Causal Role for Neutrophil Elastase in Thoracic Aortic Dissection in Mice.

BACKGROUND: Thoracic aortic dissection (TAD) is a life-threatening aortic disease without effective medical treatment. Increasing evidence has suggested a role for NE (neutrophil elastase) in vascular diseases. In this study, we aimed at investigating a causal role for NE in TAD and exploring the molecular mechanisms involved. METHODS: ß-aminopropionitrile monofumarate was administrated in mice to induce TAD. NE deficiency mice, pharmacological inhibitor GW311616A, and adeno-associated virus-2-mediated in vivo gene transfer were applied to explore a causal role for NE and associated target gene in TAD formation. Multiple functional assays and biochemical analyses were conducted to unravel the underlying cellular and molecular mechanisms of NE in TAD. RESULTS: NE aortic gene expression and plasma activity was significantly increased during ß-aminopropionitrile monofumarate-induced TAD and in patients with acute TAD. NE deficiency prevents ß-aminopropionitrile monofumarate-induced TAD onset/development, and GW311616A administration ameliorated TAD formation/progression. Decreased levels of neutrophil extracellular traps, inflammatory cells, and MMP (matrix metalloproteinase)-2/9 were observed in NE-deficient mice. TBL1x (F-box-like/WD repeat-containing protein TBL1x) has been identified as a novel substrate and functional downstream target of NE in TAD. Loss-of-function studies revealed that NE mediated inflammatory cell transendothelial migration by modulating TBL1x-LTA4H (leukotriene A4 hydrolase) signaling and that NE regulated smooth muscle cell phenotype modulation under TAD pathological condition by regulating TBL1x-MECP2 (methyl CpG-binding protein 2) signal axis. Further mechanistic studies showed that TBL1x inhibition decreased the binding of TBL1x and HDAC3 (histone deacetylase 3) to MECP2 and LTA4H gene promoters, respectively. Finally, adeno-associated virus-2-mediated Tbl1x gene knockdown in aortic smooth muscle cells confirmed a regulatory role for TBL1x in NE-mediated TAD formation. CONCLUSIONS: We unravel a critical role of NE and its target TBL1x in regulating inflammatory cell migration and smooth muscle cell phenotype modulation in the context of TAD. Our findings suggest that the NE-TBL1x signal axis represents a valuable therapeutic for treating high-risk TAD patients.

Longitudinal Associations Between Sluggish Cognitive Tempo and Academic Achievement in Adolescents: A Mediated Moderation Model.

Sluggish cognitive tempo (SCT) was initially studied in the context of attention deficit hyperactivity disorder (ADHD), but is now recognized as a distinct disorder. Despite the growing recognition of SCT, its impact on academic achievement among adolescents remains controversial, even when controlling for the level of ADHD. This may be due to the influence of other factors such as learning engagement and emotional distress. To address this gap, we conducted a longitudinal study with a sample of 782 Chinese senior high school students, measuring their SCT, learning engagement, and emotional distress at Grade 10 (Time1, T1) to predict their academic achievement evaluated based on final exams scores five months later (Time2, T2). Results showed that learning engagement mediated the negative relationship between SCT and later academic achievement. Additionally, individuals with high SCT showed less impact by emotional distress on learning engagement. These findings may shed light on the complex interplay between SCT, emotional distress and learning engagement in shaping academic achievement, underscoring the potential adaptive function of SCT as a coping strategy for managing emotional challenges.

Construction of a reading literacy test item bank for fourth graders based on item response theory.

Introduction: Reading literacy is not only central to students' academic success during their school years but also crucial to their personal development in their later life. The development of assessment instruments for reading literacy has been of interest to researchers, educators and educational administrators. The purpose of the present study was to construct and validate a comparable item bank for assessing fourth-grade students' reading literacy. Methods: One hundred fifteen reading comprehension items were developed and administered to 2,174 Grade 4 students to construct an item bank. Using the test equating technique and balanced incomplete block design, we divided participants into 10 subgroups, and the 115 items were further assigned into 10 test forms. Item response theory software was used to estimate discrimination, items' threshold parameters, and students' ability parameters. The criterion-related validity was also examined in 135 Grade 4 students who completed the reading literacy test and verbal self-description questionnaire. Results: The final item bank included 99 reading performance indicators to express high achievement. The correlation between the students' reading literacy and the verbal self-description questionnaire was significant and demonstrated the item bank's good criterion-related validity. The item bank developed in this study shows good psychometric characteristics and can be used to assess the reading literacy of fourth graders.

