Mechanical force drives the polarization and orientation of cells

Collective cells are organized to form specific patterns which play important roles in various physiological and pathological processes, such as tissue morphogenesis, wound healing, and cancer invasion. Compared to single cell behaviors, which has been intensively studied from many aspects (cell migration, adhesion, polarization, proliferation, etc.) and at various scales (molecular, subcellular, and cellular), the multiple cell behaviors are relatively less understood, particularly in a quantitative manner. In this paper, we will present our recent studies of collective polarization and orientation of multiple cells through both experimental measurement and theoretical modeling, including those cell behaviors on/in 2D and 3D substrate/tissue. We find that the collective cell behaviors, including polarization, alignment and migration are closely related to local stress states in cell layer or tissue, which demonstrate the crucial roles of mechanical forces in the living organisms. Specifically, the cells prefer to polarize and align along the maximum principal stress in the cell layer, and the aspect ratio of cell increases with the in-plane maximum shear stress, suggesting that the maximum shear stress is the underlying driving force of cell polarization and orientation. This theory of stress-driven cell behaviors of polarization and orientation provides a new perspective for understanding cell behaviors in living organisms and the guideline for tissue engineering in biomedical applications.

CONCAVE BIOLOGICAL SURFACES FOR STRONG WET ADHESION

Plant leaves, insects and geckos are masters of adhesion or anti-adhesion by smartly designed refined surface structures with micro- and nano- ＇technologies＇. Understanding the basic principles in the design of the unique surface structures is of great importance in the manufacture or synthesis of micro- and nano- devices in MEMS or NEMS. This study is right inspired by this effort, focusing on the mechanics of wet adhesion between fibers having concave tips and a flat substrate via capillary forces. We show that the concave surface can effectively enhance the wet adhesion by reducing the effective contact angle of the fiber, firmly pinning the liquid bridge at its circumferential edge. A critical contact angle is identified below which the adhesion strength can achieve its maximum, being insensitive to the contact angle between the fiber and liquid. The analytical expression for the critical angle is derived. Then a tentative design for the profile of concave surfaces is proposed, considering the effects of chamfering size, deformation and buckling, etc. The effect of liquid volume on the wet adhesion of multiple-fiber system is also discussed.

Pulling out a peptide chain from β-sheet crystallite: Propagation of instability of H-bonds under shear force

Anti-parallel β-sheet crystallite as the main component of silk fibroin has attracted much attention due to its superior mechanical properties. In this study, we examine the processes of pulling a peptide chain from β-sheet crystallite using steered molecular dynamics simulations to investigate the rupture behavior of the crystallite. We show that the failure of β-sheet crystallite was accompanied by a propagation of instability of hydrogen-bonds （H-bonds） in the crystallite. In addition, we find that there is an optimum size of the crystallite at which the H-bonds can work cooperatively to achieve the highest shear strength. In addition, we find that the stiffness of loading device and the loading rates have significant effects on the rupture behavior of β-sheet crystallite. The stiff loading device facilitates the rebinding of the Hbond network in the stick-slip motion between the chains, while the soft one suppresses it. Moreover, the rupture force of β-sheet crystallites decreases with loading rate. Particularly, when the loading rate decreases to a critical value, the rupture force of the β-sheet crystallite becomes independent of the loading rates. This study provides atomistic details of rupture behaviors of β-sheet crystallite, and, therefore, sheds valuable light on the underlying mechanism of the superior mechanical properties of silk fibroin.

Quantification of the stiffness and strength of cadherin ectodomain binding with different ions

The stiffness and strength of extracellular （EC） region of cadherin are proposed to be two important mechanical properties both for cadherin as a mechanotransductor and for the formation of cell-cell adhesion. In this study, we quantitatively characterized the stiffness and strength of EC structure when it binds with different types of ions by molecular dynamics simulations. Resuits show that EC structure exhibits a rod-like shape with high stiffness and strength when it binds with the bivalent ions of calcium or magnesium. However, it switches to a soft and collapsed conformation when it binds with the monova- lent ions of sodium or potassium. This study sheds light on the important role of the bivalent ions of calcium in the physiological function of EC.

