Lagrangian stretching reveals stress topology in viscoelastic flows.

Viscoelastic flows are pervasive in a host of natural and industrial processes, where the emergence of nonlinear and time-dependent dynamics regulates flow resistance, energy consumption, and particulate dispersal. Polymeric stress induced by the advection and stretching of suspended polymers feeds back on the underlying fluid flow, which ultimately dictates the dynamics, instability, and transport properties of viscoelastic fluids. However, direct experimental quantification of the stress field is challenging, and a fundamental understanding of how Lagrangian flow structure regulates the distribution of polymeric stress is lacking. In this work, we show that the topology of the polymeric stress field precisely mirrors the Lagrangian stretching field, where the latter depends solely on flow kinematics. We develop a general analytical expression that directly relates the polymeric stress and stretching in weakly viscoelastic fluids for both nonlinear and unsteady flows, which is also extended to special cases characterized by strong kinematics. Furthermore, numerical simulations reveal a clear correlation between the stress and stretching field topologies for unstable viscoelastic flows across a broad range of geometries. Ultimately, our results establish a connection between the Eulerian stress field and the Lagrangian structure of viscoelastic flows. This work provides a simple framework to determine the topology of polymeric stress directly from readily measurable flow field data and lays the foundation for directly linking the polymeric stress to flow transport properties.

High-content method for mechanosignaling studies using IsoStretcher technology and quantitative Ca2+ imaging applied to Piezo1 in cardiac HL-1 cells.

The importance of mechanosensory transduction pathways in cellular signalling has prominently come to focus in the last decade with the discovery of the Piezo ion channel family. Mechanosignaling involving Piezo1 ion channels in the function of the heart and cardiovascular system has only recently been identified to have implications for cardiovascular physiology and pathophysiology, in particular for heart failure (i.e., hypertrophy or dilative cardiomyopathy). These results have emphasized the need for higher throughput methods to study single-cell cardiovascular mechanobiology with the aim of identifying new targets for therapeutic interventions and stimulating the development of new pharmacological agents. Here, we present a novel method to assess mechanosignaling in adherent cardiac cells (murine HL-1 cell line) using a combination of isotropic cell stretch application and simultaneous Ca2+ fluorescence readout with quantitative analysis. The procedure implements our IsoStretcher technology in conjunction with a single-cell- and population-based analysis of Ca2+ signalling by means of automated image registration, cell segmentation and analysis, followed by automated classification of single-cell responses. The method is particularly valuable for assessing the heterogeneity of populations with distinct cellular responses to mechanical stimulation and provides more user-independent unbiased drug response classifications.

Testing fractional doses of COVID-19 vaccines.

Due to the enormous economic, health, and social costs of the COVID-19 pandemic, there are high expected social returns to investing in parallel in multiple approaches to accelerating vaccination. We argue there are high expected social returns to investigating the scope for lowering the dosage of some COVID-19 vaccines. While existing evidence is not dispositive, available clinical data on the immunogenicity of lower doses combined with evidence of a high correlation between neutralizing antibody response and vaccine efficacy suggests that half or even quarter doses of some vaccines could generate high levels of protection, particularly against severe disease and death, while potentially expanding supply by 450 million to 1.55 billion doses per month, based on supply projections for 2021. An epidemiological model suggests that, even if fractional doses are less effective than standard doses, vaccinating more people faster could substantially reduce total infections and deaths. The costs of further testing alternative doses are much lower than the expected public health and economic benefits. However, commercial incentives to generate evidence on fractional dosing are weak, suggesting that testing may not occur without public investment. Governments could support either experimental or observational evaluations of fractional dosing, for either primary or booster shots. Discussions with researchers and government officials in multiple countries where vaccines are scarce suggests strong interest in these approaches.

Directional Cell Migration Guided by a Strain Gradient.

