Liquid-Liquid Phase Separation of DDR1 Counteracts the Hippo Pathway to Orchestrate Arterial Stiffening.

BACKGROUND: The Hippo-YAP (yes-associated protein) signaling pathway is modulated in response to various environmental cues. Activation of YAP in vascular smooth muscle cells conveys the extracellular matrix stiffness-induced changes in vascular smooth muscle cells phenotype and behavior. Recent studies have established a mechanoreceptive role of receptor tyrosine kinase DDR1 (discoidin domain receptor 1) in vascular smooth muscle cells. METHODS: We conduced 5/6 nephrectomy in vascular smooth muscle cells-specific Ddr1-knockout mice, accompanied by pharmacological inhibition of the Hippo pathway kinase LATS1 (large tumor suppressor 1), to investigate DDR1 in YAP activation. We utilized polyacrylamide gels of varying stiffness or the DDR1 ligand, type I collagen, to stimulate the cells. We employed multiple molecular biological techniques to explore the role of DDR1 in controlling the Hippo pathway and to determine the mechanistic basis by which DDR1 exerts this effect. RESULTS: We identified the requirement for DDR1 in stiffness/collagen-induced YAP activation. We uncovered that DDR1 underwent stiffness/collagen binding-stimulated liquid-liquid phase separation and co-condensed with LATS1 to inactivate LATS1. Mutagenesis experiments revealed that the transmembrane domain is responsible for DDR1 droplet formation. Purified DDR1 N-terminal and transmembrane domain was sufficient to drive its reversible condensation. Depletion of the DDR1 C-terminus led to failure in co-condensation with LATS1. Interaction between the DDR1 C-terminus and LATS1 competitively inhibited binding of MOB1 (Mps one binder 1) to LATS1 and thus the subsequent phosphorylation of LATS1. Introduction of the single-point mutants, histidine-745-proline and histidine-902-proline, to DDR1 on the C-terminus abolished the co-condensation. In mouse models, YAP activity was positively correlated with collagen I expression and arterial stiffness. LATS1 inhibition reactivated the YAP signaling in Ddr1-deficient vessels and abrogated the arterial softening effect of Ddr1 deficiency. CONCLUSIONS: These findings identify DDR1 as a mediator of YAP activation by mechanical and chemical stimuli and demonstrate that DDR1 regulates LATS1 phosphorylation in an liquid-liquid phase separation-dependent manner.

In Vitro Detection of S100B and Severity Evaluation of Traumatic Brain Injury Based on Biomimetic Peptide-Modified Nanochannels.

The diagnosis and evaluation of traumatic brain injury (TBI) are crucial steps toward the treatment and prognosis of patients. A common question remains as to whether it is possible to introduce an ideal device for signal detection and evaluation that can directly connect digital signals with TBI, thereby enabling prompt response of the evaluation signal and sensitive and specific functioning of the detection process. Herein, a method is presented utilizing polymetric porous membranes with TRTK-12 peptide-modified nanochannels for the detection of S100B (a TBI biomarker) and assessment of TBI severity. The method leverages the specific bonding force between TRTK-12 peptide and S100B protein, along with the nanoconfinement effect of nanochannels, to achieve high sensitivity (LOD: 0.002 ng mL-1) and specificity (∆I/I0: 44.7%), utilizing ionic current change as an indicator. The proposed method, which is both sensitive and specific, offers a simple yet responsive approach for real-time evaluation of TBI severity. This innovative technique provides valuable scientific insights into the advancement of future diagnostic and therapeutic integration devices.

A comparative analysis of the clinical pregnancy and perinatal outcomes between oocyte vitrification and embryo vitrification based on the propensity score matching method.

