Mechanical memory based on chromatin and metabolism remodeling promotes proliferation and smooth muscle differentiation in mesenchymal stem cells.

Stem cells respond and remember mechanical cues from the microenvironment, which modulates their therapeutic effects. Chromatin organization and energy metabolism regulate the stem cell fate induced by mechanical cues. However, the mechanism of mechanical memory is still unclear. This study aimed to investigate the effects of mechanical amplitude, frequency, duration, and stretch cycle on mechanical memory in mesenchymal stem cells. It showed that the amplitude was the dominant parameter to the persistence of cell alignment. F-actin, paxillin, and nuclear deformation are more prone to be remolded than cell alignment. Stretching induces transcriptional memory, resulting in greater transcription upon subsequent reloading. Cell metabolism displays mechanical memory with sustained mitochondrial fusion and increased ATP production. The mechanical memory of chromatin condensation is mediated by histone H3 lysine 27 trimethylation, leading to much higher smooth muscle differentiation efficiency. Interestingly, mechanical memory can be transmitted based on direct cell-cell interaction, and stretched cells can remodel the metabolic homeostasis of static cells. Our results provide insight into the underlying mechanism of mechanical memory and its potential benefits for stem cell therapy.

Frizzled-9 triggers actin polymerization and activates mechano-transducer YAP to rescue simulated microgravity-induced osteoblast dysfunction.

Long-term spaceflight can result in bone loss and osteoblast dysfunction. Frizzled-9 (Fzd9) is a Wnt receptor of the frizzled family that is vital for osteoblast differentiation and bone formation. In the present study, we elucidated whether Fzd9 plays a role in osteoblast dysfunction induced by simulated microgravity (SMG). After 1-7 days of SMG, osteogenic markers such as alkaline phosphatase (ALP), osteopontin (OPN), and Runt-related transcription factor 2 (RUNX2) were decreased, accompanied by a decrease in Fzd9 expression. Furthermore, Fzd9 expression decreased in the rat femur after 3 weeks of hindlimb unloading. In contrast, Fzd9 overexpression counteracted the decrease in ALP, OPN, and RUNX2 induced by SMG in osteoblasts. Moreover, SMG regulated phosphorylated glycogen synthase kinase-3ß (pGSK3ß) and ß-catenin expression or sublocalization. However, Fzd9 overexpression did not affect pGSK3ß and ß-catenin expression or sublocalization induced by SMG. In addition, Fzd9 overexpression regulated protein kinase B also known as Akt and extracellular signal-regulated kinase (ERK) phosphorylation and induced F-actin polymerization to form the actin cap, press the nuclei, and increase nuclear pore size, thereby promoting the nuclear translocation of Yes-associated protein (YAP). Our study findings provide mechanistic insights into the role of Fzd9 in triggering actin polymerization and activating YAP to rescue SMG-induced osteoblast dysfunction and suggest that Fzd9 is a potential target to restore osteoblast function in individuals with bone diseases and after spaceflight.

Fluid shear stress promotes periodontal ligament cells proliferation via p38-AMOT-YAP.

Periodontal ligament (PDL) cells are a promising tool for periodontal regeneration therapy. Achieving a sufficient number of PDL cells is essential to PDL regeneration. In our study, appropriate flow shear stress (FSS, 1-6 dyn/cm2) promotes the proliferation of PDL cells. FSS remodels cytoskeleton and focal adhesion in a duration-dependent manner. FSS induces PDL cells to form the actin cap within 10 min, flattens the nuclei, and increases the nuclear pore size, which promotes nuclear translocation of Yes-associated protein (YAP). FSS activates p38, which plays a dual function in YAP regulation. p38 regulates the phosphorylation of Akt and cofilin, as well as induced F-actin polymerization to induce YAP activity. In addition, p38 inhibits pLATS and consecutively regulates angiomotin (AMOT) and YAP phosphorylation. AMOT competitively binds to F-actin and YAP to participate in FSS-mediated YAP nuclear translocation and cell proliferation. Taken collectively, our results provide mechanistic insights into the role of p38-AMOT-YAP in FSS-mediated PDL cells proliferation and indicate potential applications in dental regenerative medicine.