Cell traction force distribution and its implications in cell adhesion and migration

Cell-matrix interaction is the key for understanding the cell behaviors,especially the mechanosensitivity of cell adhesion,cell migration and differentiation,etc.Cells are constantly probing,pushing and pulling on the surrounding extracellular matrix.These cell-generated forces drive cell migration and tissue morphogenesis,and maintain the intrinsic mechanical tone of tissues.Therefore,knowledge of the spatial and temporal nature of these forces are essential to understanding when and where mechanical events come to play in both physiological and pathological settings.However,because of the complexity of cell geometry and insufficient

Mechanical Force Drives the Polarization and Orientation of Collective Cells

Collective cell groups are organized to form specific patterns that play an important role in various physiological and pathological processes,such as tissue morphogenesis,wound healing,and cancer invasion.Compared to the behaviors of single cells that have been studied intensively from many aspects(cell migration,adhesion,polarization,proliferation,etc.)and at various length scales(molecular,subcellular,and cellular),the behaviors of multiple cells are less well understood,particularly from a quantitative perspective.In this talk,we present our recent studies of collective polarization and orientation of multiple cells through both experimental measurement and theoretical modeling,including cell behavior on/in 2D and 3D substrate/tissue.We find that collective cell behavior,including polarization,alignment,and migration,is closely related to local stress states in cell layers or tissue,which demonstrates the crucial role of mechanical forces in living organisms.Specifically,cells demonstrate preferential polarization and alignment along the maximum principal stress in the cell layer,and the cell aspect ratio increases with in-plane maximum shear stress,suggesting that the maximum shear stress is the underlying driving force of cell polarization and orientation.This theory of stress-driven cell behaviors of polarization and orientation provides a new perspective for understanding cell behaviors in living organisms and a guideline for tissue engineering in potential biomedical applications.Strikingly,we note that with regard to the polarization and alignment of collective cells,a typical feature of cell morphology is that the cells generally align along the edge of the pattern,which was called edge effect or boundary effect by assuming that the edge plays a role in cell alignment due to a phenomenon of chemistry.However,the edge effect is an obscure explanation.Here we showed that the edge effect could be explained by the theory of stress-driven cell behavior,i.e.,inplane stress-driven cell polarization and alignment.That is,the cell layer has a stress-free boundary condition at the edge,and thus the direction of the maximum principal stress should be precisely along the edge.According to the theory of stress-driven cell polarity,the cells then preferentially align with the edge of the cell layer,independently of the geometry of the pattern.Once there is a force-free condition at the edge or the boundary,the cells align along the edge of the pattern.Otherwise,the cell may not align with the edge;for example,the cells preferentially align in the radial direction of the wound because of the presence of the contractile force by the actin ring at the wound edge,which is in contradiction with the so-called edge effect but consistent with our theory of stress-driven cell polarity.

Mechanics of water pore formation in lipid membrane under electric field

Transmembrane water pores are crucial for substance transport through cell membranes via membrane fusion, such as in neural communication. However, the molecular mechanism of water pore formation is not clear. In this study, we apply all-atom molecular dynamics and bias-exchange metadynamics simulations to study the process of water pore formation under an electric field. We show that water molecules can enter a membrane under an electric field and form a water pore of a few nanometers in diameter. These water molecules disturb the interactions between lipid head groups and the ordered arrangement of lipids. Following the movement of water molecules, the lipid head groups are rotated and driven into the hydrophobic region of the membrane. The reorientated lipid head groups inside the membrane form a hydrophilic surface of the water pore. This study reveals the atomic details of how an electric field influences the movement of water molecules and lipid head groups, resulting in water pore formation.