Global determination of reaction rates and lipid turnover kinetics in Mus musculus.

Metabolism is fundamental to life, but measuring metabolic reaction rates remains challenging. Here, we applied C13 fluxomics to monitor the metabolism of dietary glucose carbon in 12 tissues, 9 brain compartments, and over 1,000 metabolite isotopologues over a 4-day period. The rates of 85 reactions surrounding central carbon metabolism are determined with elementary metabolite unit (EMU) modeling. Lactate oxidation, not glycolysis, occurs at a comparable pace with the tricarboxylic acid cycle (TCA), supporting lactate as the primary fuel. We expand the EMU framework to track and quantify metabolite flows across tissues. Specifically, multi-organ EMU simulation of uridine metabolism shows that tissue-blood exchange, not synthesis, controls nucleotide homeostasis. In contrast, isotopologue fingerprinting and kinetic analyses reveal the brown adipose tissue (BAT) having the highest palmitate synthesis activity but no apparent contribution to circulation, suggesting a tissue-autonomous synthesis-to-burn mechanism. Together, this study demonstrates the utility of dietary fluxomics for kinetic mapping in vivo and provides a rich resource for elucidating inter-organ metabolic cross talk.

How COVID-19 Perceived Risk Causes Turnover Intention Among Chinese Flight Attendants: A Moderated Mediation Model.

Purpose: This study examined the influencing mechanism and boundary conditions underlying the relation between COVID-19 perceived risk and flight attendants' turnover intention by investigating the mediating role of job insecurity and the moderating effect of job crafting. Methods:  A two-wave survey was conducted with 240 Chinese flight attendants. We used structural equation modeling to test the moderated mediation model. Results: The results indicated that perceived risk of COVID-19 positively affected flight attendants' job insecurity and turnover intention. Moreover, job insecurity plays a fully mediating role in the relationship between perceived risk and turnover intention. Furthermore, the mediating role of job insecurity was moderated by job crafting; for higher levels of job crafting (opposed to low), the effect of job insecurity on turnover intention was significantly weaker. Conclusion:  Our findings indicate that dissipating job insecurity and increasing job crafting behavior are critical to employees' work-related attitudes and behavior during the COVID-19 pandemic.

Fear of COVID-19 and the career maturity of Chinese international high school students: The mediating effect of the intolerance of uncertainty.

This study examined the influencing mechanism underlying the relationship between the fear of COVID-19 and Chinese international high school students' career maturity by investigating the mediating role of the intolerance of uncertainty. The results indicated that the fear of COVID-19 and the intolerance of uncertainty are negatively associated with international high school students' career maturity. Moreover, intolerance of uncertainty plays a mediating role in the relationship between the fear of COVID-19 and career maturity. The findings contribute to the literature on mental health and have important practical implications for international high school students' mental health and career development.

The Hippo-YAP pathway in various cardiovascular diseases: Focusing on the inflammatory response.

The Hippo pathway was initially discovered in Drosophila melanogaster and mammals as a key regulator of tissue growth both in physiological and pathological states. Numerous studies depict the vital role of the Hippo pathway in cardiovascular development, heart regeneration, organ size and vascular remodeling through the regulation of YAP (yes-associated protein) translocation. Recently, an increasing number of studies have focused on the Hippo-YAP pathway in inflammation and immunology. Although the Hippo-YAP pathway has been revealed to play controversial roles in different contexts and cell types in the cardiovascular system, the mechanisms regulating tissue inflammation and the immune response remain to be clarified. In this review, we summarize findings from the past decade on the function and mechanism of the Hippo-YAP pathway in CVDs (cardiovascular diseases) such as myocardial infarction, cardiomyopathy and atherosclerosis. In particular, we emphasize the role of the Hippo-YAP pathway in regulating inflammatory cell infiltration and inflammatory cytokine activation.

Development and validation of the Chinese version of the perceived partner responsiveness scale (C-PPRS).

