Mechanical force promotes dimethylarginine dimethylaminohydrolase 1-mediated hydrolysis of the metabolite asymmetric dimethylarginine to enhance bone formation

Mechanical force is critical for the development and remodeling of bone. Here we report that mechanical force regulates the production of the metabolite asymmetric dimethylarginine (ADMA) via regulating the hydrolytic enzyme dimethylarginine dimethylaminohydrolase 1 (Ddah1) expression in osteoblasts. The presence of -394 4 N del/ins polymorphism of Ddah1 and higher serum ADMA concentration are negatively associated with bone mineral density. Global or osteoblast-specific deletion of Ddah1 leads to increased ADMA level but reduced bone formation. Further molecular study unveils that mechanical stimulation enhances TAZ/SMAD4-induced Ddah1 transcription. Deletion of Ddah1 in osteoblast-lineage cells fails to respond to mechanical stimulus-associated bone formation. Taken together, the study reveals mechanical force is capable of down-regulating ADMA to enhance bone formation.

Direct visualization by FRET-FLIM of a putative mechanosome complex involving Src, Pyk2 and MBD2 in living MLO-Y4 cells

Earlier, we proposed the “mechanosome” concept as a testable model for understanding how mechanical stimuli detected by cell surface adhesion molecules are transmitted to modulate gene expression inside cells. Here, for the first time we document a putative mechanosome involving Src, Pyk2 and MBD2 in MLO-Y4 osteocytes with high spatial resolution using FRET-FLIM. Src-Pyk2 complexes were concentrated at the periphery of focal adhesions and the peri-nuclear region. Pyk2-MBD2 complexes were located primarily in the nucleus and peri-nuclear region. Lifetime measurements indicated that Src and MBD2 did not interact directly. Finally, mechanical stimulation by fluid flow induced apparent accumulation of Src-Pyk2 protein complexes in the peri-nuclear/nuclear region, consistent with the proposed behavior of a mechanosome in response to a mechanical stimulus.

Recent Development of Multifunctional Sensors Based on Low-Dimensional Materials

With the demand for accurately recognizing human actions and environmental situations, multifunctional sensors are essential elements for smart applications in various emerging technologies, such as smart robots, human-machine interface, and wearable electronics. Low-dimensional materials provide fertile soil for multifunction-integrated devices. This review focuses on the multifunctional sensors for mechanical stimulus and environmental information, such as strain, pressure, light, temperature, and gas, which are fabricated from low-dimensional materials. The material characteristics, device architecture, transmission mechanisms, and sensing functions are comprehensively and systematically introduced. Besides multiple sensing functions, the integrated potential ability of supplying energy and expressing and storing information are also demonstrated. Some new process technologies and emerging research areas are highlighted. It is presented that optimization of device structures, appropriate material selection for synergy effect, and application of piezotronics and piezo-phototronics are effective approaches for constructing and improving the performance of multifunctional sensors. Finally, the current challenges and direction of future development are proposed.

Degradation of 3D-Printed Porous Polylactic Acid Scaffolds Under Mechanical Stimulus

Polylactic acid (PLA) is a biodegradable polymer commonly used as a scaffold material to repair tissue defects, and its degradation is associated with mechanical stimulus. In this study, the effect of mechanical stimulus on the degradation of 3D-printed PLA scaffolds was investigated by in vitro experiments and an author-developed numerical model. Forty-five samples with porosity 64.8% were printed to carry out the degradation experiment within 90 days. Statistical analyses of the mass, volume fraction, Young’s modulus, and number average molecular weight were made, and the in vitro experiments were further used to verify the proposed numerical model of the scaffold degradation. The results indicated that the mechanical stimulus accelerated the degradation of the PLA scaffold, and the higher mechanical stimulus led to a faster degradation of the scaffolds at the late stage of the degradation process. In addition, the Young’s modulus and the normalized number average molecular weight of the PLA scaffolds between the experiments and the numerical simulations were comparable, especially for the number average molecular weight. The present study could be helpful in the design of the biodegradable PLA scaffolds.