Wnt/ß-catenin plays a dual function in calcium hydroxide induced proliferation, migration, osteogenic differentiation and mineralization in vitro human dental pulp stem cells.

AIM: Calcium hydroxide is the gold standard material for pulp capping and has been widely used in clinical dentistry. Calcium hydroxide promotes proliferation, migration and osteogenic differentiation of dental pulp stem cells (DPSCs). However, the underlying mechanism is not clear. Our study investigated the role of Wnt/ß-catenin pathway in calcium hydroxide-induced proliferation, migration, osteogenic differentiation and mineralization of human DPSCs. METHODOLOGY: Protein and gene expression was detected by western blot (WB), immunofluorescence staining and quantitative real-time PCR (qPCR). Cell viability was analysed using the Cell Counting Kit-8 (CCK-8) assay. Wound-healing assay was used to analyse cell migration. The expression of alkaline phosphatase (ALP) was detected using ALP staining. Mineralization was analysed by alizarin red staining. RESULTS: Calcium hydroxide increased the protein expression of phosphorylated-GSK3ß/GSK3ß, ß-catenin and the gene expression of LEF-1. Inhibition of Wnt/ß-catenin abolished calcium hydroxide-induced proliferation and migration of DPSCs in 24 h. However, incubation with calcium hydroxide for 7 days and 14 days reduced Wnt/ß-catenin signalling. Inhibition of Wnt/ß-catenin promoted calcium hydroxide-induced osteogenic differentiation and mineralization in DPSCs. CONCLUSION: Wnt/ß-catenin pathway plays a dual role in calcium hydroxide-regulated DPSC behaviour. Incubation with calcium hydroxide promoted rapid proliferation and migration of DPSCs, while prolonged incubation negatively regulated osteogenic differentiation and mineralization.

Bifurcation Control on the Un-Linearizable Dynamic System via Washout Filters.

Information fusion integrates aspects of data and knowledge mostly on the basis that system information is accumulative/distributive, but a subtle case emerges for a system with bifurcations, which is always un-linearizable and exacerbates information acquisition and presents a control problem. In this paper, the problem of an un-linearizable system related to system observation and control is addressed, and Andronov-Hopf bifurcation is taken as a typical example of an un-linearizable system and detailed. Firstly, the properties of a linear/linearized system is upon commented. Then, nonlinear degeneracy for the normal form of Andronov-Hopf bifurcation is analyzed, and it is deduced that the cubic terms are an integral part of the system. Afterwards, the theoretical study on feedback stabilization is conducted between the normal-form Andronov-Hopf bifurcation and its linearized counterpart, where stabilization using washout-filter-aided feedback is compared, and it is found that by synergistic controller design, the dual-conjugate-unstable eigenvalues can be stabilized by single stable washout filter. Finally, the high-dimensional ethanol fermentation model is taken as a case study to verify the proposed bifurcation control method.

Special Issue "Complex Dynamic System Modelling, Identification and Control".

Systems are naturally or purposely formed with functional components and connection structures [...].

A microfluidic system for precisely reproducing physiological blood pressure and wall shear stress to endothelial cells.

To reproduce hemodynamic stress microenvironments of endothelial cells in vitro is of vital significance, by which one could exploit the quantitative impact of hemodynamic stresses on endothelial function and seek innovative approaches to prevent circulatory system diseases. Although microfluidic technology has been regarded as an effective method to create physiological microenvironments, a microfluidic system to precisely reproduce physiological arterial hemodynamic stress microenvironments has not been reported yet. In this paper, a novel microfluidic chip consisting of a cell culture chamber with on-chip afterload components designed by the principle of input impedance to mimic the global hemodynamic behaviors is proposed. An external feedback control system is developed to accurately generate the input pressure waveform. A lumped parameter hemodynamic model (LPHM) is built to represent the input impedance to mimic the on-chip global hemodynamic behaviors. Sensitivity analysis of the model parameters is also elaborated. The performance of reproducing physiological blood pressure and wall shear stress is validated by both numerical characterization and flow experiment. Investigation of intracellular calcium ion dynamics in human umbilical vein endothelial cells is finally conducted to demonstrate the biological applicability of the proposed microfluidic system.

Robust Stabilization and Synchronization of a Novel Chaotic System with Input Saturation Constraints.