Local buckling analysis of biological nanocomposites based on a beam-spring model

Biological materials such as bone, tooth, and nacre are load-bearing nanocomposites composed of mineral and protein. Since the mineral crystals often have slender geometry, the nanocomposites are susceptible to buckle under the compressive load. In this paper, we analyze the local buckling behaviors of the nanocomposite structure of the biological materials using a beam-spring model by which we can consider plenty of mineral crystals and their interaction in our analysis compared with existing studies. We show that there is a transition of the buckling behaviors from a local buckling mode to a global one when we continuously increase the aspect ratio of mineral, leading to an increase of the buckling strength which levels off to the strength of the composites reinforced with continuous crystals. We find that the contact condition at the mineral tips has a striking effect on the local buckling mode at small aspect ratio, but the effect diminishes when the aspect ratio is large. Our analyses also show that the staggered arrangement of mineral plays a central role in the stability of the biological nanocomposites.

Interactions of human islet amyloid polypeptide with lipid structure of different curvatures

Curvature is one of the most important features of lipid membranes in living cells,which significantly influences the structure of lipid membranes and their interaction with proteins.Taken the human islet amyloid polypeptide(h IAPP),an important protein related to the pathogenesis of type II diabetes,as an example,we performed molecular dynamics(MD)simulations to study the interaction between the protein and the lipid structures with varied curvatures.We found that the lipids in the high curvature membrane pack loosely with high mobility.The h IAPP initially forms H-bonds with the membrane surface that anchored the protein,and then inserts into the membrane through the hydrophobic interactions between the residues and the hydrophobic tails of the lipids.h IAPP can insert into the membrane more deeply with a larger curvature and with a stronger binding strength.Our result provided important insights into the mechanism of the membrane curvature-dependent property of proteins with molecular details.

C-reactive protein and cardiovascular diseases

Recently many new disease markers and risk factors have been proposed, but it is not yet clear how far the new markers are validated as predictive risk factors enable us to increase accuracy as well as enhancing our ability to predict cardiovascular (CV) events and to plan prevention and therapy.

Brief introduction on the special section of Biomechanics and Biomaterials

Biomechanics and biomaterials are research fields with long history and have unique features of both old and new, People have used the biomaterials since the beginning of human civilization, such as bamboo and wood for the construction several thousands years ago. And people have treated diseases by using the approaches of biomechanics even much earlier than using biomaterials - the mechanical force is proved to play important roles in traditional Chinese cupping treatment, and acupuncture and moxibustion treatment.

Editorial:Mechanics of biological and bio-inspired materials

The field of mechanics of biological and bio-inspired materials underwent an exciting development over the past several years, which made it stand at the cutting edge of both engineering mechanics and biomechanics. As an intriguing interdisciplinary research field, it aims at elucidating the fundamental principles in nature＇s design of strong, multi-functional and smart Materials by focusing on the assembly, deformation, stability and failure of the materials.

Cell Mechanics Regulates the Dynamic Anisotropic Remodeling of Fibril Matrix at Large Scale

Living tissues often have anisotropic and heterogeneous organizations, in which developmental processes are coordinated by cells and extracellular matrix modeling. Cells have the capability of modeling matrix in long distance;however, the biophysical mechanism is largely unknown. We investigated the dynamic remodeling of collagen I (COL) fibril matrix by cell contraction with designed patterns of cell clusters. By considering cell dynamic contractions, our molecular dynamics simulations predicted the anisotropic patterns of the observed COL bundling in experiments with various geometrical patterns without spatial limitation. The pattern of COL bundling was closely related to the dynamic remodeling of fibril under cell active contraction. We showed that cell cytoskeletal integrity (actin filaments and microtubules), actomyosin contractions, and endoplasmic reticulum calcium channels acting as force generations and transductions were essential for fiber bundling inductions, and membrane mechanosensory components integrin and Piezo played critical roles as well. This study revealed the underlying mechanisms of the cell mechanics-induced matrix remodeling in large scales and the associated cellular mechanism and should provide important guidelines for tissue engineering in potential biomedical applications.

