Mesenchymal stem cells-derived extracellular vesicles protect against oxidative stress-induced xenogeneic biological root injury via adaptive regulation of the PI3K/Akt/NRF2 pathway.

Xenogeneic extracellular matrices (xECM) for cell support have emerged as a potential strategy for addressing the scarcity of donor matrices for allotransplantation. However, the poor survival rate or failure of xECM-based organ transplantation is due to the negative impacts of high-level oxidative stress and inflammation on seed cell viability and stemness. Herein, we constructed xenogeneic bioengineered tooth roots (bio-roots) and used extracellular vesicles from human adipose-derived mesenchymal stem cells (hASC-EVs) to shield bio-roots from oxidative damage. Pretreatment with hASC-EVs reduced cell apoptosis, reactive oxygen species generation, mitochondrial changes, and DNA damage. Furthermore, hASC-EV treatment improved cell proliferation, antioxidant capacity, and odontogenic and osteogenic differentiation, while significantly suppressing oxidative damage by activating the phosphatidylinositol 3-kinase (PI3K)/Akt pathway and nuclear factor erythroid 2 (NFE2)-related factor 2 (NRF2) nuclear translocation via p62-associated Kelch-like ECH-associated protein 1 (KEAP1) degradation. Inhibition of PI3K/Akt and Nrf2 knockdown reduced antioxidant capacity, indicating that the PI3K/Akt/NRF2 pathway partly mediates these effects. In subcutaneous grafting experiments using Sprague-Dawley rats, hASC-EV administration significantly enhanced the antioxidant effect of the bio-root, improved the regeneration efficiency of periodontal ligament-like tissue, and maximized xenograft function. Conclusively, therefore, hASC-EVs have the potential to be used as an immune modulator and antioxidant for treating oxidative stress-induced bio-root resorption and degradation, which may be utilized for the generation and restoration of other intricate tissues and organs.

Family function, anxiety and depression in adults with disabilities: a network analysis.

Background: The prevalence of family dysfunction, anxiety and depression is high in people with disabilities due to long-term activity constraints and social difficulties. Recently, although studies have attempted to provide guidance for family therapy by focusing on the relationship between family function and negative emotions, the specific effects of improved family function during family therapy on alleviation of anxiety and depressive symptoms have been obscured. Thus, this study attempted to elucidate the impact of specific family functioning on specific symptoms of anxiety and depression through network analysis. Methods: Family APGAR Index Questionnaire (APGAR), Generalized Anxiety Scale (GAD-7), and Patient Health Questionnaire Depression Scale (PHQ-9) were used to survey 897 adults with disabilities in Sichuan Province. Meanwhile, network analysis for studying the relationship between anxiety, depression and family functioning among the disabled via R software. Results: The network analysis showed that (1) Nodes PHQ4 ("Energy"), APGAR3 ("Growth"), GAD1 ("Nervousness") and GAD4 ("Relaxing Trouble") were central nodes in the network model; (2) Bridge nodes linking family function, anxiety and depressive symptoms in the sample were PHQ9 ("Suicide ideation"), PHQ6 ("Worthlessness"), GAD1 ("Nervousness") and GAD5 ("Restlessness"); (3) The node APGAR5 ("Resolve") directly connects the bridge symptoms PHQ9 ("Suicide ideation") and PHQ8 ("Motor"). Conclusion: This study suggests that therapists could target the resolve of family members during family therapy to reduce suicidal ideation and enhance the level of activity of people with disabilities, thereby improving the network of anxiety and depression symptoms and alleviating negative emotions of people with disabilities.

Risk Perception and Public Pandemic Fatigue: The Role of Perceived Stress and Preventive Coping.