PURPOSE: This study investigated the safety and effectiveness of oocyte vitrification by comparing the clinical pregnancy and perinatal outcomes between transfer cycles of vitrified oocytes and those of vitrified embryos. METHODS: A retrospective cohort study was conducted to analyze the clinical data of patients who underwent cleavage-stage embryo transfer at the Department of Reproductive Medicine between January 2011 and June 2021. Seventy-seven transfer cycles of fresh cleavage-stage embryos developed from vitrified-thawed oocytes (oocyte vitrification group) and 2170 transfer cycles of vitrified-thawed cleavage-stage embryos developed from fresh oocytes (embryo vitrification group) were included. Further, 293 cases were selected from the embryo vitrification group after applying propensity score matching at 1:4. The primary outcomes were miscarriage rate, live birth rate, and neonatal birth weight. RESULTS: No statistically significant differences were observed in the baseline data, pregnancy, perinatal outcomes, or neonatal outcomes for either singleton or twin births between the two groups after matching. Backwards stepwise regression was used to analyze the length of gestation. The age of female participants (ß = - 0.410, 95% CI = - 1.339 ~ - 0.620, P < 0.001) had a statistically significant effect. CONCLUSION: Oocyte vitrification results in similar clinical pregnancy and perinatal outcomes as does embryo vitrification; hence, it is a relatively safe assisted reproductive technique.

CO Intermediate-Assisted Dynamic Cu Sintering During Electrocatalytic CO2 Reduction on Cu-N-C Catalysts.

The electrochemical CO2 reduction reaction (eCO2RR) to multicarbon products has been widely recognized for Cu-based catalysts. However, the structural changes in Cu-based catalysts during the eCO2RR pose challenges to achieving an in-depth understanding of the structure-activity relationship, thereby limiting catalyst development. Herein, we employ constant-potential density functional theory calculations to investigate the sintering process of Cu single atoms of Cu-N-C single-atom catalysts into clusters under eCO2RR conditions. Systematic constant-potential ab initio molecular dynamics simulations revealed that the leaching of Cu-(CO)x moieties and subsequent agglomeration into clusters can be facilitated by synergistic adsorption of H and eCO2RR intermediates (e.g., CO). Increasing the Cu2+ concentration or the applied potential can efficiently suppress Cu sintering. Both microkinetic simulations and experimental results further confirm that sintered Cu clusters play a crucial role in generating C2 products. These findings provide significant insights into the dynamic evolution of Cu-based catalysts and the origin of their activity toward C2 products during the eCO2RR.

Emerging Electrocatalysts in Urea Production.

Urea synthesis from abundant CO2 and N-feedstocks via renewable electricity has attracted increasing interests, offering a promising alternative to the industrial-applied Haber-Meiser process. However, the studies toward electrochemical urea production remain scarce and appeal for more research. Herein, in this perspective, an up-to-date overview on the urea electrosynthesis is highlighted and summarized. Firstly, the reaction pathways of urea formation through various feedstocks are comprehensively discussed. Then, we focus on the strategies of materials design to improve C-N coupling efficiency by identifying the descriptor and understanding the reaction mechanism. Finally, the current challenges and disadvantages in this field are reviewed and some future development directions of electrocatalytic urea synthesis are also prospected. This Minireview aims to promote future investigations of the electrochemical urea synthesis.

Theoretical Study on B-doped FeN4 Catalyst for Potential-Dependent Oxygen Reduction Reaction.

Electrochemical reactions mostly take place at a constant potential, but traditional DFT calculations operate at a neutral charge state. In order to really model experimental conditions, we developed a fixed-potential simulation framework via the iterated optimization and self-consistence of the required Fermi level. The B-doped graphene-based FeN4 sites for oxygen reduction reaction were chosen as the model to evaluate the accuracy of the fixed-potential simulation. The results demonstrate that *OH hydrogenation gets facile while O2 adsorption or hydrogenation becomes thermodynamically unfavorable due to the lower d-band center of Fe atoms in the constant potential state than the neutral charge state. The onset potential of ORR over B-doped FeN4 by performing potential-dependent simulations agree well with experimental findings. This work indicates that the fixed-potential simulation can provide a reasonable and accurate description on electrochemical reactions.

Shear stress regulates the SNAP23-mediated endothelial secretion of VWF through the GPR68/PKA/vimentin mechanotransduction pathway.

