Mechanical Stress Response Research Articles

Immune system activation and cognitive impairment in arterial hypertension.

Chronic arterial hypertension disrupts the integrity of the cerebral microvasculature, doubling the risk of age-related dementia. Despite sufficient antihypertensive therapy, in still a significant proportion of individuals blood pressure lowering alone does not preserve cognitive health. Accumulating evidence highlights the role of inflammatory mechanisms in the pathogenesis of hypertension. In this review, we introduce a temporal framework to explore how early immune system activation and interactions at neurovascular-immune interfaces pave the way to cognitive impairment. The overall paradigm suggests that pro-hypertensive stimuli induce mechanical stress and systemic inflammatory responses that shift peripheral and meningeal immune effector mechanisms towards a pro-inflammatory state. Neurovascular-immune interfaces in the brain include a dysfunctional blood-brain barrier, crossed by peripheral immune cells; the perivascular space, in which macrophages respond to cerebrospinal fluid- and blood-derived immune regulators; and the meningeal immune reservoir, particularly T cells. Immune responses at these interfaces bridge peripheral and neurovascular unit inflammation, directly contributing to impaired brain perfusion, clearance of toxic metabolites and synaptic function. We propose that deep immunophenotyping in biofluids together with advanced neuroimaging could aid in the translational determination of sequential immune and brain endotypes specific to arterial hypertension. This could close knowledge gaps on how and when immune system activation transits into neurovascular dysfunction and cognitive impairment. In the future, targeting specific immune mechanisms could prevent and halt hypertension disease progression before clinical symptoms arise, addressing the need for new interventions against one of the leading threats to cognitive health.

A Flexible Organomagnetic Single-Layer Composite Film with Built-In Multistimuli Responsivity.

Materials possessing multiple properties and functionalities, that can be controlled or modulated by external stimuli, are a central focus of current research in materials sciences due to their potential to significantly enhance various future technological applications. Herein, we report a significant advancement in this field through the development of a smart, multifunctional organomagnetic composite material. By utilizing a thin layer of polydimethylsiloxane (PDMS) and polypyrrole (PPy) precursors, doped with nickel nanoparticles (NiNPs), we have created an innovative organomagnetic, PDMS/PPy/NiNPs (PPN), single-layer composite film that displays multistimuli responsivity. The study presents the first demonstration of a multifunctional flexible, three-component film structure integrating the structural and flexible PDMS component, together with a conductive polymer component and metal-based nanoparticles into a single-layer design, which displays enhanced and unprecedented responsivity properties against multiple different stimuli. Unlike typical stacked multilayered structures, that exhibit one or two functionalities at most, this novel configuration exhibits multiple functionalities, including magnetoresistance, mechanical stress response, piezoresistivity, and temperature change sensitivity. The as-prepared film demonstrates notable magnetoresistance responsivity, with a relative electrical resistance, ΔR/R0, changing under a weak magnetic field and under ambient conditions. The significance of our study lies in the film's versatility, stability, and sensitivity, especially within the physiological temperature range, making it highly relevant for future biomedical applications. Furthemore, the film's sensitivity to mechanical deformation reveals an impressive piezoresistance behavior. Unlike existing multilayer architectures of higher complexity, our single-layer thin film offers a simpler, more flexible, and reliable solution with a broad range of stimuli-sensing capabilities. The significance of this novel multiresponsive composite material is underscored by the growing demand for advanced materials in biomedical devices, magnetic switches, sensors, electronic skin, transistors, and organic spintronic devices. These promising organomagnetic self-standing layers provide a robust platform for future technological innovations.

Roles of the Dbl family of RhoGEFs in mechanotransduction - a review.

Rho guanine nucleotide exchange factors (RhoGEFs) comprise a wide range of proteins with a common domain responsible for the activation of the Rho family of small GTPases and various domains in other regions. The evolutionary divergence of RhoGEFs enables actin cytoskeletal reorganization, leading to complex cellular responses in higher organisms. In this review, we address the involvement of RhoGEFs in the mechanical stress response of mammalian cells. The cellular mechanical stress response is essential for the proper and orderly regulation of cell populations, including the maintenance of homeostasis, tissue morphogenesis, and adaptation to the mechanical environment. In particular, this review focuses on the recent findings regarding the Dbl family of RhoGEFs involved in mechanical stress responses at the cell-cell and cell-substrate adhesion sites, and their molecular mechanisms underlying actin cytoskeleton remodeling and signal transduction.