Strain gradients widely exist in development and physiological activities. The directional movement of cells is essential for proper cell localization, and directional cell migration in responses to gradients of chemicals, rigidity, density, and topography of extracellular matrices have been well-established. However; it is unclear whether strain gradients imposed on cells are sufficient to drive directional cell migration. In this work, a programmable uniaxial cell stretch device is developed that creates controllable strain gradients without changing substrate stiffness or ligand distributions. It is demonstrated that over 60% of the single rat embryonic fibroblasts migrate toward the lower strain side in static and the 0.1 Hz cyclic stretch conditions at ≈4% per mm strain gradients. It is confirmed that such responses are distinct from durotaxis or haptotaxis. Focal adhesion analysis confirms higher rates of contact area and protrusion formation on the lower strain side of the cell. A 2D extended motor-clutch model is developed to demonstrate that the strain-introduced traction force determines integrin fibronectin pairs' catch-release dynamics, which drives such directional migration. Together, these results establish strain gradient as a novel cue to regulate directional cell migration and may provide new insights in development and tissue repairs.

Activation of skeletal muscle mechanoreceptors and nociceptors reduces the exercise performance of the contralateral homologous muscles.

INTRODUCTION: Increasing evidence suggests that activation of muscle nerve afferents may inhibit central motor drive, affecting contractile performance of remote exercising muscles. While these effects are well documented for metaboreceptors, very little is known about the activation of mechano- and mechano-nociceptive afferents on performance fatigability. Therefore, the purpose of the present study was to examine the influence of mechanoreceptors and nociceptors on performance fatigability. METHODS: Eight healthy young males undertook four randomized experimental sessions on separate occasions in which the experimental knee extensors were: a) resting (CTRL), b) passively stretched (ST), c) resting with DOMS (DOMS), or d) passively stretched with DOMS (DOMS+ST), while the contralateral leg performed an isometric time to task failure (TTF). Changes in maximal voluntary contraction (ΔMVC), potentiated twitch force (ΔQtw,pot) and voluntary muscle activation (ΔVA) were also assessed. RESULTS: TTF was reduced in DOMS+ST (-43%) and ST (­29%) compared with CTRL. DOMS+ST also showed a greater reduction of VA (-25% vs ­8%, respectively) and MVCcompared with CTRL (­28% vs -45%, respectively). RPE was significantly increased at the initial stages (20-40-60%) of the TTF in DOMS+ST compared with all conditions. CONCLUSION: These findings indicate that activation of mechanosensitive and mechano-nociceptive afferents of a muscle with DOMS reduces TTF of the contralateral homologous exercising limb, in part by reducing VA so accelerating mechanisms of central fatigue.

Stretching is not essential for managing MS spasticity: A randomized controlled trial.

BACKGROUND: Clinical practice, expert opinion, and evidence-based guidelines recommend daily stretching as first-line treatment for multiple sclerosis (MS) spasticity, but this has not been evaluated by fully powered clinical trials. OBJECTIVE: To determine whether MS Spasticity: Take Control (STC), a guideline-based program of spasticity education and stretching exercises has different effects on the impact of spasticity than a control program of different spasticity education and range of motion (ROM) exercises. METHODS: Ambulatory people with self-reported MS spasticity were randomly assigned to STC or ROM, delivered in same duration, facilitator-led, group classes, face-to-face (F2F) initially and later virtually, due to coronavirus disease 2019 (COVID-19). Multiple Sclerosis Spasticity Scale (MSSS) scores were compared between groups at 1 (primary outcome) and 6 months after interventions. RESULTS: A total of 231 people enrolled. There was no significant difference in MSSS scores between STC and ROM at 1 month (mean difference = 0.28, 95% (confidence interval (CI)) = [-9.45 to 10.01], p = 0.955). There were significant group mean improvements in MSSS scores and most other outcomes at 1 and 6 months. CONCLUSION: Education with stretching exercises, the first-line recommended treatment for MS spasticity, and education with ROM exercises may both improve MS spasticity to a similar degree. This study debunks the belief that stretching is essential to managing MS spasticity.

Mechanosensitive channel of large conductance enhances the mechanical stretching-induced upregulation of glycolysis and oxidative metabolism in Schwann cells.