Ether Anesthetics Obstructs Touch-Induced Trigger Hair Calcium-Electrical Signals Preventing Excitation of The Venus Flytrap

Plants do not have neurons. Instead they operate transmembrane ion channels and can be electrically excited by physical and chemical clues. The Venus flytrap with its distinctive hapto-electric signaling is a prime example. When an insect collides with the trigger hairs emerging from the inner surface of the trap, the mechanical stimulus in the mechanosensory organ is translated into a calcium signal and an action potential (AP). Here we asked how a Ca 2+ wave and AP are initiated in the trigger hair and how these are fed into the systemic trap calcium-electric network. When the Dionaea muscipula trigger hair matures and develops hapto-electric excitability, the mechanosensitive anion channel DmMSL10 and voltage dependent SKOR type Shaker K + channel are expressed in the shear stress-sensitive podium, which interfaces with the flytrap’s prey capture and processing networks. In the excitable state, touch stimulation of the trigger hair first evokes a rise in the podium Ca 2+ , then the calcium signal together with an action potential, travel over the entire trap surface. Seeking the mechanisms that mediate touch-induced Ca 2+ transients in the mature trigger hairs, we show that OSCA1.7 and GLR3.6 type Ca 2+ channels and ACA2/10 Ca 2+ pumps are specifically expressed in the podium. In addition, we found that direct glutamate application to the trap evoked a propagating Ca 2+ and electrical event. Given that anesthetics affect K + channels and glutamate receptors in animal systems, we exposed flytraps to ether. An ether atmosphere suppressed the propagation of touch and glutamate-induced Ca 2+ and AP long-distance signaling, a response that was completely recovered when ether was replaced by fresh air. In line with ether targeting a calcium channel, so triggering a Ca 2+ activated anion channel, the AP amplitude declined before the electrical signal ceased completely. Ether in the mechanosensory organ neither prevented the touch induction of a calcium signal nor its post stimulus decay. This finding indicates that ether prevents the touch activated GLR3.6-expressing base of the trigger hair so exciting the capture organ.

A small molecule screen identifies novel inhibitors of mechanosensory nematocyst discharge in Hydra

Cnidarians are characterized by the possession of stinging organelles, called nematocysts, which they use for prey capture and defense. Nematocyst discharge is controlled by a mechanosensory apparatus with analogies to vertebrate hair cells. Members of the transient receptor potential (TRPN) ion channel family are supposed to be involved in the transduction of the mechanical stimulus. A small molecule screen was performed to identify compounds that affect nematocyst discharge in Hydra. We identified several [2.2]paracyclophanes that cause inhibition of nematocyst discharge in the low micro-molar range. Further structure–activity analyses within the compound class of [2.2]paracyclophanes showed common features that are required for the inhibitory activity of the [2.2]paracyclophane core motif. This study demonstrates that Hydra can serve as a model for small molecule screens targeting the mechanosensory apparatus in native tissues.

Mechanical Stimulus-Related Risk Signature Plays a Key Role in the Prognostic Nomogram For Endometrial Cancer

BackgroundTumor biomechanics correlates with the progression and prognosis of endometrial carcinoma (EC). The objective of this study is to construct a risk model using the mechanical stimulus-related genes in EC.MethodsWe retrieved the transcriptome profiling and clinical data of EC from The Cancer Genome Atlas (TCGA) and Molecular Signatures Database (MSigDB). Differentially expressed mechanical stimulus-related genes were extracted from the databases, and then the least absolute shrinkage and selection operator (LASSO) regression analysis was used to construct a risk model. A nomogram integrating the genes and the clinicopathological characteristics was established and validated using the Kaplan-Meier survival and receiver operating characteristic (ROC) curves to estimate the overall survival (OS) of EC patients. Protein profiling technology and immunofluorescence technique were performed to verify the connection between biomechanics and EC.ResultsIn total, 79 mechanical stimulus-related genes were identified by analyzing the two databases. Based on the LASSO regression analysis, 7 genes were selected for the establishment of the risk model. This model showed a good performance in terms of the prognostic accuracy in high- and low-risk groups. The area under the ROC curves (AUC) of this model was 0.697, 0.712 and 0.723 for 3-, 5- and 7-year OS, respectively. Then, a nomogram integrating the genes of the risk model and clinical features was constructed. The nomogram could accurately predict the OS (AUC = 0.779, 0.812 and 0.806 for 3-, 5- and 7-year OS, respectively). The results of the protein profiling technology and immunofluorescence revealed the expression of cytoskeleton proteins to be correlated with the Matrigel stiffness degree.ConclusionsIn summary, a risk model of 7 mechanical stimulus-related genes was identified in EC. A nomogram based on this risk model and combining the clinicopathological features to assess the overall survival of EC showed high practical value.