Multifunctional Nanomaterials Mediate Cholesterol Depletion for Cancer Treatment.

Cholesterol is an essential membrane component, and the metabolites from cholesterol play important biological functions to intricately support cancer progression and dampen immune responses. Preclinical and clinical studies have demonstrated the role of cholesterol metabolism regulation on inhibiting tumor growth, remodeling the immunosuppressive tumor microenvironment (TME), and enhancing anti-tumor immunity. In this minireview, we discuss complex cholesterol metabolism in tumors, its important role in cancer progression, and its influences on immune cells in the TME. We provide an overview of recent advances in cancer treatment through regulating cholesterol metabolism. We discuss the design of cholesterol-altering multifunctional nanomaterials to regulate oxidative stress, modulate immune checkpoints, manipulate mechanical stress responses, and alter cholesterol metabolic pathways. Additionally, we examine the interactions between cholesterol metabolism regulation and established cancer treatments with the aim of identifying efficient strategies to disrupt cholesterol metabolism and synergistic combination therapies for effective cancer treatment.

Multifunctional Nanomaterials Mediate Cholesterol Depletion for Cancer Treatment

AbstractCholesterol is an essential membrane component, and the metabolites from cholesterol play important biological functions to intricately support cancer progression and dampen immune responses. Preclinical and clinical studies have demonstrated the role of cholesterol metabolism regulation on inhibiting tumor growth, remodeling the immunosuppressive tumor microenvironment (TME), and enhancing anti‐tumor immunity. In this minireview, we discuss complex cholesterol metabolism in tumors, its important role in cancer progression, and its influences on immune cells in the TME. We provide an overview of recent advances in cancer treatment through regulating cholesterol metabolism. We discuss the design of cholesterol‐altering multifunctional nanomaterials to regulate oxidative stress, modulate immune checkpoints, manipulate mechanical stress responses, and alter cholesterol metabolic pathways. Additionally, we examine the interactions between cholesterol metabolism regulation and established cancer treatments with the aim of identifying efficient strategies to disrupt cholesterol metabolism and synergistic combination therapies for effective cancer treatment.

Exploring Lignin Biosynthesis Genes in Rice: Evolution, Function, and Expression.

Lignin is nature's second most abundant vascular plant biopolymer, playing significant roles in mechanical support, water transport, and stress responses. This study identified 90 lignin biosynthesis genes in rice based on phylogeny and motif constitution, and they belong to PAL, C4H, 4CL, HCT, C3H, CCoAOMT, CCR, F5H, COMT, and CAD families. Duplication events contributed largely to the expansion of these gene families, such as PAL, CCoAOMT, CCR, and CAD families, mainly attributed to tandem and segmental duplication. Microarray data of 33 tissue samples covering the entire life cycle of rice suggested fairly high PAL, HCT, C3H, CCoAOMT, CCR, COMT, and CAD gene expressions and rather variable C4H, 4CL, and F5H expressions. Some members of lignin-related genes (OsCCRL11, OsHCT1/2/5, OsCCoAOMT1/3/5, OsCOMT, OsC3H, OsCAD2, and OsPAL1/6) were expressed in all tissues examined. The expression patterns of lignin-related genes can be divided into two major groups with eight subgroups, each showing a distinct co-expression in tissues representing typically primary and secondary cell wall constitutions. Some lignin-related genes were strongly co-expressed in tissues typical of secondary cell walls. Combined HPLC analysis showed increased lignin monomer (H, G, and S) contents from young to old growth stages in five genotypes. Based on 90 genes' microarray data, 27 genes were selected for qRT-PCR gene expression analysis. Four genes (OsPAL9, OsCAD8C, OsCCR8, and OsCOMTL4) were significantly negatively correlated with lignin monomers. Furthermore, eleven genes were co-expressed in certain genotypes during secondary growth stages. Among them, six genes (OsC3H, OsCAD2, OsCCR2, OsCOMT, OsPAL2, and OsPAL8) were overlapped with microarray gene expressions, highlighting their importance in lignin biosynthesis.