BACKGROUND: Perceived partner responsiveness (PPR) refers to the belief that the relational partner knows and is sensitive and supportive. Instead of translating the English version of the Perceived Partner Responsiveness Scale (PPRS) into Chinese, this study aimed to construct and analyze the psychometric properties of the Chinese version of the Perceived Partner Responsiveness Scale (C-PPRS). On the one hand, some words in the original scale are inappropriate for the Chinese due to cultural differences. On the other hand, we intended the scale to apply just to persons in romantic relationships, not to friends or roommates. METHOD: We conducted two studies. In the first study, 441 participants who completed the C-PPRS were randomly divided into two samples for exploratory factor analysis and confirmatory factor analysis. Concurrent validity was assessed in a group of 224 participants who completed the C-PPRS and the Quality of Relationship Index in the second study. RESULTS: The results indicated that the four-factor model (understanding, intimacy, acceptance, and trust) was a feasible representation of the C-PPRS factor structure (χ2/df = 2.27, CFI = 0.94, TLI = 0.93, RMSEA = 0.08, SRMR = 0.05) and had robust internal consistency reliability (alpha = 0.90) and concurrent validity (moderately correlated with the Quality of Relationship Index, r = 0.66, p < 0.001). CONCLUSION: PPR is a concept to understand the psychological manifestations of a person who believes that his or her partner is concerned with core characteristics of the self. The C-PPRS has good psychometric characteristics to evaluate such manifestations and can be applied to future intimacy research.

Metacomprehension Monitoring Accuracy: Effects of Judgment Frames, Cues and Criteria.

This study aimed to investigate the effects of judgment frames, cues, and test criteria on the accuracy of metacomprehension monitoring. The design was a 2 (rating comprehension vs. predicting performance) × 2 (memory cues vs. comprehension cues) × 2 (detailed questions test vs. inferential questions test) mixed design with judgment frames and cues as the between-subjects factors and test criteria as the within-subjects factor. The results showed that the influence of judgment frames on accuracy was moderated by the test criteria. The readers' monitoring was more accurate in rating comprehension than predicting performance when inferential questions were used as the criteria; when detailed questions were used as the criteria, this situation was reversed. The interaction effect of judgment cues and criteria on metacomprehension monitoring accuracy was significant. When readers predicted their performances on a test, those who received memory cues were more accurate than those who received comprehension cues. However, when readers rated their comprehension, those who received comprehension cues were more accurate than those who received memory cues.

Effects of Leader-Follower Extraversion Congruence and Sectoral Difference on Leader-Member Exchange: A Cross-Sectional Study.

PURPOSE: Drawing upon self-categorization theory and the comparative literature on public and private sectors, the purpose of this study is to examine whether leader-follower extraversion congruence is positively related to leader-member exchange (LMX) and whether congruence at high levels of extraversion results in higher LMX than congruence at low levels. Furthermore, the study aims to investigate the moderating role of sectoral difference in the relationship between extraversion fit and LMX. METHODS: Participants were 320 leader-follower dyads (53 leaders and 320 followers) from various public and private sectors in the Chinese cultural context. The extraversion part of the Revised NEO Personality Inventory (NEO-PI-R) and leader-member exchange multidimensional measure (LMX-MDM) were used to measure extraversion and LMX, respectively. Hypotheses were tested using cross-level moderated polynomial regression and response surface analysis. RESULTS: Leader-follower extraversion congruence was not significantly associated with LMX, and there was no significant difference in LMX between congruence at high levels of extraversion and congruence at low levels. However, sectoral difference moderated the relationship between extraversion fit and LMX. Specifically, in the public sector, leader-follower extraversion congruence was positively related to LMX, and LMX was higher when leader and follower extraversion were both at a high level compared to when they were at a low level. In the private sector, this fit effect vanished. PRACTICAL IMPLICATIONS: The results suggest that, in the public sector, when organizations deal with the deployment of staff, taking leader-follower extraversion fit into account may mitigate possible later relationship conflicts. However, in the private sector, by not emphasizing extraversion fit, organizations can focus resources on more crucial factors. ORIGINALITY/VALUE: By considering sectoral difference as the boundary condition of leader-follower extraversion fit, this study extends the comparative literature on public and private sectors and supports self-categorization theory.