In this paper, the robust stabilization and synchronization of a novel chaotic system are presented. First, a novel chaotic system is presented in which this system is realized by implementing a sigmoidal function to generate the chaotic behavior of this analyzed system. A bifurcation analysis is provided in which by varying three parameters of this chaotic system, the respective bifurcations plots are generated and evinced to analyze and verify when this system is in the stability region or in a chaotic regimen. Then, a robust controller is designed to drive the system variables from the chaotic regimen to stability so that these variables reach the equilibrium point in finite time. The robust controller is obtained by selecting an appropriate robust control Lyapunov function to obtain the resulting control law. For synchronization purposes, the novel chaotic system designed in this study is used as a drive and response system, considering that the error variable is implemented in a robust control Lyapunov function to drive this error variable to zero in finite time. In the control law design for stabilization and synchronization purposes, an extra state is provided to ensure that the saturated input sector condition must be mathematically tractable. A numerical experiment and simulation results are evinced, along with the respective discussion and conclusion.

Precise generation of dynamic biochemical signals by controlling the programmable pump in a Y-shaped microfluidic chip with a "christmas tree" inlet.

The generation of dynamic biochemical signals in a microfluidic control system is of importance for the study of the interaction between biological cells and their niches. However, most of microfluidic control systems are not able to provide dynamic biochemical signals with high precision and stability due to inherent mechanical vibrations caused by the actuators of the programmable pumps. In this paper, we propose a novel microfluidic feedback control system integrating an external feedback control system with a Y-shaped microfluidic chip with a "Christmas tree" inlet. The Proportional Integral Derivative (PID) controller is implemented to reduce the influence of vibrations. In order to regulate the control parameters efficiently, a mathematical model is built to describe the actuator of the programmable pump, in which a fractional-order model is utilized. Both simulation and experimental studies are carried out, confirming that the microfluidic feedback control system can precisely and stably generate desired dynamic biochemical signals.

[Effects of Maxing Shigan Decoction Decocted by Different Methods and Its Drug Containing Serum on Neuraminidase Activity of Influenza A Virus].

Objective To observe the effects of Maxing Shigan Decoction (MSD) decocted by different methods and its drug containing serum on neuraminidase ( NA ) activity of influenza A virus (IAV). Methods The effects of MSD decocted by different methods, its corresponding drug containing serums , and drug containing serum in inhibiting the proliferation of virus on NA activity of IAV were detected using 2-(4-methyl umbelliferyl )-α-D-N-acetyl neuraminic acid (MUNANA) as substrate. Results (1) Effect of MSD on NA activity of IAV: OD value was less in groups with Ephedra decocted 25-min earlier and 30-min earlier than the group with four drugs decocted at the same time (P <0. 05, P <0. 01) ; (2) Effect of MSD on NA activity of IAV: OD value was less in groups with Ephedra decocted 30-min earlier and 40-min earlier than the group with four drugs decocted at the same time (P <0. 05, P <0. 01) ; (3) In the process of inhibiting viral multiplication, effect of MSD containing serum on NA activity of IAV: OD value was less in groups with Ephedra decocted 5 -20 min earlier, 30 min earlier, 35 min earlier than the group with four drugs decocted at the same time (P <0. 05, P <0. 01). In terms of drug concentration, OA value decreased more in 6. 25% and 12. 50% MSD containing serums than in 25. 00% MSD containing serum (P <0. 01). Conclusion MSD decocted by different methods might lead to different anti-IAV effects.

Adaptive neural identification and non-singular control of pure-feedback nonlinear systems.

This paper proposes a new constructive identification and adaptive control method for nonlinear pure-feedback systems, which remedies the 'explosion of complexity' and potential control singularity encountered in the traditional adaptive backstepping controllers. First, to avoid using the backstepping recursive design, alternative state variables and the corresponding coordinate transformation are introduced to reformulate the pure-feedback system into an equivalent canonical model. Then, a high-order sliding mode (HOSM) observer is used to reconstruct the unknown states for this canonical model. To remedy the potential singularity in the control, the unknown system dynamics are lumped to derive an alternative identification structure and one-step control synthesis, where two radial basis function neural networks (RBFNN) are adopted to online estimate these lumped dynamics. In this framework, the online estimation of control gain is not in the denominator of controller, and thus the division by zero in the controllers is avoided. Finally, a new online learning algorithm is constructed to obtain the RBFNNs' weights, ensuring the convergence to the neighborhood of true values and allowing accurate identification of unknown dynamics. Theoretical analysis elaborates that the convergence of both the tracking error and the estimation error is obtained simultaneously. Simulations and practical experiments on a hydraulic servo test-rig verify the effectiveness and utility of the suggested methods.