Fatigue crack initiation in lead-bismuth eutectic and its effect on the cyclic stress behaviour of austenitic stainless steel 316L

Active media such as liquid metals have an effect on the fatigue resistance of steels when compared to vacuum or inert environments. This effect might impact the initiation of fatigue cracks, their propagation, or both. This paper focusses on the initiation of fatigue cracks in an austenitic stainless steel when in contact with three environments: vacuum, air, and lead-bismuth eutectic (LBE), and the impact of such cracks on cyclic loading behaviour.Solid cylindrical samples of a 316L-type steel were fatigued under strain control in vacuum, air, and LBE in order to induce the initiation of cracks on their surface. The characteristics of fatigue damage in the form of surface microcracks were analysed with microscopy techniques. It was found that the nucleation of fatigue microcracks is enhanced by LBE, but the majority of these cracks do not propagate beyond the grain size of the steel (50 μm). An analysis with finite element methods showed that the large number of small (<10 μm) microcracks nucleated in LBE environments has a negligible impact on the sample's stiffness, as opposed to the fewer but deeper (100–500 μm) microcracks that initiate in air, which produce a loss of stiffness, observable on the mechanical stress response of the fatigue sample.A model based on the adsorption of LBE atoms along surface slip bands is proposed to explain the phenomenon of enhanced fatigue crack nucleation in LBE.

Stretchable Functional Nanocomposites for Soft Implantable Bioelectronics.

Material advances in soft bioelectronics, particularly those based on stretchable nanocomposites─functional nanomaterials embedded in viscoelastic polymers with irreversible or reversible bonds─have driven significant progress in translational medical device research. The unique mechanical properties inherent in the stretchable nanocomposites enable stiffness matching between tissue and device, as well as its spontaneous mechanical adaptation to in vivo environments, minimizing undesired mechanical stress and inflammation responses. Furthermore, these properties allow percolative networks of conducting fillers in the nanocomposites to be sustained even under repetitive tensile/compressive stresses, leading to stable tissue-device interfacing. Here, we present an in-depth review of materials strategies, fabrication/integration techniques, device designs, applications, and translational opportunities of nanocomposite-based soft bioelectronics, which feature intrinsic stretchability, self-healability, tissue adhesion, and/or syringe injectability. Among many, applications to brain, heart, and peripheral nerves are predominantly discussed, and translational studies in certain domains such as neuromuscular and cardiovascular engineering are particularly highlighted.

O08 Exploring the effect of skin ageing-related basement membrane collagen loss on nuclear mechanics

Abstract Introduction and aims Skin ageing is a universal process that can increase susceptibility to inflammation and disease. Basement membrane collagens (BMCs) are reduced during ageing and the consequences are poorly understood. BMC sensing of mechanical stress, vital for skin homeostasis, elicits signalling sensed via cytoskeletal actin filaments to the linker of nucleoskeleton and cytoskeleton (LINC) complex (composed of nesprin and sun proteins), nuclear lamina and lamina-associated chromatin. Our hypothesis is that BMC loss during ageing leads to a deformation of the nucleocytoskeleton and disrupts chromatin organization in keratinocytes, leading to impairment of epidermal differentiation and inability to withstand mechanical stress. Methods To explore the role of BMC in mechanical stress response, stable lentiviral short hairpin (sh)RNA knockdowns of Col7 (shCol7) and Col17 (shCol17) were generated in immortalized N/TERT keratinocytes. Western blot (WB) validated knockdowns were compared with shC nontargeting control. IncuCyte assays showed shCol17 had a hyperproliferative phenotype compared with shC. Sun2 was reduced in shCol17 (P &amp;lt; 0.001) compared with shC (n = 5 experimental replicates). The mechanical stretch effect on cells on a flexible membrane was studied using immunofluorescence and WB analysis. Images taken from the IN Cell Analyzer confocal microscope were analysed to detect changes in protein expression and localization. Nuclear and cytoplasmic fractions made before and after stretch were analysed by WB. Results We observed collagen-specific responses to stretch-induced stress with changes to actin, components of the nuclear membrane, and LINC complex proteins. Additionally, work on investigating chromatin changes with BMC knockdown using Cleavage Under Targets &amp; Tagmentation and Cleavage Under Targeted Accessible Chromatin assays is ongoing. Conclusions Our data show an altered nucleocytoskeleton in the context of BMC loss and mechanotransduction in skin. These data could provide novel insights into epidermal regulation by BMC in ageing.