Mid-Air Tactile Sensations Evoked by Laser-Induced Plasma: A Neurophysiological Study

This study demonstrates the feasibility of a mid-air means of haptic stimulation at a long distance using the plasma effect induced by laser. We hypothesize that the stress wave generated by laser-induced plasma in the air can propagate through the air to reach the nearby human skin and evoke tactile sensation. To validate this hypothesis, we investigated somatosensory responses in the human brain to laser plasma stimuli by analyzing electroencephalography (EEG) in 14 participants. Three types of stimuli were provided to the index finger: a plasma stimulus induced from the laser, a mechanical stimulus transferred through Styrofoam stick, and a sham stimulus providing only the sound of the plasma and mechanical stimuli at the same time. The event-related desynchronization/synchronization (ERD/S) of sensorimotor rhythms (SMRs) in EEG was analyzed. Every participant verbally reported that they could feel a soft tap on the finger in response to the laser stimulus, but not to the sham stimulus. The spectrogram of EEG evoked by laser stimulation was similar to that evoked by mechanical stimulation; alpha ERD and beta ERS were present over the sensorimotor area in response to laser as well as mechanical stimuli. A decoding analysis revealed that classification error increased when discriminating ERD/S patterns between laser and mechanical stimuli, compared to the case of discriminating between laser and sham, or mechanical and sham stimuli. Our neurophysiological results confirm that tactile sensation can be evoked by the plasma effect induced by laser in the air, which may provide a mid-air haptic stimulation method.

Cross-Disorder Genomics Data Analysis Elucidates a Shared Genetic Basis Between Major Depression and Osteoarthritis Pain

Osteoarthritis (OA) and major depression (MD) are two debilitating disorders that frequently co-occur and affect millions of the elderly each year. Despite the greater symptom severity, poorer clinical outcomes, and increased mortality of the comorbid conditions, we have a limited understanding of their etiologic relationships. In this study, we conducted the first cross-disorder investigations of OA and MD, using genome-wide association data representing over 247K cases and 475K controls. Along with significant positive genome-wide genetic correlations (rg = 0.299 ± 0.026, p = 9.10 × 10–31), Mendelian randomization (MR) analysis identified a bidirectional causal effect between OA and MD (βOA→MD = 0.09, SE = 0.02, z-score p-value < 1.02 × 10–5; βMD→OA = 0.19, SE = 0.026, p < 2.67 × 10–13), indicating genetic variants affecting OA risk are, in part, shared with those influencing MD risk. Cross-disorder meta-analysis of OA and MD identified 56 genomic risk loci (Pmeta ≤ 5 × 10–8), which show heightened expression of the associated genes in the brain and pituitary. Gene-set enrichment analysis highlighted “mechanosensory behavior” genes (GO:0007638; Pgene_set = 2.45 × 10–8) as potential biological mechanisms that simultaneously increase susceptibility to these mental and physical health conditions. Taken together, these findings show that OA and MD share common genetic risk mechanisms, one of which centers on the neural response to the sensation of mechanical stimulus. Further investigation is warranted to elaborate the etiologic mechanisms of the pleiotropic risk genes, as well as to develop early intervention and integrative clinical care of these serious conditions that disproportionally affect the aging population.