Purpose: This study explores the status of pandemic fatigue, predictors, and their mechanisms of action based on a stress-response framework and a parallel model of future-oriented response. Patients and methods: Study 1 investigated 8426 Chinese adult residents' understanding of and willingness to cooperate with the pandemic prevention and control policies and Study 2 surveyed 1635 Chinese residents on their activeness of pandemic prevention and control (APPC), pandemic risk perception, perceived stress, and future-oriented coping. Results: Study 1 found that public understanding of and willingness to cooperate with prevention policies were significantly lower in 2022 than in 2020 and 2021. Study 2 found that risk perception negatively predicted the APPC; perceived stress and preventive coping significantly mediated the relationship between risk perception and APPC; but perceived stress and proactive coping did not significantly mediate the relationship between risk perception and APPC. Conclusion: This revealed an increase in public fatigue in the third year of the pandemic. Pandemic fatigue can be predicted by pandemic risk perception, but the direct pathway of action is not significant and requires the mediation of perceived stress and preventive coping.

Inhibition of Wnt Signaling in Colon Cancer Cells via an Oral Drug that Facilitates TNIK Degradation.

We have synthesized an oxetane derivative of the benzimidazole compound mebendazole (OBD9) with enhanced solubility and strong anticancer activity in multiple types of cancer cells, especially colorectal cancer. In this report, we provide evidence that OBD9 suppresses colorectal cancer growth by interfering with the Wnt signaling pathway, a main driver of cell growth in colorectal cancer. Specifically, we find that OBD9 induces autophagic degradation of TNIK (traf2 and Nck-interacting kinase), which promotes T-cell factor-4 (TCF4)/beta-catenin-mediated gene expression. Thus, OBD9 as a TNIK inhibitor blocks Wnt/beta-catenin signaling at the final step of transcriptional activation. We suggest that OBD9 provides a potential novel autophagy-mediated, Wnt-damping therapeutic strategy for the treatment of colorectal cancer.

Performance of oxalate-doped hydroxyapatite as well as relative contribution of oxalate and phosphate for aqueous lead removal.

An oxalate-doped hydroxyapatite (O-HAP) was hydrothermally synthesized for aqueous lead (Pb) removal based on the solubility-limiting ability of oxalate and phosphate over pH range 4-9. Free Pb2+ activities in oxalate and/or phosphate systems were controlled by oxalate to form soluble ion pairs Pb-Ox (aq) and Pb-Ox22- at pH 4-7 while in preference to persist as PbHPO4 (aq) when pH ≥ 8. Both phosphate and oxalate exhibited excellent efficiency in reducing Pb solubility, causing over 99 % of Pb precipitated from solution following oxalate < oxalate-phosphate < phosphate. The Visual MINTEQ model overestimated dissolved Pb and free Pb2+ in nearly all of the reaction systems due to the ill-defined stability constants and solubility products for Pb ion-pair formation. The addition of phosphate acting as a buffer in Pb-oxalate systems tended to lessen the spontaneous pH shifts within 24 h to equilibrate proton release from Pb precipitation and hydrolysis, indicating lower solubility products and faster kinetics of Pb-phosphate mineral formation. The TEM-EDS, FTIR and XRD identified a block-shaped Pb-oxalate mineral phase as the only precipitate at acidic pH while substituted by phosphate to form rod-shaped Pb5(PO4)3OH and Pb3(PO4)2 precipitates as pH increased. The optimum hydrothermal conditions of O-HAP were 433 K, pH 9 and P/Ox doping ratio of 0.5 for 24 h. Batch experiments revealed the endothermic process of O-HAP toward Pb with the maximum adsorption capacity reaching 2333 mg/g at a pH of 7, reaction time of 12 h, initial Pb concentration of 600 mg/L and temperature of 308 K, which were best fitted with the pseudo-second-order kinetic model and Langmuir isotherm. The synergetic mechanisms of O-HAP for Pb removal involved dissolution-precipitation, adsorption and ion exchange. This study provides an insight in developing effective remediation strategies for heavy metal contamination by interacting between low-molecular-weight organic acids and secondary mineral phases.

Effect of social support on anxiety of medical staff one year after COVID-19 outbreak: a moderated mediating model.

