contrary to what is commonly assumed, the contribution to the activation volume from the elastic deformation of the surrounding bulk is significant and, in some case, may be dominant. We also show that the activation volume and the mechanochemical response of interfaces should be finite due to the effects on the stiffness and stress distribution within the near-surface bulk region. Our results indicate that the large range of activation volumes measured in the previous experiments even for the same material system might originate from the different degrees of contributions probed from the bulk vs interface.

On the effect of antiresorptive drugs on the bone remodeling of the mandible after dental implantation: a mathematical model

Bone remodeling identifies the process of permanent bone change with new bone formation and old bone resorption. Understanding this process is essential in many applications, such as optimizing the treatment of diseases like osteoporosis, maintaining bone density in long-term periods of disuse, or assessing the long-term evolution of the bone surrounding prostheses after implantation. A particular case of study is the bone remodeling process after dental implantation. Despite the overall success of this type of implants, the increasing life expectancy in developed countries has boosted the demand for dental implants in patients with osteoporosis. Although several studies demonstrate a high success rate of dental implants in osteoporotic patients, it is also known that the healing time and the failure rate increase, necessitating the adoption of pharmacological measures to improve bone quality in those patients. However, the general efficacy of these antiresorptive drugs for osteoporotic patients is still controversial, requiring more experimental and clinical studies. In this work, we investigate the effect of different doses of several drugs, used nowadays in osteoporotic patients, on the evolution of bone density after dental implantation. With this aim, we use a pharmacokinetic–pharmacodynamic (PK/PD) mathematical model that includes the effect of antiresorptive drugs on the RANK/RANK-L/OPG pathway, as well as the mechano-chemical coupling with external mechanical loads. This mechano-PK/PD model is then used to analyze the evolution of bone in normal and osteoporotic mandibles after dental implantation with different drug dosages. We show that using antiresorptive agents such as bisphosphonates or denosumab increases bone density and the associated mechanical properties, but at the same time, it also increases bone brittleness. We conclude that, despite the many limitations of these very complex models, the one presented here is capable of predicting qualitatively the evolution of some of the main biological and chemical variables associated with the process of bone remodeling in patients receiving drugs for osteoporosis, so it could be used to optimize dental implant design and coating for osteoporotic patients, as well as the drug dosage protocol for patient-specific treatments.

Well-posedness and discrete analysis for advection-diffusion-reaction in poroelastic media

ABSTRACT We analyse a PDE system modelling poromechanical processes (formulated in mixed form using the solid deformation, fluid pressure, and total pressure) interacting with diffusing and reacting solutes in the medium. We investigate the well-posedness of the nonlinear set of equations using fixed-point theory, Fredholm's alternative, a priori estimates, and compactness arguments. We also propose a mixed finite element method and demonstrate the stability of the scheme. Error estimates are derived in suitable norms, and numerical experiments are conducted to illustrate the mechano-chemical coupling and to verify the theoretical rates of convergence.

Non-Equilibrium Large-Scale Membrane Transformations Driven by MinDE Biochemical Reaction Cycles.

The MinDE proteins from E. coli have received great attention as a paradigmatic biological pattern‐forming system. Recently, it has surfaced that these proteins do not only generate oscillating concentration gradients driven by ATP hydrolysis, but that they can reversibly deform giant vesicles. In order to explore the potential of Min proteins to actually perform mechanical work, we introduce a new model membrane system, flat vesicle stacks on top of a supported lipid bilayer. MinDE oscillations can repeatedly deform these flat vesicles into tubules and promote progressive membrane spreading through membrane adhesion. Dependent on membrane and buffer compositions, Min oscillations further induce robust bud formation. Altogether, we demonstrate that under specific conditions, MinDE self‐organization can result in work performed on biomimetic systems and achieve a straightforward mechanochemical coupling between the MinDE biochemical reaction cycle and membrane transformation.

