Osteoclasts are essential for bone remodeling by adapting their resorptive activity in response to their mechanical in vivo environment. However, the molecular mechanisms underlying this process remain unclear. Here, we demonstrated the role of tartrate-resistant acid phosphatase (TRAP, Acp5), a key enzyme secreted by osteoclasts, in bone remodeling and mechanosensitivity. Using CRISPR/Cas9 reporter mice, we demonstrated bone cell reporter (BCRIbsp/Acp5) mice feature fluorescent TRAP-deficient osteoclasts and examined their activity during mechanically driven trabecular bone remodeling. Although BCRIbsp/Acp5 mice exhibited trabecular bone impairments and reduced resorption capacity in vitro, RNA sequencing revealed unchanged levels of key osteoclast-associated genes such as Ctsk, Mmp9, and Calcr. These findings, in conjunction with serum carboxy-terminal collagen crosslinks (CTX) and in vivo mechanical loading outcomes collectively indicated an unaltered bone resorption capacity of osteoclasts in vivo. Furthermore, we demonstrated similar mechanoregulation during trabecular bone remodeling in BCRIbsp/Acp5 and wild-type (WT) mice. Hence, this study provides valuable insights into the dynamics of TRAP activity in the context of bone remodeling and mechanosensation.

Magnetogenetics emerges as a transformative approach for modulating cellular signaling pathways through the strategic application of magnetic fields and nanoparticles. This technique leverages the unique properties of magnetic nanoparticles (MNPs) to induce mechanical or thermal stimuli within cells, facilitating the activation of mechano- and thermosensitive proteins without the need for traditional ligand-receptor interactions. Unlike traditional modalities that often require invasive interventions and lack precision in targeting specific cellular functions, magnetogenetics offers a non-invasive alternative with the capacity for deep tissue penetration and the potential for targeting a broad spectrum of cellular processes. This review underscores magnetogenetics\' broad applicability, from steering stem cell differentiation to manipulating neuronal activity and immune responses, highlighting its potential in regenerative medicine, neuroscience, and cancer therapy. Furthermore, the review explores the challenges and future directions of magnetogenetics, including the development of genetically programmed magnetic nanoparticles and the integration of magnetic field-sensitive cells for in vivo applications. Magnetogenetics stands at the forefront of cellular manipulation technologies, offering novel insights into cellular signaling and opening new avenues for therapeutic interventions.

Alteration in the normal mechanical forces of breathing can contribute to changes in contractility and remodeling characteristic of airway diseases, but the mechanisms that mediate these effects in airway cells are still under investigation. Airway smooth muscle (ASM) cells contribute to both contractility and extracellular matrix (ECM) remodeling. In this study, we explored ASM mechanisms activated by mechanical stretch, focusing on mechanosensitive piezo channels and the key Ca2+ regulatory protein stromal interaction molecule 1 (STIM1). Expression of Ca2+ regulatory proteins, including STIM1, Orai1, and caveolin-1, mechanosensitive ion channels Piezo-1 and Piezo-2, and NLRP3 inflammasomes were upregulated by 10% static stretch superimposed on 5% cyclic stretch. These effects were blunted by STIM1 siRNA. Histamine-induced [Ca2+]i responses and inflammasome activation were similarly blunted by STIM1 knockdown. These data show that the effects of mechanical stretch in human ASM cells are mediated through STIM1, which activates multiple pathways, including Piezo channels and the inflammasome, leading to potential downstream changes in contractility and ECM remodeling.NEW & NOTEWORTHY Mechanical forces on the airway can contribute to altered contractility and remodeling in airway diseases, but the mechanisms are not clearly understood. Using human airway smooth muscle cells exposed to cyclic forces with static stretch to mimic breathing and static pressure, we found that the effects of stretch are mediated through STIM1, resulting in the activation of multiple pathways, including Piezo channels and the inflammasome, with potential downstream influences on contractility and remodeling.