Von Willebrand Factor (VWF) can promote platelet adhesion to the post-atherosclerotic regions to initiate thrombosis. The synthesis and secretion of VWF are important functions of endothelial cells (ECs). However, the mechanism through which blood flow regulates endothelial secretion of VWF remains unclear. We utilized a parallel-plate flow apparatus to apply fluid shear stress to human umbilical vein endothelial cells (HUVECs). Compared with pulsatile shear stress that mimics laminar flow in the straight parts of arteries or upstream of atherosclerotic stenosis sites, short-term exposure to oscillatory shear stress (OS) that mimics disturbed flow increased VWF secretion independent of affecting synaptosomal-associated protein 23 (SNAP23) expression and promoted the translocation of SNAP23 to the cell membrane. Vimentin associated with SNAP23, and this association was enhanced by OS or histamine. Acrylamide, a reagent that disrupts vimentin intermediate filaments, prevented histamine/OS-induced SNAP23 translocation, as well as VWF secretion. Immunofluorescence analysis revealed that the polarity of the vimentin intermediate filament network decreased after stimulation with histamine or OS. In addition, inhibition of protein kinase A (PKA) or G protein coupled receptor 68 (GPR68) eliminated the histamine/OS-induced phosphorylation of vimentin at Ser38 and secretion of VWF. Furthermore, syntaxin 7 might assist with the translocation of SNAP23 to the cell membrane, thus playing a role in promoting VWF secretion. The GPR68/PKA/vimentin signaling pathway may represent a novel mechanism for the regulation of SNAP23-mediated VWF secretion by ECs under OS and provide strategies for the prevention of atherosclerosis-related thrombosis.

[The detection and evaluation of vascular stiffness].

Cardiovascular homeostasis is regulated by both physical and chemical factors. Vascular stiffness, a physical property of vessel, is crucial in maintaining the physiological function of vasculature. Vascular stiffness has been indicated to be correlated with hypertension, heart failure and other cardiovascular diseases. It has been the most widely accepted clinical index for assessment of vascular function and dysfunction. This paper reviews the commonly used experimental and clinical techniques for evaluating vascular stiffness including direct detection of the Young's modulus and indirect detection method that is based on ultrasound technique and others. Principles of these methodologies, as well as their advantages and disadvantages, are also presented here. Researchers and clinical staff are encouraged to choose the most suitable methods for detecting vascular stiffness according to their purposes and objects, so as to effectively evaluate vascular function.

Graphitic Carbon Nitride Stabilized Water-in-Water Emulsions.

Aqueous multiphase systems have attracted a lot of interest recently espeically due to target applications in the biomedical field, cosmetics, and food. In turn, water-in-water Pickering emulsions are investigated frequently. In here, graphitic carbon nitride (g-CN) stabilized water-in-water Pickering emulsions are fabricated via the dextran and poly(ethylene glycol)-based aqueous two-phase system. Five different derivatives of g-CN as the Pickering stabilizer are described and the effect of g-CN concentration on droplet sizes is investigated. Stable emulsions (up to 16 weeks) are obtained that can be broken on purpose via various approaches, including dilution, surfactant addition, and most notably light irradiation. The novel approach of water-in-water emulsion stabilization via g-CN opens up considerable advances in aqueous multiphase systems and may also introduce photocatalytic properties.

Cascade Kinetics in an Enzyme-Loaded Aqueous Two-Phase System.

Macromolecular crowding plays a critical role in the kinetics of enzymatic reactions. Dynamic compartmentalization of biological components in living cells due to liquid-liquid phase separation represents an important cell regulatory mechanism that can increase enzyme concentration locally and influence the diffusion of substrates. In the present study, we probed partitioning of two enzymes (horseradish-peroxidase and urate-oxidase) in a poly(ethylene glycol)-dextran aqueous two-phase system (ATPS) as a function of salt concentration and ion position in the Hofmeister series. Moreover, we investigated enzymatic cascade reactions and their kinetics within the ATPS, which revealed a strong influence of the ion hydration stemming from the background electrolyte on the partitioning coefficients of proteins following the Hofmeister series. As a result, we were able to realize cross-partitioning of two enzymes because of different protein net charges at a chosen pH. Our study reveals a strong dependency of the enzyme activity on the substrate type and crowding agent interaction on the final kinetics of enzymatic reactions in the ATPS and therefore provides substantial implications en route toward dynamic regulation of reactivity in synthetic protocells.

Supramolecular Compartmentalized Hydrogels via Polydopamine Particle-Stabilized Water-in-Water Emulsions.