BACKGROUND: Physical exercise directly stretching the peripheral nerve promotes nerve regeneration; however, its action mechanism remains elusive. Our present study aimed to investigate the effects of mechanosensitive channel of large conductance (MscL) activated by mechanical stretching on the cultured Schwann cells (SCs) and explore the possible mechanism. METHODS: Primary SCs from neonatal mice at 3-5 days of age were derived and transfected with the lentivirus vector expressing a mutant version of MscL, MscL-G22S. We first detected the cell viability and calcium ion (Ca2+) influx in the MscL-G22S-expressing SCs with low-intensity mechanical stretching and the controls. Proteomic and energy metabolomics analyses were performed to investigate the comprehensive effects of MscL-G22S activation on SCs. Measurement of glycolysis- and oxidative phosphorylation-related molecules and ATP production were respectively performed to further validate the effects of MscL-G22S activation on SCs. Finally, the roles of phosphatidylinositol-3-kinase (PI3K)/AKT/mammalian target of rapamycin (mTOR) signaling pathway in the mechanism of energy metabolism modulation of SCs by MscL-G22S activation was investigated. RESULTS: Mechanical stretching-induced MscL-G22S activation significantly increased the cell viability and Ca2+ influx into the SCs. Both the proteomic and targeted energy metabolomics analysis indicated the upregulation of energy metabolism as the main action mechanism of MscL-G22S-activation on SCs. MscL-G22S-activated SCs showed significant upregulation of glycolysis and oxidative phosphorylation when SCs with stretching alone had only mild upregulation of energy metabolism than those without stimuli. MscL-G22S activation caused significant phosphorylation of the PI3K/AKT/mTOR signaling pathway and upregulation of HIF-1α/c-Myc. Inhibition of PI3K abolished the MscL-G22S activation-induced upregulation of HIF-1α/c-Myc signaling in SCs and reduced the levels of glycolysis- and oxidative phosphorylation-related substrates and mitochondrial activity. CONCLUSION: Mechanical stretching activates MscL-G22S to significantly promote the energy metabolism of SCs and the production of energic substrates, which may be applied to enhance nerve regeneration via the glia-axonal metabolic coupling.

Exploiting and Enhancing the Heat Transport Rate of MoS2-Ag/EO Hybrid Nanofluid Flow via a Stretching Cylinder using Extended Yamada-Ota and Xue Models.

The current model offers valuable insights for materials science, heat exchangers, renewable energy production, nanotechnology, manufacturing, medicinal treatments, and environmental engineering. The findings of this study have the potential to improve material design, increase heat transfer efficiency across various systems, enhance energy conversion processes, and drive advancements in nanotechnology, medicinal treatments, and engineering design. The goal of the current research is to analyze the effects of thermal radiation and the volume fraction of nanoparticles in MoS2-Ag/engine oil-based hybrid nanofluid flow passing through a cylinder. After performing a substantial similarity transformation, the nonlinear dimensionless framework is recast as ODEs. The Yamada-Ota and Xue models are then applied to the dimensionless equation setup, which is numerically solved using the BVP4C approach. The resulting velocity and temperature fields, corresponding to various parameters, are examined and compared across both models. This investigation demonstrates a significant variation in heat transfer rates between the Yamada-Ota and Xue models, with the former having a larger impact. The velocity and temperature fields decrease as the magnetic field parameter increases in both nanofluids. However, as the magnetic field parameter values grow, the velocity fields in the two nanofluids behave differently. The Yamada-Ota and Xue models are used to determine the behavior of the hybrid nanofluid flow over a nonlinear extended cylinder. In all situations, the velocity and temperature fields exhibit superior decay characteristics.

Microstructural Evolution of P(NDI2OD-T2) Films with Different Molecular Weight during Stretching Deformation.

Conjugated polymers exhibit excellent electrical and mechanical properties when their molecular weight (Mw) is above the critical molecular weight (Mc). The microstructural changes of polymers under strain are crucial to establish a structure-performance relationship. Herein, the tensile deformation of P(NDI2OD-T2) is visualized, and cracks are revealed either along the (100) crystal plane of side chain packing or along the main chain direction which depends on the Mw is below or above the Mc. When Mw < Mc, the film cracks along the (100) plane under small strains. When Mw > Mc, the polymer chains first undergo stretch-induced orientation and then fracture along the main chain direction at large strains. This is attributed to the fact that the low Mw film exhibits large crystalline domains and the absence of interdomain connectivity, which are vulnerable to mechanical stress. In contrast, the high Mw film displays a nearly amorphous morphology with adequate entanglements, the molecular chains can endure stresses in the stretching direction to release substantial strain energy under greater mechanical deformation. Therefore, the film with Mw > Mc exhibits the optimal electrical and mechanical performances simultaneously, i.e., the electron mobility is retained under 100% strain and after 100 stretching-releasing cycles.