To date, there is no general physical model of the mechanism by which unfolded polypeptide chains with different properties are imported into the mitochondria. At the molecular level, it is still unclear how transit polypeptides approach, are captured by the protein translocation machinery in the outer mitochondrial membrane, and how they subsequently cross the entropic barrier of a protein translocation pore to enter the intermembrane space. This deficiency has been due to the lack of detailed structural and dynamic information about the membrane pores. In this review, we focus on the recently determined sub-nanometer cryo-EM structures and our current knowledge of the dynamics of the mitochondrial two-pore outer membrane protein translocation machinery (TOM core complex), which provide a starting point for addressing the above questions. Of particular interest are recent discoveries showing that the TOM core complex can act as a mechanosensor, where the pores close as a result of interaction with membrane-proximal structures. We highlight unusual and new correlations between the structural elements of the TOM complexes and their dynamic behavior in the membrane environment.

The endometrial epithelium and underlying stroma undergo profound changes to support and limit embryo adhesion and invasion, which occur in the secretory phase of the menstrual cycle during the window of implantation. This coincides with a peak in progesterone and estradiol production. We hypothesized that the interplay between hormone-induced changes in the mechanical properties of the endometrial epithelium and stroma supports this process. To study it, we used hormone-responsive endometrial adenocarcinoma-derived Ishikawa cells growing on substrates of different stiffness. We showed that Ishikawa monolayers on soft substrates are more tightly clustered and uniform than on stiff substrates. Probing for mechanical alterations, we found accelerated stress-relaxation after apical nanoindentation in hormone-stimulated monolayers on stiff substrates. Traction force microscopy furthermore revealed an increased number of foci with high traction in the presence of estradiol and progesterone on soft substrates. The detection of single cells and small cell clusters positive for the intermediate filament protein vimentin and the progesterone receptor further underscored monolayer heterogeneity. Finally, adhesion assays with trophoblast-derived AC-1M-88 spheroids were used to examine the effects of substrate stiffness and steroid hormones on endometrial receptivity. We conclude that the extracellular matrix and hormones act together to determine mechanical properties and, ultimately, embryo implantation.

Ultrasound neuromodulation is a promising technology that could revolutionize study and treatment of brain conditions ranging from mood disorders to Alzheimer\'s disease and stroke. An understanding of how ultrasound directly modulates specific ion channels could provide a roadmap for targeting specific neurological circuits and achieving desired neurophysiological outcomes. Although experimental challenges make it difficult to unambiguously identify which ion channels are sensitive to ultrasound in vivo, recent progress indicates that there are likely several different ion channels involved, including members of the K2P, Piezo, and TRP channel families. A recent result linking TRPM2 channels in the hypothalamus to induction of torpor by ultrasound in rodents demonstrates the feasibility of targeting a specific ion channel in a specific population of neurons.

Botulinum neurotoxin A (BoNT/A) is a potent neurotoxin that silences cholinergic neurotransmission through the cleavage of the synaptic protein SNAP-25. Previous studies have shown that, in addition to its paralytic effects, BoNT/A can inhibit sensory nerve activity. The aim of this study was to identify how BoNT/A inhibits afferent signalling from the bladder. To investigate the role of SNAP-25 cleavage in the previously reported BoNT/A-dependent inhibition of sensory signalling, we developed a recombinant form of BoNT/A with an inactive light chain, rBoNT/A (0), unable to paralyse muscle. We also developed recombinant light chain (LC)-domain-only proteins to better understand the entry mechanisms, as the heavy chain (HC) of the protein is responsible for the internalisation of the light chain. We found that, despite a lack of catalytic activity, rBoNT/A (0) potently inhibited the afferent responses to bladder distension to a greater degree than catalytically active rBoNT/A. This was also clear from the testing of the LC-only proteins, as the inactive rLC/A (0) protein inhibited afferent responses significantly more than the active rLC/A protein. Immunohistochemistry for cleaved SNAP-25 was negative, and purinergic and nitrergic antagonists partially and totally reversed the sensory inhibition, respectively. These data suggest that the BoNT/A inhibition of sensory nerve activity in this assay is not due to the classical well-characterised \'double-receptor\' mechanism of BoNT/A, is independent of SNAP25 cleavage and involves nitrergic and purinergic signalling mechanisms.