Solo regulates the localization and activity of PDZ-RhoGEF for actin cytoskeletal remodeling in response to substrate stiffness.

Recent findings indicate that Solo, a RhoGEF, is involved in cellular mechanical stress responses. However, the mechanism of actin cytoskeletal remodeling via Solo remains unclear. Therefore, this study aimed to identify Solo-interacting proteins using the BioID, a proximal-dependent labeling method, and elucidate the molecular mechanisms of function of Solo. We identified PDZ-RhoGEF (PRG) as a Solo-interacting protein. PRG colocalized with Solo in the basal area of cells, depending on Solo localization, and enhanced actin polymerization at the Solo accumulation sites. Additionally, Solo and PRG interaction was necessary for actin cytoskeletal remodeling. Furthermore, the purified Solo itself had little or negligible GEF activity, even its GEF-inactive mutant directly activated the GEF activity of PRG through interaction. Moreover, overexpression of the Solo and PRG binding domains, respectively, had a dominant-negative effect on actin polymerization and actin stress fiber formation in response to substrate stiffness. Therefore, Solo restricts the localization of PRG and regulates actin cytoskeletal remodeling in synergy with PRG in response to the surrounding mechanical environment.

Regional differences in stomach stretch during organ filling and their implications on the mechanical stress response

As part of the digestive system, the stomach plays a crucial role in the health and well-being of an organism. It produces acids and performs contractions that initiate the digestive process and begin the break-up of ingested food. Therefore, its mechanical properties are of interest. This study includes a detailed investigation of strains in the porcine stomach wall during passive organ filling. In addition, the observed strains were applied to tissue samples subjected to biaxial tensile tests. The results show inhomogeneous strains during filling, which tend to be higher in the circumferential direction (antrum: 13.2%, corpus: 22.0%, fundus: 67.8%), compared to the longitudinal direction (antrum: 4.8%, corpus: 24.7%, fundus: 50.0%) at a maximum filling of 3500 ml. Consequently, the fundus region experienced the greatest strain. In the biaxial tensile experiments, the corpus region appeared to be the stiffest, reaching nominal stress values above 400 kPa in the circumferential direction, whereas the other regions only reached stress levels of below 50 kPa in both directions for the investigated stretch range. Our findings gain new insight into stomach mechanics and provide valuable data for the development and validation of computational stomach models.

Bone Density Distribution Pattern in the Lateral Wall of the Femoral Intercondylar Notch: Implications for the Direct Insertion of the Femoral ACL Attachment

Background: The ideal position of the femoral bone tunnel in the anterior cruciate ligament (ACL) is controversial. The functional importance of the ACL fiber varies depending on where it is attached to the femur. Functionally important fibers can cause high mechanical stress on the bone, and the Wolff law predicts that bone mineral density will increase at high mechanical stress sites. Purpose/Hypothesis: The purpose of this study was to use computed tomography imaging to determine the distribution pattern of bone density in the lateral intercondylar wall. It was hypothesized that the high-density area (HDA) of the lateral intercondylar wall would reflect the functional insertion of the ACL as reported in previous anatomic studies. Study Design: Descriptive epidemiology study. Methods: Data from 39 knees without ACL injuries were retrospectively collected. The HDA of the lateral intercondylar wall was defined as the region containing the top 10% of the radiodensity values. The shape of the HDA was approximated as an ellipse, and the quadrant method was used to determine the center of the ellipse. The association between the ratio of the minor axis to the major axis of the ellipse and background characteristics was investigated. Results: According to the quadrant method, the center of the HDA ellipse was 33.6% in the deep-shallow direction and 23.4% in the high-low direction. The center of the ellipse was comparable to the anatomic center of the ACL footprint, as previously reported. The ratio of the minor axis to the major axis of the ellipse was 0.58 (95% CI, 0.54-0.62). There was a significant negative correlation between the ratio of the minor axis to the major axis of the HDA ellipse and the posterior tibial slope ( r = −0.38, P = .02). Conclusion: The center of the HDA ellipse was found to be similar to the anatomic center of the ACL footprint. Considering the mechanical stress responses in bone, the HDA of the lateral intercondylar wall has the potential to represent the ACL insertion, especially functional insertion.