Acupuncture for treating adolescent depression:Study protocol for a randomized controlled trial

The prevalence of depression among adolescents has been significantly increasing in recent years.However,current antidepressants for adolescents have limited safety and efficacy.Acupuncture has been shown to be effective in treating depression in adults,but there is a lack of high-quality evidence for its effect on the treatment of adolescent depression,and the underlying mechanism is still unclear.Therefore,we designed a randomized controlled trial to explore the effectiveness and the therapeutic mechanisms of acupuncture on adolescent depression.This study will be designed as a multi-center,sham and randomized controlled clinical trial.For this purpose,a total of 96 adolescent depression patients diagnosed with moderate and severe depression will be randomly divided into the manual acupuncture group and the sham one,respectively.The two groups received acupuncture treatment 3 times a week for a total course lasting 4 weeks.All patients will be assessed according to the primary outcomes including Beck Depression Inventory-II(BDI-II),Hamilton Depression Rating Scale(HAMD-24)and Zung self-rating depression scale(SDS)at baseline,week 2,4 and 8.Additionally,the secondary outcomes will be assessed at baseline and week 4,which includes intestinal flora structure,fecal short chain fatty acids(SCFAs)content and serum serotonin(5-HT)level.This study is the first randomized trial of acupuncture treatment of adolescent depression.

CELL AND MOLECULAR BIOMECHANICS: PERSPECTIVES AND CHALLENGES

As an intriguing interdisciplinary research field, cell and molecular biomechanics is at the cutting edge of mechanics in general and biomechanics in particular. It has the potential to provide a quantitative understanding of how forces and deformation at tissue, cellular and molecular levels affect human health and disease. In this article, we review the recent advances in cell and molecular biomechanics, examine the available computational and experimental tools, and discuss important issues including protein deformation in mechanotransduction, cell deformation and constitutive behavior, cell adhesion and migration, and the associated models and theories. The opportunities and challenges in cell and molecular biomechanics are also discussed. We hope to provide readers a clear picture of the current status of this field, and to stimulate a broader interest in the applied mechanics community.

An atomistic model of silk protein network for studying the effect of pre-stretching on the mechanical performances of silks

Silk protein builds one of the strongest natural fibers based on its complex nanocomposite structures.However,the mechanical performance of silk protein,related to its molecular structure and packing is still elusive.In this study,we constructed an atomistic silk protein network model,which reproduces the extensive connection topology of silk protein with structure details of theβ-sheet crystallites and amorphous domains.With the silk protein network model,we investigated the structure evolution and stress distribution of silk protein under external loading.We found a pre-stretching treatment during the spinning process can improve the strength of silk protein.This treatment improves the properties of silk protein network,i.e.,increases the number of nodes and bridges,makes the nodes distributed homogeneously,and induces the bridges in the network well aligned to the loading direction,which is of great benefit to the mechanical performances of silk protein.Our study not only provides a realized atomistic model for silk protein network that well represents the structures and deformations of silk proteins under loading,but also gains deep insights into the mechanism how the pre-loading on silk proteins during spinning improves the mechanical properties of silk fibers.

Protein conformational transitions coupling with ligand interactions:Simulations from molecules to medicine

The functions and activities of proteins are closely related to their structures and dynamics,and their interactions with ligands.Knowledge of the mechanistic events of proteins’conformational transitions and interactions with ligands is crucially important to understand the functions and biological activities of proteins and thus to the design of novel inhibitors of the targeted receptor.In this review article,taking two important systems as examples,i.e.,human immunodeficiency virus type 1 protease(HIV-1 PR)and adenylate kinase(AdK),and focusing on the molecular dynamics simulations of the conformational transitions of protein and the protein-ligand association/dissociation,we explain how the conformational transitions of proteins influence the interactions with their ligands,and how the ligands impact the function and dynamics of proteins.These results of structural dynamics of HIV-1 PR and AdK and their interactions with ligands can help to understand the principle of conformational transitions of proteins,or the interactions of ligands to their biological targets,and thus provide meaningful message in chemistry and biology of drug design and discovery.