Mechanochromic Polymer Film with High Sensitivity toward Tensile Strain by the Post-Curing Ring-Closure Induced Pre-Stretching.

Mechanochromic materials have received broad research interests recently, owing to its ability to monitor the in situ stress/strain in polymer materials in a straightforward way. However, one major setback that hinders the practical application of these materials is their low sensitivity toward tensile strain. Here a new strategy for pre-stretching of the mechanochromic agent in a polymer film on the molecular scale, which can effectively enhance the mechanochromic sensitivity of a polymer film toward tensile strain, is shown. In situ fluorescent measurement during tensile test shows an early activation of the mechanochromic agent at tensile strain as low as 50%. The pre-stretching effect is realized by first inducing ring-opening of the mechanochromic agent by molecular functionalization, and then compelling the ring-closure process in the cured film by elevated temperature. This post-curing ring-closure process will result in pre-stretched mechanochromic agent in a crosslinked network. The mechanism for mechanochromic activation of polymer films with different composition is elaborated by visco-elastic measurements, and the effect of pre-stretching is further confirmed by films with other compositions. Combined with the simplicity of the method developed, this work could offer an alternative strategy to enhance the sensitivity of different mechanochromic agents toward tensile strain.

Effect of muscle stretching and isometric exercises on quality of life in children undergoing regular hemodialysis.

BACKGROUND: Chronic kidney disease (CKD) is a prevalent health issue that can have detrimental effects on the quality of life (QoL) of children. Nevertheless, with adequate management and support, many children with CKD can have satisfying lives. The study aimed to investigate the effect of muscle stretching and isometric exercises on QoL of children undergoing hemodialysis. METHODS: Sixty-eight children aged 6-18 years with kidney failure undergoing hemodialysis at Assiut University Children Hospital were included. They were randomly assigned to two groups. The study group received a 40-min exercise program three times per week for 2 months, while the control group received routine hospital care. For outcome measures, two tools were used: a simple questionnaire sheet for personal and medical data and PedsQL™ scale. RESULTS: After 2 months of exercise, it was shown that most children in the study group (66.7%) had good QoL, in contrast to only 3.3% in the control group, with a highly statistically significant variation between the two examined groups pertaining to the health-related QoL scale (P value = 0.001) after exercise. CONCLUSION: The intensity of care for children on hemodialysis has a distinguished impact upon their quality of life. The implementation of muscle stretching and isometric exercises during hemodialysis represents an important aspect of such care that may be associated with significant improvement in all domains of QoL. Children undergoing hemodialysis need well-organized programs that cover all physical and psychological aspects with smart time manipulation and increased attention from their staff.

Comparison of the acute effects of different techniques on the ankle joint range of motion in healthy older adults: a randomized controlled trial.

AIM: This study aimed to compare the acute effects of different methods on ankle joint range of motion (ROM) in older adults. MATERIALS AND METHODS: Seventy-eight older adults were randomly divided into three groups. After the warming-up, static stretching, proprioceptive neuromuscular facilitation (PNF) contract-relax, and roller massage were applied, at the same period. Before application, immediately after, 10 and 20 min after application, ankle joint dorsiflexion ROM was measured in the weight-bearing position. RESULTS: No statistically significant difference between the groups in demographic characteristics and baseline ankle ROM (p = 0.413). In all groups, post-application measurements revealed increased ankle joint motion (p < 0.0125). Groups were compared, and a statistically significant difference between the three groups was found (p < 0.05). There was no significant difference in the change of ROM between the Static Stretching and PNF Stretching Groups in the change of ROM group comparisons (p = 0.089). There was a statistically significant difference in ROM changes Roller Massage Group and both Static Stretching and the PNF Stretching Group (p = 0.001). CONCLUSION: The acute effects of roller massage, on ankle ROM, were superior to static and PNF stretching. The application of roller massage, which was shown to be an effective method for increasing ROM, can be safely applied in physiotherapy programs for older adults.