Surgical procedures and techniques in robot-assisted uterine artery-preserving radical trachelectomy.

The aim of the study was to study robotic cervical radical trachelectomy, aimed at standardizing and optimizing surgical procedures, thereby facilitating the learning process. All surgical procedures were based on the anatomy of the embryonic compartments, which not only help prevent tumor spillage due to disruption of the embryonic compartments, but also maximize the avoidance of inadequate resection margins. Using robotics to perform radical trachelectomy, combined with the concept of membrane anatomy, not only enables a bloodless surgical process, but also streamlines and simplifies the procedure, making it more efficient and precise. Utilizing robotics for radical hysterectomy can lead to a more meticulous and refined outcome. Precise surgical techniques contribute to standardizing and optimizing surgical procedures, thereby facilitating the learning process.

Extracellular matrix stiffness as an energy metabolism regulator drives osteogenic differentiation in mesenchymal stem cells.

The biophysical factors of biomaterials such as their stiffness regulate stem cell differentiation. Energy metabolism has been revealed an essential role in stem cell lineage commitment. However, whether and how extracellular matrix (ECM) stiffness regulates energy metabolism to determine stem cell differentiation is less known. Here, the study reveals that stiff ECM promotes glycolysis, oxidative phosphorylation, and enhances antioxidant defense system during osteogenic differentiation in MSCs. Stiff ECM increases mitochondrial fusion by enhancing mitofusin 1 and 2 expression and inhibiting the dynamin-related protein 1 activity, which contributes to osteogenesis. Yes-associated protein (YAP) impacts glycolysis, glutamine metabolism, mitochondrial dynamics, and mitochondrial biosynthesis to regulate stiffness-mediated osteogenic differentiation. Furthermore, glycolysis in turn regulates YAP activity through the cytoskeletal tension-mediated deformation of nuclei. Overall, our findings suggest that YAP is an important mechanotransducer to integrate ECM mechanical cues and energy metabolic signaling to affect the fate of MSCs. This offers valuable guidance to improve the scaffold design for bone tissue engineering constructs.

Early Predicting Osteogenic Differentiation of Mesenchymal Stem Cells Based on Deep Learning Within One Day.

Osteogenic differentiation of mesenchymal stem cells (MSCs) is proposed to be critical for bone tissue engineering and regenerative medicine. However, the current approach for evaluating osteogenic differentiation mainly involves immunohistochemical staining of specific markers which often can be detected at day 5-7 of osteogenic inducing. Deep learning (DL) is a significant technology for realizing artificial intelligence (AI). Computer vision, a branch of AI, has been proved to achieve high-precision image recognition using convolutional neural networks (CNNs). Our goal was to train CNNs to quantitatively measure the osteogenic differentiation of MSCs. To this end, bright-field images of MSCs during early osteogenic differentiation (day 0, 1, 3, 5, and 7) were captured using a simple optical phase contrast microscope to train CNNs. The results showed that the CNNs could be trained to recognize undifferentiated cells and differentiating cells with an accuracy of 0.961 on the independent test set. In addition, we found that CNNs successfully distinguished differentiated cells at a very early stage (only 1 day). Further analysis showed that overall morphological features of MSCs were the main basis for the CNN classification. In conclusion, MSCs differentiation detection can be achieved early and accurately through simple bright-field images and DL networks, which may also provide a potential and novel method for the field of cell detection in the near future.

Multi-H∞ Controls for Unknown Input-Interference Nonlinear System With Reinforcement Learning.