Heterogeneous oxidization of graphene nanosheets damages membrane

Graphene-based materials exhibit unique properties that have been sought to utilize for various potential applications. Many studies suggest that graphene-based materials can be cytotoxic, which may be attributed to destructive effects on cell membranes.However, there still are conflicting results regarding interactions between graphene-based materials and lipid membranes. Here,through cryo-electron microscopy(Cryo-EM) and dye-leakage experiments along with in silico methods, we found that graphene oxide nanosheets induce significant membrane damage, while the effect of pristine graphene is negligible. We revealed the importance of heterogeneous oxidization of graphene-based nanosheets in damaging vesicle membranes. Moreover, that not only the oxidization degree but also the oxidization loci and membrane tension play important roles in the cytotoxicity of the graphene-based nanosheets.

Single-vesicle imaging quantifies calcium’s regulation of nanoscale vesicle clustering mediated by α-synuclein

Although numerous studies have shown that the proteinα-synuclein(α-Syn)plays a central role in Parkinson’s disease,dementia with Lewy bodies,and other neurodegenerative diseases,the protein’s physiological function remains poorly understood.Furthermore,despite recent reports suggesting that,under the influence of Ca^(2+),α-Syn can interact with synaptic vesicles,the mechanisms underlying that interaction are far from clear.Thus,we used single-vesicle imaging to quantify the extent to which Ca^(2+)regulates nanoscale vesicle clustering mediated by α-Syn.Our results revealed not only that vesicle clustering requiredα-Syn to bind to anionic lipid vesicles,but also that different concentrations of Ca^(2+)exerted different effects on howα-Syn induced vesicle clustering.In particular,low concentrations of Ca^(2+)inhibited vesicle clustering by blocking the electrostatic interaction between the lipid membrane and the N terminus of α-Syn,whereas high concentrations promoted vesicle clustering,possibly due to the electrostatic interaction between Ca^(2+)and the negatively charged lipids that is independent of α-Syn.Taken together,our results provide critical insights intoα-Syn’s physiological function,and how Ca^(2+) regulates vesicle clustering mediated by α-Syn.

Traditional Chinese Medicine is effective for COVID-19:A systematic review and meta-analysis

Traditional Chinese Medicine(TCM)has played crucial roles in treating COVID-19 in China.But its effectiveness has not yet been widely realized/recognized over the world.We performed a systematic review and meta-analysis to investigate the clinical efficacy of TCM medicine in the treatment for COVID-19.We obtained the data of COVID-19 and traditional Chinese medicine from PubMed,MEDLINE,Web of Science and other databases,and searched from January 1,2020 to January 26,2022 to determine the randomized controlled trials(RCTs)without language restrictions.The review includes 26 randomized clinical trials including 2981 patients.The treatment of COVID-19 by TCM combined with conventional treatment is more effective than by pure conventional treatment in many aspects,including increasing of the effective rate[OR=2.47,95%CI(1.85,3.30),P<0.00001],fever disappearance rate[OR=3.68,95%CI(1.95,6.96),P<0.0001],fatigue disappearance rate[OR=3.15,95%CI(1.60,6.21),P=0.0009],cough disappearance rate[OR=2.89,95%CI(1.84,4.54),P<0.00001],expectoration disappearance rate[OR=5.94,95%CI(1.98,17.84),P=0.001],disappearance rate of shortness of breath[OR=2.57,95%CI(1.13,5.80),P=0.02],improvement rate of CT image[OR=2.43,95%CI(1.86,3.16),P<0.00001],and reduction of the hospitalization time[MD=3.16,95%CI(3.75,2.56),P<0.00001],and deterioration rate[OR=0.49,95%CI(0.29,0.83),P=0.007].The findings of this meta-analysis suggest that TCM can effectively relieve symptoms,boosted patients' recovery,cut the rate of patients developing into severe conditions,and reduce the deterioration rate.