Simultaneous Real-Time Imaging of Leading and Lagging Strand Synthesis Reveals the Coordination Dynamics of Single Replisomes.

The molecular machinery responsible for DNA replication, the replisome, must efficiently coordinate DNA unwinding with priming and synthesis to complete duplication of both strands. Due to the anti-parallel nature of DNA, the leading strand is copied continuously, while the lagging strand is produced by repeated cycles of priming, DNA looping, and Okazaki-fragment synthesis. Here, we report a multidimensional single-molecule approach to visualize this coordination in the bacteriophage T7 replisome by simultaneously monitoring the kinetics of loop growth and leading-strand synthesis. We show that loops in the lagging strand predominantly occur during priming and only infrequently support subsequent Okazaki-fragment synthesis. Fluorescence imaging reveals polymerases remaining bound to the lagging strand behind the replication fork, consistent with Okazaki-fragment synthesis behind and independent of the replication complex. Individual replisomes display both looping and pausing during priming, reconciling divergent models for the regulation of primer synthesis and revealing an underlying plasticity in replisome operation.

The development, use, and challenges of electromechanical tissue stimulation systems.

BACKGROUND: Tissue stimulations greatly affect cell growth, phenotype, and function, and they play an important role in modeling tissue physiology. With the goal of understanding the cellular mechanisms underlying the response of tissues to external stimulations, in vitro models of tissue stimulation have been developed in hopes of recapitulating in vivo tissue function. METHODS: Herein we review the efforts to create and validate tissue stimulators responsive to electrical or mechanical stimulation including tensile, compression, torsion, and shear. RESULTS: Engineered tissue platforms have been designed to allow tissues to be subjected to selected types of mechanical stimulation from simple uniaxial to humanoid robotic stain through equal-biaxial strain. Similarly, electrical stimulators have been developed to apply selected electrical signal shapes, amplitudes, and load cycles to tissues, lending to usage in stem cell-derived tissue development, tissue maturation, and tissue functional regeneration. Some stimulators also allow for the observation of tissue morphology in real-time while cells undergo stimulation. Discussion on the challenges and limitations of tissue simulator development is provided. CONCLUSIONS: Despite advances in the development of useful tissue stimulators, opportunities for improvement remain to better reproduce physiological functions by accounting for complex loading cycles, electrical and mechanical induction coupled with biological stimuli, and changes in strain affected by applied inputs.

Influence of 8-weeks of supervised static stretching or resistance training of pectoral major muscles on maximal strength, muscle thickness and range of motion.

OBJECTIVES: Current research suggests static stretch-induced maximal strength increases and muscle hypertrophy with potential to substitute resistance-training routines. However, most studies investigated the plantar flexors. This study explored the effects of a static stretching program on maximal strength, hypertrophy and flexibility of the pectoralis major and compared the effects with those of traditional resistance training. METHODS: Eighty-one (81) active participants were allocated to either a static stretching, strength-training or control group. Pectoralis stretching was applied 15 min/day, 4 days per week for 8 weeks, while resistance training trained 3 days per week, 5 × 12 repetitions. RESULTS: There was an increase in all parameters (strength: p < 0.001, ƞ2 = 0.313, muscle thickness: p < 0.001, ƞ2 = 0.157-0.264, flexibility: p < 0.001, ƞ2 = 0.316) and a time*group interaction (strength: p = 0.001, ƞ2 = 0.154, muscle thickness: p = 0.008-0.001, ƞ2 = 0.117-0.173, flexibility: p < 0.001, ƞ2 = 0.267). Post-hoc testing showed no difference between both intervention groups regarding maximal strength and muscle thickness (p = 0.905-0.983, d = 0.036-0.087), while flexibility increased in the stretching group (p = 0.001, d = 0.789). CONCLUSION: Stretching showed increases in maximal strength and hypertrophy, which were comparable with commonly used resistance training. Based on current literature, the influence of mechanical tension as the underlying mechanism is discussed. Furthermore, as equipment and comparatively long stretching durations are requested to induce meaningful strength increases in recreationally active participants, practical application seems limited to special circumstances.