Compartmentalized hydrogels constitute a significant research area, for example, for catalytic and biomedical applications. As presented here, a generic method is used for compartmentalization of supramolecular hydrogels by using water-in-water emulsions based on aqueous two-phase systems. By forming the supramolecular hydrogel throughout the continuous phase of all-aqueous emulsions, distinct, microcompartmentalized materials were created. The basis for the presented compartmentalized water-in-water hydrogels is polydopamine particle-stabilized water-in-water emulsions from dextran and poly(ethylene glycol) (PEG). Addition of α-cyclodextrin (α-CD) led to supramolecular complexation with PEG and subsequent hydrogel formation showing no signs of creaming. Due to the supramolecular nature of the compartmentalized hydrogels, selective network cleavage could be induced via competing guest addition, while keeping the emulsion substructure intact.

Water-in-Water Pickering Emulsion Stabilized by Polydopamine Particles and Cross-Linking.

All aqueous multiphase systems have attracted significant attention recently, in particular water-in-water Pickering emulsions. In here, polydopamine nanoparticles (PDP) are investigated as stabilizers for dextran and poly(ethylene glycol) (PEG)-based aqueous emulsions. Remarkably, stable emulsions are obtained from the all-biocompatible materials that can be broken either via dilution or surfactant addition. Further cross-linking of PDP via poly(acrylic acid) and carbodiimide strengthens the stability of emulsion droplets in a colloidosome-like structure. After cross-linking, demulsification via dilution or surfactant addition was largely hindered. The PDP-mediated formation of all aqueous emulsions is expected to be generalized to different types of water-in-water emulsions with other polymers and offers new opportunities in surface modification as well as microencapsulation.

Facile Fabrication of Cyclodextrin-Modified Magnetic Particles for Effective Demulsification from Various Types of Emulsions.

Effective oil-water phase separation from various emulsions, especially those stabilized by surfactant, is of great importance. Although superhydrophobic and superoleophilic materials have attracted considerable attention in recent years, they are incapable of directly separating all types of oil-water mixtures. To separate various types of emulsions, one of the most important features of particles is that they can be dispersed in the continuous phase for delivery and target dispersed phases. In this study, cyclodextrin-modified magnetic composite particles (M-CDs) have been fabricated for this goal, based on their special interfacial activity and response to an external magnetic field. Though M-CDs are hydrophilic, the intelligent M-CDs can switch from hydrophilicity to hydrophobicity spontaneously, due to the formation of CD-oil inclusion complexes (ICs) at the oil-water interface. Physicochemical characterization reveals that M-CDs can adsorb at the oil-water interface and locate at the droplet surface as an effective Pickering emulsifier. By applying an external magnetic field, M-CDs are removed from the droplet surface and a rapid oil-water phase separation occurs. Our M-CDs can demulsify, for the first time, surfactant-free or surfactant-stabilized oil-in-water (O/W) and water-in-oil (W/O) emulsions directly, with high separation efficiency. Furthermore, the recycled MNPs still show high demulsification efficiency. In view of the sustainability of cyclodextrin and effective recycling ability of MNPs, M-CDs provides a new opportunity to develop an environmentally friendly interfacial material for practical applications in wastewater treatment.

Antidepressant-like effects of the phosphodiesterase-4 inhibitor etazolate and phosphodiesterase-5 inhibitor sildenafil via cyclic AMP or cyclic GMP signaling in mice.

Inhibition of phosphodiesterase-4 or 5 (PDE4 or PDE5) increases cyclic adenosine monophosphate (cAMP)- or cyclic guanosine monophosphate (cGMP), respectively, which activates cAMP response element-binding protein (CREB)/brain-derived neurotrophic factor (BDNF)/neuropeptide VGF (non-acryonimic) signaling and produces antidepressant-like effects on behavior. However, causal links among these actions have not been established. In the present study, mice were evaluated for the effects of etazolate and sildenafil, the inhibitor of PDE4 or PDE5, respectively, on depressive-like behavior induced by chronic unpredictable mild stress (CUMS) in the forced-swimming test (FST) and tail suspension test (TST), in the presence or absence of the inhibitor of protein kinase A (PKA) or protein kinase G (PKG) via intracerebroventricular (i.c.v.) infusions. The levels of cAMP, cGMP and expression of pCREB, CREB, BDNF and VGF in both the hippocampus and prefrontal cortex were determined. The results showed that etazolate at 5.0 mg/kg or sildenafil at 30 mg/kg significantly reversed CUMS-induced depressive-like behavior; the effects were paralleled with the increased levels of cAMP/pCREB/BDNF/VGF or cGMP/pCREB/BDNF/VGF signaling, respectively. These effects were completely abolished following inhibition of PKA or PKG, respectively. The results suggest that inhibition of PDE4 by etazolate or PDE5 by sildenafil produced antidepressant-like effects in CUMS-treated animals via cAMP or cGMP signaling, which shares the common downstream signal pathway of CREB/BDNF/VGF.