One year after the outbreak of COVID-19, medical staff are facing high anxiety due to multiple work stresses. Social support has become a protective factor for healthcare workers' anxiety symptoms, but the exact mechanism of action is not yet known. Based on the buffering model, this study aims to explore the impact and mechanisms of action of healthcare workers' perception of social support (PSS) on anxiety symptoms in the context of the epidemic and to further explore how the emotional characteristics of risk perception (ECRP) and resilience play their influence. To this end, this study measured 839 healthcare workers using an online questionnaire from 4 February to 1 March 2021. The results found that PSS among healthcare workers negatively predicted anxiety symptoms. ECRP partially mediated the relationship between PSS and anxiety symptoms, and resilience moderated the first half of the pathway in the model of PSS through ECRP on anxiety symptoms. The emotional characteristics of risk perception of COVID-19 in individuals with high resilience decrease significantly with the increase of PSS, while this change is not significant in individuals with low resilience.

Thrombospondin 1 missense alleles induce extracellular matrix protein aggregation and TM dysfunction in congenital glaucoma.

Glaucoma is a highly heritable disease that is a leading cause of blindness worldwide. Here, we identified heterozygous thrombospondin 1 (THBS1) missense alleles altering p.Arg1034, a highly evolutionarily conserved amino acid, in 3 unrelated and ethnically diverse families affected by congenital glaucoma, a severe form of glaucoma affecting children. Thbs1R1034C-mutant mice had elevated intraocular pressure (IOP), reduced ocular fluid outflow, and retinal ganglion cell loss. Histology revealed an abundant, abnormal extracellular accumulation of THBS1 with abnormal morphology of juxtacanalicular trabecular meshwork (TM), an ocular tissue critical for aqueous fluid outflow. Functional characterization showed that the THBS1 missense alleles found in affected individuals destabilized the THBS1 C-terminus, causing protein misfolding and extracellular aggregation. Analysis using a range of amino acid substitutions at position R1034 showed that the extent of aggregation was correlated with the change in protein-folding free energy caused by variations in amino acid structure. Extracellular matrix (ECM) proteins, especially fibronectin, which bind to THBS1, also accumulated within THBS1 deposits. These results show that missense variants altering THBS1 p.Arg1034 can cause elevated IOP through a mechanism involving impaired TM fluid outflow in association with accumulation of aggregated THBS1 in the ECM of juxtacanalicular meshwork with altered morphology.

COVID-19 vaccine hesitancy and GAD: The role of risk perception and vaccination status.

Background and purpose: As Coronavirus disease (COVID-19) continues to spread around the world, COVID-19 vaccines are the most effective weapons against the global pandemic. Yet vaccine hesitancy remains a serious problem and can pose certain hazards to individuals' mental health, such as rising anxiety. Therefore, based on Self-Discrepancy Theory, this paper aims to explore the role of COVID-19 vaccine hesitancy on individual generalized anxiety disorder and its influence mechanisms through two studies. Methods: Study one involved 654 Chinese participants using the Vaccine Hesitancy Questionnaire and the Generalized Anxiety Disorder 7-item (GAD-7) scale. In Study two, the Vaccine Hesitation Questionnaire, GAD-7 scale, Perceived Risk of COVID-19 pandemic scale, and Vaccination Status Questionnaire were used and data from 3,282 Chinese residents was collected. Results: Vaccine hesitancy directly increases generalized anxiety disorder; risk perception plays a partial mediating role between vaccine hesitancy and generalized anxiety disorder; vaccination status moderated vaccine hesitancy's effect on risk perception and generalized anxiety disorder. Conclusion: Vaccine hesitancy predicts generalized anxiety disorder through risk perception, but the mediating role of risk perception is moderated by vaccination status, which means that for the vaccinated group when their vaccine hesitancy is reduced, it will be easier to reduce the risk perception and thus the generalized anxiety disorder.

α-Hemihydrate calcium sulfate/n-hydroxyapatite combined with metformin promotes osteogenesis in vitro and in vivo.