Acute effect of static stretching on non-muscular tissue stiffness and joint flexibility: a comparative study between older and young men.

PURPOSE: Non-muscular tissue stiffness is assumed to have a negative impact on joint flexibility, and a reduction in non-muscular tissue stiffness may be important, especially in older adults. The present study aimed to compare the acute effects of static stretching on non-muscular tissue stiffness between older and young adults and to investigate whether a decrease in tissue stiffness improves joint flexibility. METHODS: Twenty older (62-83 years) and 20 young (21-24 years) males participated. Ankle dorsiflexion static stretching (five sets of 90 s each) was performed, and before and after stretching, the ankle dorsiflexion range of motion (RoM), passive ankle joint stiffness, and shear wave speed (SWS) (an index of stiffness) of the sciatic nerve, tibial nerve, and posterior thigh fascia were measured. RESULTS: Stretching led to an increase in RoM and a decrease in passive joint stiffness in both groups (P < 0.001) with no significant between-group differences (P ≥ 0.055). The between-group difference in the effect of stretching on SWS was evident only for the sciatic nerve, and a decline in sciatic nerve SWS was only observed in the older adult group (pre-stretching: 2.5 ± 0.3 m/s; post-stretching: 2.3 ± 0.4 m/s; P = 0.027). A significant positive repeated-measures correlation was observed between the sciatic nerve SWS and passive joint stiffness (P = 0.014, rrm = 0.540). CONCLUSION: The reduction in sciatic nerve stiffness by stretching was noticeable in older men and led to improved joint flexibility. These findings may provide insight into tissue adaptation by stretching and may be used to explore effective exercises for improving joint flexibility in older adults.

A scoping review of the effect of chronic stretch training on sleep quality in people with sleep disorders.

PURPOSE: The widespread and health-detrimental sleep disorders have resulted in stretching exercises being investigated as a non-drug solution for enhanced sleep quality. However, a comprehensive understanding of the impact of stretching exercises on individuals with sleep disorders is lacking. METHODS: This scoping review systematically maps the existing literature and identifies research gaps on the impact of stretching exercises on sleep quality in individuals with sleep disorders. RESULTS: Sixteen eligible studies were included, where the weighted mean changes indicate a positive trend in sleep quality improvement, ranging from trivial to very large magnitudes. However, concerning the individual study results only 5 out of 16 studies reported significant improvements. Notable enhancements include a small 1.22% overall sleep quality improvement, a large 6.51% reduction in insomnia severity, a large 8.88% increase in sleep efficiency, a moderate 4.36% decrease in sleep onset latency, a large 8.27% decrease in wake after sleep onset, and a very large 14.70% improvement in total sleep time. Trivial changes are noted in sleep duration (0.58%), sleep disturbance reduction (0.07%), and daytime dysfunction reduction (0.19%). Likely mechanisms for the improvement of sleep include autonomic nervous system modulation, muscle tension relief, cortisol regulation, enhanced blood circulation, and psychological benefits such as stress reduction and mood enhancement. CONCLUSION: There is little evidence that stretching exercises positively impact sleep quality in individuals with sleep disorders. Additionally, further research is vital for designing optimal protocols, understanding of the long-term effects, and clarification of the mechanisms.

Critical evaluation and recalculation of current systematic reviews with meta-analysis on the effects of acute and chronic stretching on passive properties and passive peak torque.