This article studies the multi- [Formula: see text] controls for the input-interference nonlinear systems via adaptive dynamic programming (ADP) method, which allows for multiple inputs to have the individual selfish component of the strategy to resist weighted interference. In this line, the ADP scheme is used to learn the Nash-optimization solutions of the input-interference nonlinear system such that multiple [Formula: see text] performance indices can reach the defined Nash equilibrium. First, the input-interference nonlinear system is given and the Nash equilibrium is defined. An adaptive neural network (NN) observer is introduced to identify the input-interference nonlinear dynamics. Then, the critic NNs are used to learn the multiple [Formula: see text] performance indices. A novel adaptive law is designed to update the critic NN weights by minimizing the Hamiltonian-Jacobi-Isaacs (HJI) equation, which can be used to directly calculate the multi- [Formula: see text] controls effectively by using input-output data such that the actor structure is avoided. Moreover, the control system stability and updated parameter convergence are proved. Finally, two numerical examples are simulated to verify the proposed ADP scheme for the input-interference nonlinear system.

Efficacy and Safety Comparative of Sacubitril/Valsartan vs. Olmesartan in the Treatment of hypertension: A Meta-analysis of RCTs.

BACKGROUND: Sacubitril/valsartan (LCZ696) is a widely used drug for hypertension in Asia, popular for its efficacy and safety. However, there has been no comprehensive literature review comparing it with olmesartan. This meta-analysis compared the antihypertensive and adverse effects of sacubitril/valsartan and olmesartan. METHODS: We conducted a comprehensive search of Pubmed, Web of Science, Embase, Cochrane Library, and ClinicalTrials.gov databases to identify eligible randomized controlled trials (RCTs). The data were then analyzed and processed using Revman 5.4 and Stata SE14 software. RESULTS: Six RCTs with 4,127 patients were identified, showing that LCZ696 had better blood pressure control than olmesartan; mean sitting systolic and diastolic blood pressure, sitting pulse pressure, 24-hour ambulatory systolic blood pressure, and 24-hour ambulatory diastolic blood pressure were significantly decreased with LCZ696 compared with olmesartan. No significant difference between LCZ696 and olmesartan was observed in the occurrence of the majority of adverse events, with a decreased probability of headache in patients with sacubitril/valsartan compared with olmesartan. The subgroup analysis showed treatment with 400 mg/d LCZ696 was better than olmesartan in reducing serious adverse events. CONCLUSIONS: Sacubitril/valsartan was better than olmesartan in controlling blood pressure in patients with hypertension, with relatively higher safety.

The correlation between multiple HPV infections and the occurrence, development, and prognosis of cervical cancer.

Cervical carcinoma is the fourth female malignant tumor in the world, and the persistent infection of high-risk human papillomavirus (HPV) is recognized as the most common cause. This article studies the correlation between multiple HPV infections and the occurrence, development, and prognosis of cervical cancer in order to provide more references for clinical diagnosis and treatment. We conducted a retrospective analysis of the clinical data of 400 cervical carcinoma patients admitted to our hospital from 2015 to 2023. The collected patient data include age, HPV infection status, tumor size and morphology, local infiltration depth, diagnostic staging, surgical approach, vascular cancer thrombus status, lymph node status, and postoperative HPV follow-up status. We use SPSS statistical software for data analysis. Our research shows that the high-risk age group for cervical carcinoma is concentrated between 41 and 60 years old, which is basically consistent with the age range of the high incidence of HPV infection. In the statistics for HPV infection types, ~67.7% of patients are single HPV-infected, 25.29% are double infected, and 7.00% are infected with three or more types of HPV. Among the multiple HPV infections, most of the patients are younger than 40 years old and older than 70 years old, with double infection accounting for the majority. The top five HPV subtypes with high detection rates belong to high-risk subtypes, which are the HPV16, 18, 58, 33, and 52 subtypes, respectively. There was no significant relationship between multiple HPV infections and cervical cancer stage, lesion size, pathological tissue type, tissue differentiation degree/vascular cancer thrombus, and lymph node metastasis, and there was no significant difference in the results between the groups. In summary, multiple types of HPV infection in the cervix are common. We found that multiple infections, mainly HPV16, are closely related to cervical cancer. For the HPV16, 18, 58, 33, and 52 subtypes of infection, especially for patients younger than 40 years old and older than 70 years old, priority should be given to prevention and treatment. The relationship between multiple HPV infections and the progression and prognosis of cervical carcinoma requires further research, which could better guide cancer prevention and treatment.

A study on the correlation between the prognosis of HPV infection and lesion recurrence after cervical conization.