Exploring potential of MXenes in smart sensing and energy harvesting

In present work, MXene based piezo-resistive stress sensor device is fabricated using a freeze-dry method. The device was tested to measure the mechanical stress, sensitivity, and triboelectric response by converting them into electrical signals as readout. With high electrical conductivity, mechanical flexibility, and piezo-resistive characteristics, MXene-based device offers novel sensing and triboelectric-related applications. This study showed an extensive characterization after fabricating the sensor using a simple and scalable process to ensure their performance in terms of sensitivity, stability, and repeatability. Using pure MXene layer as the core material, this paper pioneers an interesting investigation focusing on stress monitoring by piezoresistive stress sensor and triboelectric nanogenerator.

Characterizing the role of PP2A B'' family subunits in mechanical stress response and plant development through calcium and ABA signaling in Arabidopsis thaliana.

Protein phosphatase 2AB'' (PP2A B'') family subunits have calcium-binding EF-hand motifs, facilitating interaction with PP2A substrates. In Arabidopsis thaliana, the PP2A B'' family subunits consist of six members, AtB''α-ε and FASS. These subunits can interact with a basic leucine zipper transcription factor, VIP1, and its close homologs. Mechanical stress triggers PP2A-mediated dephosphorylation of VIP1 and its close homologs, leading to nuclear localization and gene upregulation to alleviate touch-induced root bending and leaf damage. However, the physiological roles of PP2A B'' family subunits in the mechanical stress response in Arabidopsis remain unclear. This study aims to characterize such roles. A quadruple knockout mutant with T-DNA insertions in AtB''α, AtB''β, AtB''γ, and AtB''δ was generated. atb''αβγδ mutants exhibited no significant damage upon brushing or touch-induced root bending compared to the wild type. Transcriptome analysis showed a significant decrease in the expression of CYP707A3, a gene potentially targeted by VIP1 that regulates abscisic acid (ABA) catabolism, in the atb''αβγδ mutant compared to wild type leaves. However, other genes, including XTH23, EXLA1, and CYP707A1, also VIP1 targets, exhibited similar induction in both brushed atb''αβγδ mutants and wild type leaves. We observed an enrichment of the CAMTA motif, CGCG(C/T) in the promoters of genes showing downregulated expression levels in brushed atb''αβγδ leaves compared to brushed wild type leaves. These findings suggest that PP2A B'' family subunits exhibit functional redundancy in the VIP1-dependent pathway but influence CAMTA-dependent gene expression under mechanical stress. Under calcium-deficient and ABA-supplemented conditions, growth of atb''αβγδ seedlings was retarded when compared to wild type and single knockout mutants, atb''γ and atb''δ, indicating a crucial role in plant development by modulating calcium or ABA signaling.

Roles for group I bZIP transcription factors and CAMTAs in mechanical stress responses of plants

Roles for group I bZIP transcription factors and CAMTAs in mechanical stress responses of plants

The antioxidant Glycitin protects against intervertebral disc degeneration through antagonizing inflammation and oxidative stress in nucleus pulposus cells.

Intervertebral disc degeneration (IVDD) is a kind of typical degenerative disorder of the skeletal muscle system caused by many factors including aging, abnormal mechanical stress and inflammatory responses. Glycitin is a natural isoflavone extracted from legumes. Previous studies have found that it is anti-inflammatory and promotes wound repair. However, the role of Glycitin in IVDD has not been elucidated. In the present research, we were surprised that Glycitin antagonized the NF-κB pathway activity. In addition, we also found that Glycitin alleviated TNF-α-induced metabolic disorders, extracellular matrix degradation, oxidative stress, inflammation responses, and mitochondrial damage. Furthermore, in in vivo experimental study, we discovered Glycitin attenuated IVDD. The results revealed that Glycitin alleviated the degenerative phenotype of IVDD. According to this research, Glycitin has anti-inflammatory properties that might exert a protective function in IVDD, suggesting a prospective therapeutic approach for IVDD.