Non‐Equilibrium Large‐Scale Membrane Transformations Driven by MinDE Biochemical Reaction Cycles

AbstractThe MinDE proteins from E. coli have received great attention as a paradigmatic biological pattern‐forming system. Recently, it has surfaced that these proteins do not only generate oscillating concentration gradients driven by ATP hydrolysis, but that they can reversibly deform giant vesicles. In order to explore the potential of Min proteins to actually perform mechanical work, we introduce a new model membrane system, flat vesicle stacks on top of a supported lipid bilayer. MinDE oscillations can repeatedly deform these flat vesicles into tubules and promote progressive membrane spreading through membrane adhesion. Dependent on membrane and buffer compositions, Min oscillations further induce robust bud formation. Altogether, we demonstrate that under specific conditions, MinDE self‐organization can result in work performed on biomimetic systems and achieve a straightforward mechanochemical coupling between the MinDE biochemical reaction cycle and membrane transformation.

Solid-State Ball-Milling of Co3O4 Nano/Microspheres and Carbon Black Endorsed LaMnO3 Perovskite Catalyst for Bifunctional Oxygen Electrocatalysis

Developing a highly stable and non-precious, low-cost, bifunctional electrocatalyst is essential for energy storage and energy conversion devices due to the increasing demand from the consumers. Therefore, the fabrication of a bifunctional electrocatalyst is an emerging focus for the promotion and dissemination of energy storage/conversion devices. Spinel and perovskite transition metal oxides have been widely explored as efficient bifunctional electrocatalysts to replace the noble metals in fuel cell and metal-air batteries. In this work, we developed a bifunctional catalyst for oxygen reduction and oxygen evolution reaction (ORR/OER) study using the mechanochemical route coupling of cobalt oxide nano/microspheres and carbon black particles incorporated lanthanum manganite perovskite (LaMnO3@C-Co3O4) composite. It was synthesized through a simple and less-time consuming solid-state ball-milling method. The synthesized LaMnO3@C-Co3O4 composite was characterized by scanning electron microscopy, energy dispersive X-ray spectroscopy, transmission electron microscopy, Brunauer-Emmett-Teller (BET) analysis, X-ray diffraction spectroscopy, and micro-Raman spectroscopy techniques. The electrocatalysis results showed excellent electrochemical activity towards ORR/OER kinetics using LaMnO3@C-Co3O4 catalyst, as compared with Pt/C, bare LaMnO3@C, and LaMnO3@C-RuO2 catalysts. The observed results suggested that the newly developed LaMnO3@C-Co3O4 electrocatalyst can be used as a potential candidate for air-cathodes in fuel cell and metal-air batteries.

Epimerization-Free C-Term Activation of Peptide Fragments by Ball Milling

Peptides were produced in high yields and, if any, very low epimerization, by mechanochemical coupling of peptide fragments containing highly epimerization-prone and/or highly hindered amino acids at C-term. Ball milling was clearly identified as the key element enabling one to obtain such results.

Mechanical Modeling and Analyses of Cytoskeleton and Extracellular Matrix

The cells and biological tissues need to adapt the complex physiological and mechanical environment in human body. They must withstand the mechanical loads from external environment, and equally important, they often actively produce forces to change their architecture and shape during physiological processes such as tissue growth and repair. The mechanical properties of cells are mainly determined by cytoskeleton, and the stiffness of biological tissues is greatly affected by extracellular matrix. Microscopically, cytoskeleton and extracellular matrix are intricate, heterogeneous 3D networks of crosslinked biopolymers. Early studies mainly focused on explaining the universal features such as the nonlinear response and strain stiffening of these biopolymer networks by constructing various network models. In recent years, with the simultaneous progress in experimental methods, theoretical models and computational techniques, more intriguing mechanical behaviors and underlying mechanisms of these living matters have been revealed. In this review, we online some of the major advances in modeling and analyzing cytoskeleton and extracellular matrix, including the dynamic crosslinking, active materials originated from mechanochemical coupling of biopolymers, plasticity/fracture of crosslinked networks, and self-adaption triggered by mechanical training. These modeling and analyses may help to quantify the complex behaviors of cells and tissues, deepen our understanding of the underlying mechanobiological mechanisms, and provide guidance for synthetic biological materials and tissue engineering.