Introduction: Persistent human papillomavirus infection is an important factor in the development of cervical cancer, which is usually a long process evolving from the development of squamous intraepithelial lesions (SIL), also referred to as cervical intraepithelial neoplasia (CIN). Local treatment of advanced squamous intraepithelial lesions, also regarded as High-Grade Squamous Intraepithelial Lesion, may be effective in preventing cancer. Objective: To promptly identify high-risk patients with a tendency to recurrence. Methods: We retrospectively analyzed the clinical data of 300 patients with high-grade squamous intraepithelial lesions of the cervix admitted to the Second Affiliated Hospital of Dalian Medical University from 2019 to 2020 to investigate the relationship between recurrence of cervical lesions and postoperative regression of HPV infection, as well as other related risk factors. Results: We found that the HPV-negative rates were 81.81, 85.71, and 90.91% at 6, 12, and 24 months, respectively, and the average lesion recurrence rate was 8.16%, with a median time to recurrence of 14 months in patients undergoing CKC for HSIL. The risk of cervical squamous intraepithelial lesions was highest in patients with HPV16. Patients over 61 years of age had the lowest postoperative HPV-negative rate. The conversion rate was significantly lower in patients with multiple HPV genotypes than in those with single HPV infection (p < 0.05). The probability of recurrence was higher in patients with the same HPV infection genotype before and after surgery than in patients with different infection genotypes before and after surgery (p < 0.05). Conclusion: Combined with the literature review, we believe that patients aged ≥50 years, with ≥3 pregnancies and births, a history of smoking, and consistent genotypes of preoperative and postoperative HPV infection in cervical conization have more HPV re-infection or persistent infection, and that these factors may be high-risk factors for lesion recurrence. For patients with possible potential high-risk factors, we need to carry out individualized follow-up and focused management, take timely and effective management measures, optimize the treatment plan, reduce the recurrence rate, prevent HSIL and cervical cancer, improve the quality of patient's survival, and improve the prognosis.

Fabricating a multi-component microfluidic system for exercise-induced endothelial cell mechanobiology guided by hemodynamic similarity.

Generating precise in vivo arterial endothelial hemodynamic microenvironments using microfluidics is essential for exploring endothelial mechanobiology. However, a hemodynamic principle guiding the fabrication of microfluidic systems is still lacking. We propose a hemodynamic similarity principle for quickly obtaining the input impedance of the microfluidic system in vitro derived from that of the arterial system in vivo to precisely generate the desired endothelial hemodynamic microenvironments. First, based on the equivalent of blood pressure (BP) and wall shear stress (WSS) waveforms, we establish a hemodynamic similarity principle to efficiently map the input impedance in vivo to that in vitro, after which the multi-component microfluidic system is designed and fabricated using a lumped parameter hemodynamic model. Second, numerical simulation and experimental studies are carried out to validate the performance of the designed microfluidic system. Finally, the intracellular Ca2+ responses after exposure to different intensities of exercise-induced BP and WSS waveforms are measured to improve the reliability of EC mechanobiological studies using the designed microfluidic system. Overall, the proposed hemodynamic similarity principle can guide the fabrication of a multi-component microfluidic system for endothelial cell mechanobiology.

Offline and online parameter estimation of nonlinear systems: Application to a solid oxide fuel cell system.

In this paper, an offline tuning strategy and an online parameter estimation method are exploited to calibrate the solid oxide fuel cell mathematical model. Different to existing offline tuning strategy, the developed strategy is designed in order to tune the model under various operation conditions. First, the particle swarm optimization method combined with the gradient-based search method is applied to tune unknown parameters in the state-space model and the steady-state model for each operation condition. Then, the sensitive parameters are expanded to the polynomial equations. Moreover, the reconstructed model including coefficients in the polynomial equations are determined by using the particle swarm optimization method with gradient-based search method for whole operation conditions. To show the slowly time-varying performance of a solid oxide fuel cell, an adaptive optimal learning law based on the optimization technology is proposed to online minimize a cost function with the information of the estimation error. The estimation error is extracted through several low-pass filters and simple algebraic calculation. Finally, the proposed offline tuning strategy and the developed online adaptive estimation method are verified by conducting experiments on a practical solid oxide fuel cell test bench.