Nonbone Marrow CD34+ Cells Are Crucial for Endothelial Repair of Injured Artery.

[Figure: see text].

Role of VEGFR2 in Mediating Endoplasmic Reticulum Stress Under Glucose Deprivation and Determining Cell Death, Oxidative Stress, and Inflammatory Factor Expression.

Retinal pigment epithelium (RPE), a postmitotic monolayer located between the neuroretina and choroid, supports the retina and is closely associated with vision loss diseases such as age-related macular degeneration (AMD) upon dysfunction. Although environmental stresses are known to play critical roles in AMD pathogenesis and the roles of other stresses have been well investigated, glucose deprivation, which can arise from choriocapillary flow voids, has yet to be fully explored. In this study, we examined the involvement of VEGFR2 in glucose deprivation-mediated cell death and the underlying mechanisms. We found that VEGFR2 levels are a determinant for RPE cell death, a critical factor for dry AMD, under glucose deprivation. RNA sequencing analysis showed that upon VEGFR2 knockdown under glucose starvation, endoplasmic reticulum (ER) stress and unfolded protein response (UPR) are reduced. Consistently, VEGFR2 overexpression increased ER stress under the same condition. Although VEGFR2 was less expressed compared to EGFR1 and c-Met in RPE cells, it could elicit a higher level of ER stress induced by glucose starvation. Finally, downregulated VEGFR2 attenuated the oxidative stress and inflammatory factor expression, two downstream targets of ER stress. Our study, for the first time, has demonstrated a novel role of VEGFR2 in RPE cells under glucose deprivation, thus providing valuable insights into the mechanisms of AMD pathogenesis and suggesting that VEGFR2 might be a potential therapeutic target for AMD prevention, which may impede its progression.

Neutrophil elastase promotes neointimal hyperplasia by targeting toll-like receptor 4 (TLR4)-NF-κB signalling.

BACKGROUND AND PURPOSE: Neointimal hyperplasia (NIH) is the fundamental cause for vascular diseases and vascular smooth muscle cell (VSMC) dysregulation has been widely implicated in NIH. Neutrophil elastase is a potential therapeutic target for multiple diseases. We investigated the role of neutrophil elastase in VSMC functions and injury-induced NIH and explored the therapeutic potential of targeting neutrophil elastase in NIH. EXPERIMENTAL APPROACH: VSMCs were used to analyse the effects of neutrophil elastase. Proteomic analysis was used to identify potential neutrophil elastase targets. Artery injury model and neutrophil elastase inhibitor GW311616A were used to investigate the role of neutrophil elastase in NIH. KEY RESULTS: TNF-α up-regulated neutrophil elastase in VSMCs through modulating GAPBα/Runx1/CEBPα/c-Myb signalling. Up-regulated neutrophil elastase promoted VSMC migration, proliferation and inflammation. Toll-like receptor 4 (TLR4) was identified as a target protein for neutrophil elastase in VSMCs and the TLR4/MyD88/IRAK1/TRAF6/NF-κB regulatory axis was shown to be the signalling pathway for neutrophil elastase in VSMC pathology. Importantly, TLR4 inhibition abolished neutrophil elastase-mediated VSMC dysregulation. Injury-induced NIH was significantly reduced in both neutrophil elastase-deficient mice and mice treated with GW311616A. The formation of neutrophil extracellular traps was impaired in injured arteries from neutrophil elastase-deficient mice. Finally, a similar role for neutrophil elastase in human VSMC pathology was confirmed and we observed higher expression levels of neutrophil elastase but lower expression levels of TLR4 in human atherosclerotic lesions. CONCLUSION AND IMPLICATIONS: We provide new insight into the molecular mechanisms underlying NIH and identify neutrophil elastase as a potential therapeutic target for vascular disease.

Ego-Resiliency and Perceived Social Support in Late Childhood: A Latent Growth Modeling Approach.