This study aimed to examine the effects of loading different concentrations of metformin onto an α-hemihydrate calcium sulfate/nano-hydroxyapatite (α-CSH/nHA) composite. The material characteristics, biocompatibility, and bone formation were compared as functions of the metformin concentration. X-ray diffraction results indicated that the metformin loading had little influence on the phase composition of the composite. The hemolytic potential of the composite was found to be low, and a CCK-8 assay revealed only weak cytotoxicity. However, the metformin-loaded composite was found to enhance the osteogenic ability of MC3T3-E1 cells, as revealed by alkaline phosphate and alizarin red staining, real-time PCR, and western blotting, and the optimal amount was 500 µM. RNA sequencing results also showed that the composite material increased the expression of osteogenic-related genes. Cranial bone lacks muscle tissue, and the low blood supply leads to poor bone regeneration. As most mammalian cranial and maxillofacial bones are membranous and of similar embryonic origin, the rat cranial defect model has become an ideal animal model for in vivo experiments in bone tissue engineering. Thus, we introduced a rat cranial defect with a diameter of 5 mm as an experimental defect model. Micro-computed tomography, hematoxylin and eosin staining, Masson staining, and immunohistochemical staining were used to determine the effectiveness of the composite as a scaffold in a rat skull defect model. The composite material loaded with 500 µM of metformin had the strongest osteoinduction ability under these conditions. These results are promising for the development of new methods for repairing craniofacial bone defects.

The Effect of Risk Perception on Anxiety in Emerging Adulthood Under the Local Outbreak of COVID-19: A Conditional Process Analysis.

This study aims to explore the influence mechanism of COVID-19 risk perception on anxiety in emerging adulthood in the context of public health events of the second round of COVID-19 outbreaks and provide support for exploring the path of mental health after the normalization of the epidemic situation. An online questionnaire, combined with community social work, was used in this study, and data of 522 emerging adults were collected in February 2021. The Perceived Risk of COVID-19 pandemic scale (PRCPS), the generalized anxiety disorder 7-item (GAD-7) scale, the scale of affect balance, and the connor-davidson resilience scale (CD-RISC) were used to investigate. The results showed that: first, the risk perception of COVID-19 in early adulthood was positively predictive of anxiety symptoms [B = 0.110, p < 0.05, 95%CI = (0.042, 0.176)]. Second, the affective quality of life plays a mediating role between the risk perception of COVID-19 and anxiety [B = 0.108, 95%CI = (0.060, 0.161)]. Thirdly, resilience plays a moderating role between the risk perception of COVID-19 and anxiety, the higher the resilience of emerging adulthood, the weaker effects of the risk perception of COVID-19 negative prediction of anxiety [B = -0.110, p < 0.001, 95%CI = (-0.170, -0.049)]. Therefore, to control the anxiety of emerging adulthood in public health events, we should pay attention to the propaganda and management of epidemic information, improve the quality of life, and attention should be paid to the emerging adulthood with low resilience.

Social support and well-being of adolescents in worst-stricken areas 10 years after Wenchuan Earthquake: A mediating role of resilience.

The purpose of this current study is to find the characteristics and influence mechanism of the perceived social support (PSS) and general well-being (GWB) of adolescents and to explore the mediating role of resilience on the relationship between PSS and GWB in the worst-stricken areas 10 years after the Wenchuan Earthquake. This study was conducted in two secondary schools in Beichuan (N = 1969) using the Perceived Social Support Scale, the Connor-Davidson Resilience Scale, and the General Well-Being Scale. Results showed that PSS of adolescents in the worst-stricken area significantly decreased compared to 10 years ago and their current PSS was lower than their peers' in developed cities. Significant correlations were observed between PSS, resilience, and GWB. PSS significantly predicted resilience and GWB, and resilience significantly predicted GWB with resilience having a partially mediating effect ratio of 16.39% between PSS and GWB. These results indicated that PSS not only directly affected GWB but also had a mediated effect on GWB through resilience. The present results suggest that interventions to strengthen resilience and social networks could be effective ways to enhance adolescents' general well-being.

Relationship between Depression and Cognitive Inhibition in Men with Heroin or Methamphetamine Use Disorder in First-Time Mandatory Detoxification.