PURPOSE: Muscle, tendon, and muscle-tendon unit (MTU) stiffness as well as passive peak torque (PPT) or delayed stretching pain sensation are typical explanatory approaches for stretching adaptations. However, in literature, differences in the study inclusion, as well as applying meta-analytical models without accounting for intrastudy dependency of multiple and heteroscedasticity of data bias the current evidence. Furthermore, most of the recent analyses neglected to investigate PPT adaptations and further moderators. METHODS: The presented review used the recommended meta-analytical calculation method to investigate the effects of stretching on stiffness as well as on passive torque parameters using subgroup analyses for stretching types, stretching duration, and supervision. RESULTS: Chronic stretching reduced muscle stiffness ( - 0.38, p = 0.01) overall, and also for the supervised ( - 0.49, p = 0.004) and long static stretching interventions ( - 0.61, p < 0.001), while the unsupervised and short duration subgroups did not reach the level of significance (p = 0.21, 0.29). No effects were observed for tendon stiffness or for subgroups (e.g., long-stretching durations). Chronic PPT (0.55, p = 0.005) in end ROM increased. Only long-stretching durations sufficiently decreased muscle stiffness acutely. No effects could be observed for acute PPT. CONCLUSION: While partially in accordance with previous literature, the results underline the relevance of long-stretching durations when inducing changes in passive properties. Only four acute PPT in end ROM studies were eligible, while a large number were excluded as they provided mathematical models and/or lacked control conditions, calling for further randomized controlled trials on acute PPT effects.

Primary cilia and the reciprocal activation of AKT and SMAD2/3 regulate stretch-induced autophagy in trabecular meshwork cells.

Activation of autophagy is one of the responses elicited by high intraocular pressure (IOP) and mechanical stretch in trabecular meshwork (TM) cells. However, the mechanosensor and the molecular mechanisms by which autophagy is induced by mechanical stretch in these or other cell types is largely unknown. Here, we have investigated the mechanosensor and downstream signaling pathway that regulate cyclic mechanical stretch (CMS)-induced autophagy in TM cells. We report that primary cilia act as a mechanosensor for CMS-induced autophagy and identified a cross-regulatory talk between AKT1 and noncanonical SMAD2/3 signaling as critical components of primary cilia-mediated activation of autophagy by mechanical stretch. Furthermore, we demonstrated the physiological significance of our findings in ex vivo perfused eyes. Removal of primary cilia disrupted the homeostatic IOP compensatory response and prevented the increase in LC3-II protein levels in response to elevated pressure challenge, strongly supporting a role of primary cilia-mediated autophagy in regulating IOP homeostasis.

Efficacy of a high-intensity home stretching device and traditional physical therapy in non-operative management of adhesive capsulitis - a prospective, randomized control trial.

BACKGROUND: Historically, in-person physical therapy serves as a foundational component of nonoperative treatment of adhesive capsulitis (AC). This study compares the effectiveness of an at-home high-intensity stretch (HIS) device to traditional physical therapy (PT) and to PT in combination with the HIS device. We hypothesize that the HIS device will be as effective as PT alone or as combination therapy in the first-line treatment of AC and use of the HIS device will exhibit improvement at higher rate. METHODS: Thirty-four patients with idiopathic adhesive capsulitis and a minimum of 12 months follow-up were included in this study. Patients were randomized into one of the three groups: HIS device, PT alone, or HIS device + PT. Passive range of motion (ROM), American Shoulder and Elbow Surgeons (ASES), and Simple Shoulder Test (SST) scores were measured. Additionally, patient satisfaction, compliance and complications were recorded. Paired t-test, ANOVA and Chi-squared tests were used in analysis. RESULTS: Final ROM in all planes improved for all groups compared to baseline (p < 0.001), with only HIS device group able to restore > 95% of contralateral ROM in all planes at final follow-up. Patients with PT alone were on average slowest to improve ROM from baseline, at 3 months, 6 months, and 1 year in all planes except internal rotation. ASES and SST scores improved for all groups when compared to baseline (p < 0.001). Use of HIS-device resulted in greater improvement in SST and ASES Total scores compared to PT alone (p = 0.045, and p = 0.048, respectively). CONCLUSIONS: Use of an at-home high-intensity stretching device for conservative treatment of idiopathic adhesive capsulitis improves outcomes in ROM and in ASES and SST scores both when used as an adjunct to physical therapy and when used alone. TRIAL REGISTRATION: The study protocol was registered at www. CLINICALTRIALS: gov (20/05/2022, NCT05384093).