This study explored the change trajectory of schoolchildren's ego-resiliency and perceived social support and investigated the effect of perceived social support on ego-resiliency across four time points. A sample of 437 children aged 8-13 years (M = 10.99, SD = 0.70, 51.5% boys) completed assessments at four time points. The results indicated that ego-resiliency showed an increasing linear trend and perceived social support showed a declining linear trend. Perceived social support had a positive effect on ego-resiliency over time. In addition, the initial status of perceived social support negatively predicted the growth trend of ego-resiliency, and the initial status of ego-resiliency negatively predicted the declining trend of perceived social support. The implications for theory and practice are discussed.

Relationships Among Leaders' and Followers' Work Engagement and Followers' Subjective Career Success: A Multilevel Approach.

Using a sample of 52 work teams (52 work team leaders and their 348 followers) in China, we investigated the influence mechanism of leaders' work engagement on their followers' work engagement and subjective career success. A multilevel structural equation model (MSEM) was applied to analyze the survey data. The results of this study indicated that leaders' work engagement positively influenced their followers' subjective career success, and this relationship was mediated by the followers' work engagement. Implications of these findings, limitations, and directions for future research are discussed in the final section of the paper.

TNF-α-Induce Protein 8-Like 1 Inhibits Hepatic Steatosis, Inflammation, and Fibrosis by Suppressing Polyubiquitination of Apoptosis Signal-Regulating Kinase 1.

BACKGROUND AND AIMS: Characterized by hepatocyte steatosis, inflammation, and fibrosis, NASH is a complicated process that contributes to end-stage liver disease and, eventually, HCC. TNF-α-induced protein 8-like 1 (TIPE1), a new member of the TNF-α-induced protein 8 family, has been explored in immunology and oncology research; but little is known about its role in metabolic diseases. APPROACH AND RESULTS: Here, we show that hepatocyte-specific deletion of TIPE1 exacerbated diet-induced hepatic steatosis, inflammation, and fibrosis as well as systemic metabolic disorders during NASH pathogenesis. Conversely, hepatocyte-specific overexpression of TIPE1 dramatically prevented the progression of these abnormalities. Mechanically, TIPE1 directly interacted with apoptosis signal-regulating kinase 1 (ASK1) to suppress its TNF receptor-associated factor 6 (TRAF6)-catalyzed polyubiquitination activation upon metabolic challenge, thereby inhibiting the downstream c-Jun N-terminal kinase and p38 signaling pathway. Importantly, dramatically reduced TIPE1 expression was observed in the livers of patients with NAFLD, suggesting that TIPE1 might be a promising therapeutic target for NAFLD and related metabolic diseases. CONCLUSIONS: TIPE1 protects against hepatic steatosis, inflammation, and fibrosis through directly binding ASK1 and restraining its TRAF6-catalyzed polyubiquitination during the development of NASH. Therefore, targeting TIPE1 could be a promising therapeutic approach for NAFLD treatment.

miR-214-3p-Sufu-GLI1 is a novel regulatory axis controlling inflammatory smooth muscle cell differentiation from stem cells and neointimal hyperplasia.

BACKGROUND: Inflammatory smooth muscle cells (iSMCs) generated from adventitial stem/progenitor cells (AdSPCs) have been recognised as a new player in cardiovascular disease, and microRNA-214-3p (miR-214-3p) has been implicated in mature vascular SMC functions and neointimal hyperplasia. Here, we attempted to elucidate the functional involvements of miR-214-3p in iSMC differentiation from AdSPCs and unravel the therapeutic potential of miR-214-3p signalling in AdSPCs for injury-induced neointimal hyperplasia. METHODS: The role of miR-214-3p in iSMC differentiation from AdSPCs was evaluated by multiple biochemistry assays. The target of miR-214-3p was identified through binding site mutation and reporter activity analysis. A murine model of injury-induced arterial remodelling and stem cell transplantation was conducted to study the therapeutic potential of miR-214-3p. RT-qPCR analysis was performed to examine the gene expression in healthy and diseased human arteries. RESULTS: miR-214-3p prevented iSMC differentiation/generation from AdSPCs by restoring sonic hedgehog-glioma-associated oncogene 1 (Shh-GLI1) signalling. Suppressor of fused (Sufu) was identified as a functional target of miR-214-3p during iSMC generation from AdSPCs. Mechanistic studies revealed that miR-214-3p over-expression or Sufu inhibition can promote nuclear accumulation of GLI1 protein in AdSPCs, and the consensus sequence (GACCACCCA) for GLI1 binding within smooth muscle alpha-actin (SMαA) and serum response factor (SRF) gene promoters is required for their respective regulation by miR-214-3p and Sufu. Additionally, Sufu upregulates multiple inflammatory gene expression (IFNγ, IL-6, MCP-1 and S100A4) in iSMCs. In vivo, transfection of miR-214-3p into the injured vessels resulted in the decreased expression level of Sufu, reduced iSMC generation and inhibited neointimal hyperplasia. Importantly, perivascular transplantation of AdSPCs increased neointimal hyperplasia, whereas transplantation of AdSPCs over-expressing miR-214-3p prevented this. Finally, decreased expression of miR-214-3p but increased expression of Sufu was observed in diseased human arteries. CONCLUSIONS: We present a previously unexplored role for miR-214-3p in iSMC differentiation and neointima iSMC hyperplasia and provide new insights into the therapeutic effects of miR-214-3p in vascular disease.