Previous studies have shown that males with substance use disorder (SUD) in their first mandatory detoxification experience high rates of depression. It is unknown whether this high depression incidence contributes to impaired inhibition. In this work, two studies were undertaken to examine the role of depression in cognitive inhibition in heroin and methamphetamine withdrawal. We used the Beck Depression Inventory (BDI) and the self-control scale (SCS) to explore the relationship between depression and impulse inhibition in patients participating in mandatory drug treatment for the first time (Study 1). The results showed that depression negatively predicted impulse inhibition. The Stroop color-word interference task was used to explore the role of patients' depression in their inhibitory abilities (Study 2). The results showed that the high-depression group had weaker inhibition performances in the Stroop color-word interference task compared to the low-depression group. This study shows that cognitive inhibition is weaker in people with high-depression addiction than in those with low depression. This result suggests that attention should be paid to the role of depressive comorbidity when conducting working memory training treatment for substance addiction.

Detection of peripheral blood circulating tumor cells in oral squamous cell carcinoma and its clinical significance.

OBJECTIVES: This study aims to investigate the diagnostic value of peripheral blood circulating tumor cells (CTCs) in oral squamous cell carcinoma (OSCC) and its correlation with the clinicopathological features of OSCC. METHODS: Ninety-three patients diagnosed as OSCC in the First Affiliated Hospital of Zhengzhou University from May 2019 to May 2020 were selected as the experimental group, and 20 healthy volunteers were employed as the control group. The CTCs value of peripheral blood of the patients were measured by CTCs detection technology, and its clinical significance was analyzed. RESULTS: The CTCs values in the experimental group were higher than those in the control group, and the difference was statistically significant (P<0.000 1). The CTCs value in the peripheral blood of patients in the experimental group were not correlated with gender, site of onset, and presence or absence of peripheral tissue infiltration (P>0.05), but was correlated with age (P=0.022), tumor T stage (P=0.02), tumor N stage (P=0.007 5), tumor M stage (P=0.013), clinical stage (P=0.029), early or late stage (P=0.022), tumor differentiation degree (P<0.001), and node metastasis (P=0.006 4). The AUC value of CTCs in OSCC diagnosis was 0.925, and the energy efficiency was statistically significant [P=0.000, 95%CI (0.876, 0.974)]. When the CTC value was 8.450 FU/3 mL, the maximum value of the Yoden index was 0.853, and the sensitivity and specificity of OSCC diagnosis were 90.3% and 95.0%, respectively. The AUC value of CTCs in the diagnosis of OSCC metastasis was 0.691, and the energy efficiency was statistically significant [P=0.000, 95%CI (0.580, 0.803)]. When the blood CTC value was 12.250 FU/3 mL, the maximum value of Yoden index was 0.367, the sensitivity was 63.6%, and the specificity was 73.3%. Multivariate regression analysis showed that buccal tumor was negatively correlated with CTCs in patients with OSCC (P=0.001 08), N2 stage (P=0.000 74) and M stage (P=0.026 38). High differentiation (P<0.000 1) and moderate differentiation (P=0.001 5) were negatively correlated with CTCs values in patients with OSCC. CONCLUSIONS: Peripheral blood CTCs has important clinical value for early screening, auxiliary diagnosis, evaluation of metastasis, and determination of malignant degree, progression, and pathological grade of OSCC and a relatively reliable tumor detection indicator.

Angiogenic responses in a 3D micro-engineered environment of primary endothelial cells and pericytes.

Angiogenesis plays a key role in the pathology of diseases such as cancer, diabetic retinopathy, and age-related macular degeneration. Understanding the driving forces of endothelial cell migration and organization, as well as the time frame of these processes, can elucidate mechanisms of action of important pathological pathways. Herein, we have developed an organ-specific microfluidic platform recapitulating the in vivo angiogenic microenvironment by co-culturing mouse primary brain endothelial cells with brain pericytes in a three-dimensional (3D) collagen scaffold. As a proof of concept, we show that this model can be used for studying the angiogenic process and further comparing the angiogenic properties between two different common inbred mouse strains, C57BL/6J and 129S1/SvlmJ. We further show that the newly discovered angiogenesis-regulating gene Padi2 promotes angiogenesis through Dll4/Notch1 signaling by an on-chip mechanistic study. Analysis of the interplay between primary endothelial cells and pericytes in a 3D microfluidic environment assists in the elucidation of the angiogenic response.