Continuous administration of low-intensity whole-body vibration (WBV) gradually diminishes bone mechanosensitivity over time, leading to a weakening of its osteogenic effect. We investigated whether discretizing WBV into bouts with short rest intervals was effective in enhancing osteoporotic bone repair. Ten-week-old female mice were ovariectomized and underwent drill-hole defect surgery (Day 0) on the right tibial diaphysis at 11 weeks of age. The mice underwent one of three regimens starting from Day 1 for 5 days/week: continuous WBV at 45 Hz and 0.3 g for 7.5 min/day (cWBV); 3-s bouts of WBV at 45 Hz, 0.3 g followed by 9-s rest intervals, repeated for 30 min/day (repeated bouts of whole-body vibration with short rest intervals [rWBV]); or a sham treatment. Both the cWBV and rWBV groups received a total of 20,250 vibration cycles per day. On either Day 7 or 14 posteuthanasia (n = 6/group/timepoint), the bone and angiogenic vasculature in the defect were computed tomography imaged using synchrotron light. By Day 14, the bone repair was most advanced in the rWBV group, showing a higher bone volume fraction and a more uniform mineral distribution compared with the sham group. The cWBV group exhibited an intermediate level of bone repair between the sham and rWBV groups. The rWBV group had a decrease in large-sized angiogenic vessels, while the cWBV group showed an increase in such vessels. In conclusion, osteoporotic bone repair was enhanced by WBV bouts with short rest intervals, which may potentially be attributed to the improved mechanosensitivity of osteogenic cells and alterations in angiogenic vasculature.

The straight leg raise test (SLR) has been proposed to detect increased nerve mechanosensitivity of the lower limbs in individuals with low back pain. However, its validity in the diagnosis of lumbosacral radiculopathy shows very variable results. The aim of this study was to analyse the diagnostic validity of the SLR including well-defined diagnostic criteria (a change in symptoms with the structural differentiation manoeuvre and the reproduction of the patient\'s symptoms during the test or the asymmetries in the range of motion or symptoms location between limbs) in a sample of participants in phase III with suspicion of lumbar radiculopathy using the electrodiagnostic studies (EDX) as the reference standard. A phase III diagnostic accuracy study was designed. In total, 142 individuals with suspected lumbosacral radiculopathy referred for EDX participated in the study. Each participant was tested with EDX and SLR. SLR was considered positive using three diagnostic criteria. The sensitivity of the SLR for Criterion 3 was 89.02% (CI 81.65-96.40), the specificity was 25.00% (CI 13.21-36.79), and the positive and negative likelihood ratios were 1.19 (CI 1.01-1.40) and 0.44 (0.21-0.94), respectively. SLR showed limited validity in the diagnosis of lumbosacral radiculopathy. The incorporation of more objective diagnostic criteria (asymmetry in range of motion or localisation of symptoms) improved the diagnostic validity but the imprecision of the confidence intervals limited the interpretation of the results.

The endoplasmic reticulum acts as a protein quality control center where a range of chaperones and foldases facilitates protein folding. IRE1 is a sensory transmembrane protein that transduces signals of proteotoxic stress by forming clusters and activating a cellular program called the unfolded protein response (UPR). Recently, membrane thickness variation due to membrane compositional changes have been shown to drive IRE1 cluster formation, activating the UPR even in the absence of proteotoxic stress. Here, we demonstrate a direct relationship between bilayer tension and UPR activation based on IRE1 dimer stability. The stability of the IRE1 dimer in a (50%DOPC-50%POPC) membrane at different applied bilayer tensions was analyzed via molecular dynamics simulations. The potential of mean force for IRE1 dimerization predicts a higher concentration of IRE1 dimers for both tensed and compressed ER membranes. This study shows that IRE1 may be a mechanosensitive membrane protein and establishes a direct biophysical relationship between bilayer tension and UPR activation.