Single-cell gene profiling and lineage tracing analyses revealed novel mechanisms of endothelial repair by progenitors.

Stem/progenitor cells (SPCs) have been implicated to participate in vascular repair. However, the exact role of SPCs in endothelial repair of large vessels still remains controversial. This study aimed to delineate the cellular heterogeneity and possible functional role of endogenous vascular SPCs in large vessels. Using single-cell RNA-sequencing (scRNA-seq) and genetic lineage tracing mouse models, we uncovered the cellular heterogeneity of SPCs, i.e., c-Kit+ cells in the mouse aorta, and found that endogenous c-Kit+ cells acquire endothelial cell fate in the aorta under both physiological and pathological conditions. While c-Kit+ cells contribute to aortic endothelial turnover in the atheroprone regions during homeostasis, recipient c-Kit+ cells of nonbone marrow source replace both luminal and microvessel endothelial cells in transplant arteriosclerosis. Single-cell pseudotime analysis of scRNA-seq data and in vitro cell experiments suggest that vascular SPCs display endothelial differentiation potential and undergo metabolic reprogramming during cell differentiation, in which AKT/mTOR-dependent glycolysis is critical for endothelial gene expression. These findings demonstrate a critical role for c-Kit lineage cells in aortic endothelial turnover and replacement, and may provide insights into therapeutic strategies for vascular diseases.

Macrophage-derived MMP-8 determines smooth muscle cell differentiation from adventitia stem/progenitor cells and promotes neointima hyperplasia.

AIMS: Emerging evidence has suggested that adventitia stem/progenitor cells (AdSPCs) migrate into the intima of arteries in response to injury, where they differentiate towards smooth muscle cells (SMCs) and participate in neointimal hyperplasia. We have previously identified matrix metalloproteinase-8 (MMP8) as a key player in atherogenesis. In this study, we aimed to investigate the functional roles of macrophage-derived MMP8 in AdSPC differentiation and injury-induced arterial remodelling. METHODS AND RESULTS: We first observed an important role for MMP8 in SMC differentiation from embryonic stem cells, but this effect was not seen in AdSPCs. Instead, through macrophages/AdSPCs co-culture and macrophage conditional culture medium studies, we have demonstrated that the MMP8 protein secreted from macrophages promotes SMC differentiation from AdSPCs. Mechanistically, we showed that macrophage-derived MMP8 promotes SMC differentiation from AdSPCs through modulating transforming growth factor-ß activity and a disintegrin and metalloproteinase domain-containing protein 10 (ADAM10)/Notch1 signalling. We further demonstrated that the binding site for CBF1, Suppressor of Hairless, and Lag-1 (CSL) within SMC gene promoters is responsible for Notch1 mediated SMC differentiation. Finally, we demonstrated that macrophage-derived MMP8 increased injury-induced neointimal SMC hyperplasia by activating ADAM10/Notch1 signalling. CONCLUSIONS: We have identified macrophage-derived MMP8 as a regulator in SMC differentiation from AdSPCs and neointimal SMC hyperplasia in response to injury. Our data provide new insights into the roles of MMP8 in AdSPC differentiation and the pathogenesis of neointima formation in the context of angiographic restenosis, and therefore may aid in the development of novel therapeutic agents for the prevention of this disease.