Social Support from Adult Children, Parent-Child Relationship, Emotion Regulation Strategy, and Depressive Symptoms Among Chinese Older Adults.

We examined the association between social support from adult children (SSAC) and depressive symptoms among Chinese older adults, as well as the moderated mediation mechanism with the parent-child relationship as a mediator and with emotion regulation strategies (cognitive reappraisal and expressive suppression) as moderators. With a cross-sectional design, 356 Chinese older adults completed our questionnaire survey. Results revealed the negative association between SSAC and depressive symptoms among Chinese older adults, and the parent-child relationship mediated this association. In addition, the indirect effect of SSAC on depressive symptoms through the parent-child relationship depended on emotion regulation strategies. Specifically, the parent-child relationship mediated the association between SSAC and depressive symptoms only for older adults with less cognitive reappraisal or more expressive suppression. Our study highlighted the complementary role of family and individual factors in ameliorating older adults' depressive symptoms.

A Method for Developing Novel 3D Cornea-on-a-Chip Using Primary Murine Corneal Epithelial and Endothelial Cells.

Microfluidic-based organ-on-a-chip assays with simultaneous coculture of multi-cell types have been widely utilized for basic research and drug development. Here we describe a novel method for a primary cell-based corneal microphysiological system which aims to recapitulate the basic functions of the in vivo cornea and to study topically applied ocular drug permeation. In this study, the protocols for isolating and cultivating primary corneal epithelial cells and endothelial cells from mouse inbred strain C57BL/6J were optimized, to allow for the development of a primary-cell based microfluidic 3D micro-engineered cornea. This tissue unit, by overcoming the limitations of 2D conventional cell culture, supports new investigations on cornea function and facilitates drug delivery testing.

Relationships of orientation discrimination threshold and visual acuity with macular lesions in age-related macular degeneration.

PURPOSE: To measure visual acuity and metamorphopsia in patients with age-related macular degeneration (AMD) and to explore their relationship with macular lesions. METHODS: In this cross-sectional study, a total of 32 normal subjects (32 eyes) and 35 AMD patients (35 eyes) were recruited. They were categorized into 4 groups: normal, dry AMD, non-active wet AMD, and active wet AMD. Best-corrected visual acuity (BCVA) was measured using the Early Treatment Diabetic Retinopathy Study protocol. Metamorphopsia was quantified with the orientation discrimination threshold (ODT). Macular lesions, including drusen, sub-retinal fluid (SRF), intra-retinal fluid (IRF), pigmented epithelium detachment (PED), and scarring, were identified with spectral-domain optical coherence tomography (SD-OCT). A linear regression model was established to identify the relationships between the functional and structural changes. RESULTS: BCVA progressively worsened across the normal, dry AMD, non-active wet AMD, and active wet AMD groups (P < 0.001), and ODT increased across the groups (P < 0.001). The correlation between BCVA and ODT varied among the groups. The partial correlation between BCVA and ODT was -0.61 (P < 0.001). Linear regression showed that ODT significantly depended on IRF (ß = 0.61, P < 0.001), SRF (ß = 0.34, P = 0.003), and scarring (ß = 0.26, P = 0.050), while BCVA significantly depended only on scarring (ß = -0.52, P < 0.001), and IRF (ß = -0.36, P = 0.016). CONCLUSIONS: From dry AMD to active wet AMD, BCVA gradually worsened while ODT increased. The correlation between BCVA and ODT varied among these groups, indicating that AMD lesions affect them differently. ODT and BCVA should be used concurrently for better monitoring of the disease.