A preliminary study of phosphodiesterases and adenylyl cyclase signaling pathway on red blood cell deformability of sickle cell patients.

Sickle cell disease (SCD) is an inherited hemoglobinopathy characterized by chronic anemia, intravascular hemolysis, and the occurrence of vaso-occlusive crises due to the mechanical obstruction of the microcirculation by poorly deformable red blood cells (RBCs). RBC deformability is a key factor in the pathogenesis of SCD, and is affected by various factors. In this study, we investigated the effects of adenylyl cyclase (AC) signaling pathway modulation and different phosphodiesterase (PDE) modulatory molecules on the deformability and mechanical stress responses of RBC from SCD patients (HbSS genotype) by applying 5Pa shear stress with an ektacytometer (LORRCA). We evaluated RBC deformability before and after the application of shear stress. AC stimulation with Forskolin had distinct effects on RBC deformability depending on the application of 5Pa shear stress. RBC deformability was increased by Forskolin before shear stress application but decreased after 5Pa shear stress. AC inhibition with SQ22536 and protein kinase A (PKA) inhibition with H89 increased RBC deformability before and after the shear stress application. Non-selective PDE inhibition with Pentoxifylline increased RBC deformability. However, modulation of the different PDE types had distinct effects on RBC deformability, with PDE1 inhibition by Vinpocetine increasing deformability while PDE4 inhibition by Rolipram decreased RBC deformability after the shear stress application. The effects of the drugs varied greatly between patients suggesting some could benefit from one drug while others not. Developing drugs targeting the AC signaling pathway could have clinical applications for SCD, but more researches with larger patient cohorts are needed to identify the differences in the responses of sickle RBCs.

Nuclear envelope dynamics in connection to chromatin remodeling.

The nucleus is a central organelle of eukaryotic cells undergoing dynamic structural changes during cellular fundamental processes such as proliferation and differentiation. These changes rely on the integration of developmental and stress signals at the nuclear envelope (NE), orchestrating responses at the nucleo-cytoplasmic interface for efficient genomic functions such as DNA transcription, replication and repair. While in animals, correlation has already been established between NE dynamics and chromatin remodeling using last-generation tools and cutting-edge technologies, this topic is just emerging in plants, especially in response to mechanical cues. This review summarizes recent data obtained in this field with more emphasis on the mechanical stress response. It also highlights similarities/differences between animal and plant cells at multiples scales, from the structural organization of the nucleo-cytoplasmic continuum to the functional impacts of NE dynamics.

Sa1249 SMOOTH MUSCLE PHENOTYPIC CLASS SWITCHING IN RESPONSE TO MECHANICAL STRESS: A STORY TOLD BY RNA SEQ

Sa1249 SMOOTH MUSCLE PHENOTYPIC CLASS SWITCHING IN RESPONSE TO MECHANICAL STRESS: A STORY TOLD BY RNA SEQ

ACTIVATION OFGLUCOSE TRANSPORTER 1 (GLUT1) IS REQUIRED FOR THE MECHANICAL STRESS-INDUCED BONE FORMATIONVIA THE SIGNAL TRANSDUCTION NETWORK BETWEEN THE CELLULAR ENERGY SENSOR, NAD+-DEPENDENT DEACETYLASE (SIRTUIN1), AND THE OSTEOGENIC TRANSCRIPTION FACTOR, RUNT-RELATED TRANSCRIPTION FACTOR 2 (RUNX2), IN OSTEOBLASTS.

Purpose: Mechanical stress is a critically-important factor affecting bone tissue homeostasis. To determine whether physiologic mechanical loading affects the expression of factors regulating energy metabolism and transcription factors controlling osteoblast differentiation, we focused on the interaction between glucose uptake via glucose transporter 1 (Glut1) and the cellular energy sensor sirtuin 1 (SIRT1) in osteoblast energy metabolism, since it has been recognized that SIRT1, an NAD+-dependent deacetylase, may function as a master regulator of mechanical stress response as well as cellular energy metabolism (glucose metabolism).