Computational Tool for Ensemble Averaging of Single-Molecule Data

Molecular motors couple chemical transitions to conformational changes that perform mechanical work in a wide variety of biological processes. Disruption of this coupling can lead to diseases, and therefore there is a need to accurately measure mechanochemical coupling in motors in both health and disease. Optical tweezers with nanometer spatial and millisecond temporal resolution have provided valuable insights into these processes. However, fluctuations due to Brownian motion can make it difficult to precisely resolve these conformational changes. One powerful analysis technique that has improved our ability to accurately measure mechanochemical coupling in motor proteins is ensemble averaging of individual trajectories. Here, we present a user-friendly computational tool, Software for Precise Analysis of Single Molecules (SPASM), for generating ensemble averages of single-molecule data. This tool utilizes several conceptual advances, including optimized procedures for identifying single-molecule interactions and the implementation of a change-point algorithm, to more precisely resolve molecular transitions. Using both simulated and experimental data, we demonstrate that these advances allow for accurate determination of the mechanics and kinetics of the myosin working stroke with a smaller set of data. Importantly, we provide our open-source MATLAB-based program with a graphical user interface that enables others to readily apply these advances to the analysis of their own data.

Systematic Experimental Investigation on In-Situ Self-Adaptive Sealing Property of Composite Pressure-Activated Sealant for Curing Minor Tubular Leaks

Curing minor leaks and restoring the integrity of a wellbore in a safe and economical way is always challenging in oil and gas production. In this work, a composite pressure-activated sealant, combined with liquid and solid sealing materials, was prepared via the demulsification approach. The structure, morphology, and size distribution of key particulates in the sealant were examined, and the in-situ self-adaptive sealing property was examined with a specially design dynamic sealing detector. The results indicated that the pressure-activated sealant was a multi-dispersed phase system, and the dispersed colloid particles were regular in shape and had a narrow size distribution of 300–400 μm. The solid sealing materials were introduced to construct a composite pressure-activated sealant, and the sealing capability can be markedly reinforced by cooperativity of liquid and solid sealing materials. A mechanochemical coupling model was put forward to rationalize the dynamic sealing process. Finally, such sealant system was employed in a certain offshore gas well with sustained casing pressure to verify its applicability in minor defect repairs.

Unlocking the Potential of Mechanochemical Coupling: Boosting the Oxygen Evolution Reaction by Mating Proton Acceptors with Electron Donors

AbstractThe oxygen evolution reaction (OER) is the bottleneck of many sustainable energy conversion systems, including water splitting technologies. The kinetics of the OER is generally sluggish unless precious metal‐based catalysts are used. Perovskite oxides have shown promise as alternatives to these expensive materials. However, for several perovskites, including SrCoO3−δ, the rate‐limiting step is proton‐transfer. In this study, it is shown that such a kinetic limitation can be overcome by coupling those perovskites with MoS2 mechanochemically. By studying composites of SrMO3−δ (M = Co, Fe, Ti) and MoS2, the role that the formed heterointerfaces play in enhancing the activity is investigated. Mechanochemically mating SrCoO3−δ and MoS2 increases the mass activity toward OER by a factor of ten and led to a Tafel slope of only 37 mV dec−1. In contrast, combining MoS2 with SrFeO3−δ or SrTiO3−δ, two materials whose OER is not limited by proton‐transfer, does not result in an improvement of the performance. The experimental measurements and first‐principle calculations reveal that the MoS2 at the MoS2@SrCoO3−δ heterointerfaces is both an electron and a proton acceptor, thereby facilitating deprotonation of the perovskite and resulting in faster OER kinetics.