Flexible iontronics with super stretchability, toughness and enhanced conductivity based on collaborative design of high-entropy topology and multivalent ion-dipole interactions.

All-solid-state ionic conductive elastomers (ASSICEs) are emerging as a promising alternative to hydrogels and ionogels in flexible electronics. Nevertheless, the synthesis of ASSICEs with concomitant mechanical robustness, superior ionic conductivity, and cost-effective recyclability poses a formidable challenge, primarily attributed to the inherent contradiction between mechanical strength and ionic conductivity. Herein, we present a collaborative design of high-entropy topological network and multivalent ion-dipole interaction for ASSICEs, and successfully mitigate the contradiction between mechanical robustness and ionic conductivity. Benefiting from the synergistic effect of this design, the coordination, de-coordination, and intrachain transfer of Li+ are effectively boomed. The resultant ASSICEs display exceptional mechanical robustness (breaking strength: 7.45 MPa, fracture elongation: 2621%, toughness: 107.19 MJ m-3) and impressive ionic conductivity (1.15 × 10-2 S m-1 at 25 °C). Furthermore, these ASSICEs exhibit excellent environmental stability (fracture elongation exceeding 1400% at 50 °C or -60 °C) and recyclability. Significantly, the application of these ASSICEs in a strain sensor highlights their potential in various fields, including human-interface communication, aerospace vacuum measurement, and medical balloon monitoring.

Exploring the factors influencing the intention to clothing and textiles recycling among Chinese college students': a study based on TPB and VBN.

Recycling apparel and fabrics is essential for preserving resources and protecting the environment, providing considerable global advantages for ecology and society. This study sought to explore the participation of Chinese college students in the recycling of clothing and fabrics by combining the Theory of Planned Behavior (TPB), the Value-Belief-Norm theory (VBN), self-identity, school education, and perceived policy effectiveness to create a comprehensive model. A total of 1,027 valid samples were obtained through stratified sampling and random sampling, primarily sourced from Eastern China, and analyzed through Structural Equation Modeling (SEM) utilizing AMOS. The results of the research suggested the following: (1) College students' biospheric values emerged as the most influential factor in predicting their inclination to participate in recycling behavior. (2) VBN (encompassing biospheric and altruistic values) and self-identity significantly contributed to shaping attitude and perceived behavioral control, which in turn impacted individuals' intention to participate in recycling. (3) School education exerted a stronger moderating influence than perceived policy effectiveness on the relationship between attitude, perceived behavioral control, and intention. The comprehensive model proposed in this study demonstrated superior predictive capability in explaining college students' willingness to participate in clothing and textiles recycling. It has been proven to be practical and effective. Lastly, schools should promote the practice of clothing and textiles recycling, cultivate good values, and utilize the power of social influence to encourage college students to participate in clothing and textiles recycling. The government should improve relevant laws and regulations, collaborate with academia, and adopt measures like incentives to create a pro-environment atmosphere.

Analysis of the static and dynamic characteristics of the electro-hydraulic pressure servo valve of robot.

In this study, we comprehensively investigate the structure and operational principles of the Rotary Direct Drive Electro-Hydraulic Pressure Servo Valve (RDDPV). Our objective is to establish the dynamics equations governing the motor, slide valve, and bias mechanism of the valve. Additionally, we construct a mathematical model for the servo valve controller, while ensuring the linearization of the controller model. Furthermore, we conduct an in-depth analysis of the static characteristics of the valve, including linearity, dead zone, hysteresis loop, and zero drift. Regarding the dynamic characteristics, we establish a dynamic mathematical model for the RDDPV valve. Subsequently, we subject the servo valve to analysis with a focus on frequency response and dynamic response, using the control current as the input and the pressure as the output. To perform these analyses, we employ the software package SIMULINK of MATLAB, facilitating dynamic simulations. Remarkably, the simulation results exhibit the valve's conformity to design requirements, underscoring its suitability for subsequent research and development endeavors. Through our rigorous investigation, we offer essential technical support for the forthcoming stages of the valve's research and development, thereby laying a robust foundation for its further advancement.

Effects of chromosomal translocation characteristics on fertilization and blastocyst development - a retrospective cohort study.

OBJECTIVE: To determine the effect of different translocation characteristics on fertilization rate and blastocyst development in chromosomal translocation patients. METHODS: This retrospective cohort study was conducted at the Third Affiliated Hospital of Zhengzhou University From January 2017 to December 2022.All couples were diagnosed as reciprocal translocation or Robertsonian translocation by karyotype of peripheral blood lymphocytes test. After adjusting for confounding factors, the effect of chromosomal rearrangement characteristics, such as carrier sex, translocation type, chromosome length and break sites, on fertilization rate and embryo development were analysed separately using multiple linear regression. RESULTS: In cases of Robertsonian translocation (RobT), the carrier sex plays an independent role in fertilization rate, and the male carriers was lower than that of female carriers (76.16% vs.86.26%, P = 0.009). In reciprocal translocation (RecT), the carrier sex, chromosome types and break sites had no influence on fertilization rate, blastocyst formation rate (P > 0.05). However, patients with human longer chromosomal (chromosomes 1-5) translocation have a lower available blastocyst formation rate (Group AB vs. Group CD: 41.49%vs.46.01%, P = 0.027). For male carriers, the translocation types was an independent factor affecting the fertilization rate, and the RobT was the negative one (B = - 0.075, P = 0 0.009). In female carriers, we did not observe this difference (P = 0.227). CONCLUSIONS: In patients with chromosomal translocation, the fertilization rate may be influenced by carrier sex and translocation type, chromosomes 1-5 translocation may adversely affect the formation of available blastocysts. Break sites have no role in fertilization and blastocyst development.

Echinatin maintains glutathione homeostasis in vascular smooth muscle cells to protect against matrix remodeling and arterial stiffening.

Decreased vascular compliance of the large arteries as indicated by increased pulse wave velocity is shown to be associated with atherosclerosis and the related cardiovascular events. The positive correlation between arterial stiffening and disease progression derives a hypothesis that softening the arterial wall may protect against atherosclerosis, despite that the mechanisms controlling the cellular pathological changes in disease progression remain unknown. Here, we established a mechanical-property-based screening to look for compounds alleviating the arterial wall stiffness through their actions on the interaction between vascular smooth muscle cells (VSMCs) and the wall extracellular matrix (ECM). We found that echinatin, a chalcone preferentially accumulated in roots and rhizomes of licorice (Glycyrrhiza inflata), reduced the stiffness of ECM surrounding cultured VSMCs. We examined the potential beneficial effects of echinatin on mitigating arterial stiffening and atherosclerosis, and explored the mechanistic basis by which the compound exert the effects. Administration of echinatin in mice fed on an adenine diet and in hyperlipidemia mice subjected to 5/6 nephrectomy mitigated arterial stiffening and atherosclerosis. Mechanistic insights were gained from the RNA-sequencing results showing that echinatin upregulated the expression of glutamate cysteine ligases (GCLs), both the catalytic (GCLC) and modulatory (GCLM) subunits. Further study indicated that upregulation of GCLC/GCLM in VSMCs by echinatin maintains the homeostasis of glutathione (GSH) metabolism; adequate availability of GSH is critical for counteracting arterial stiffening. As a consequence of regulating the GSH synthesis, echinatin inhibits ferroptosis and matrix remodeling that being considered two contributors of arterial stiffening and atherosclerosis. These data demonstrate a pivotal role of GSH dysregulation in damaging the proper VSMC-ECM interaction and uncover a beneficial activity of echinatin in preventing vascular diseases.