PAK1 inhibition increases TRIM21-induced PD-L1 degradation and enhances responses to anti-PD-1 therapy in pancreatic cancer.

Pancreatic ductal adenocarcinoma (PDA) is a common malignancy with a 5-year survival <10 %. Immunosuppressive tumor microenvironment (TME) plays a critical role in the progression of PDA. In recent years, programmed death-ligand 1 (PD-L1)/programmed cell death protein-1 (PD-1) blockade has emerged as a potent anti-tumor immunotherapy, while is yet to achieve significant clinical benefits for PDA patients. P21-Activated kinase 1 (PAK1) is highly upregulated in PDA and has been reported to be involved in the regulation of anti-tumor immunity. This study aims to investigate the combined effect of PAK1 inhibition and anti-PD-1 therapy on PDA and the underlying mechanisms. We have shown that PAK1 expression positively correlated with PD-L1 in PDA patients, and that inhibition of PAK1 downregulated PD-L1 expression of PDA cells. More importantly, we have demonstrated that PAK1 competed with PD-L1 in binding to tripartite motif-containing protein 21 (TRIM21), a ubiquitin E3 ligase, resulting in less ubiquitination and degradation of PD-L1. Moreover, PAK1 inhibition promoted CD8+ T cells activation and infiltration. In a murine PDA model, the combination of PAK1 inhibition and anti-PD-1 therapy showed significant anti-tumor effects compared with the control or monotherapy. Our results indicated that the combination of PAK1 inhibition and anti-PD-1 therapy would be a more effective treatment for PDA patients.

Current Understanding of Marginal Grafts in Liver Transplantation.

End-stage liver disease (ESLD), stemming from a spectrum of chronic liver pathologies including chronic liver failure, acute cirrhosis decompensation and hepatocellular carcinoma, imposes a significant global healthcare burden. Liver transplantation (LT) remains the only treatment for ESLD. However, the escalating mortality on transplant waitlists has prompted the utilization of marginal liver grafts in LT procedures. These grafts primarily encompass elderly livers, steatotic livers, livers from donation after circulatory death, split livers and those infected with the hepatitis virus. While the expansion of the donor pool offers promise, it also introduces concomitant risks. These encompass graft failure, biliary and cardiovascular complications, the recurrence of liver disease and reduced patient and graft survival. Consequently, various established strategies, ranging from improved donor-recipient matching to surgical interventions, have emerged to mitigate these risks. This article undertakes a comprehensive assessment of the current landscape, evaluating the viability of diverse marginal liver grafts. Additionally, it synthesizes approaches aimed at enhancing the quality of such marginal liver grafts. The overarching objective is to augment the donor pool and ameliorate the risk factors associated with the shortage of liver grafts.

Influence of sex on outcomes of liver transplantation for hepatocellular carcinoma: a multicenter cohort study in China.

OBJECTIVE: Sex-specific differences are observed in various liver diseases, but the influence of sex on the outcomes of hepatocellular carcinoma (HCC) after liver transplantation (LT) remains to be determined. This study is the first Chinese nationwide investigation of the role of sex in post-LT outcomes in patients with HCC. METHODS: Data for recipients with HCC registered in the China Liver Transplant Registry between January 2015 and December 2020 were analyzed. The associations between donor, recipient, or donor-recipient transplant patterns by sex and the post-LT outcomes were studied with propensity score matching (PSM). The survival associated with different sex-based donor-recipient transplant patterns was further studied. RESULTS: Among 3,769 patients enrolled in this study, the 1-, 3-, and 5-year overall survival (OS) rates of patients with HCC after LT were 96.1%, 86.4%, and 78.5%, respectively, in female recipients, and 95.8%, 79.0%, and 70.7%, respectively, in male recipients after PSM (P = 0.009). However, the OS was comparable between recipients with female donors and male donors. Multivariate analysis indicated that male recipient sex was a risk factor for post-LT survival (HR = 1.381, P = 0.046). Among the donor-recipient transplant patterns, the male-male donor-recipient transplant pattern was associated with the poorest post-LT survival (P < 0.05). CONCLUSIONS: Our findings highlighted that the post-LT outcomes of female recipients were significantly superior to those of male recipients, and the male-male donor-recipient transplant pattern was associated with the poorest post-LT survival. Livers from male donors may provide the most benefit to female recipients. Our results indicate that sex should be considered as a critical factor in organ allocation.

A novel nomogram for prognosis stratification in salvage liver transplantation: a national-wide study with propensity score matching analysis in China.

Background: Salvage liver transplantation (SLT) has been reported to be an efficient treatment option for patients with recurrent hepatocellular carcinoma (HCC) after liver resection (LR). However, for recipients who underwent liver transplantation (LT) due to recurrent HCC after LR in China, the selection criteria are not well established. Methods: In this study, data from the China Liver Transplant Registry (CLTR) of 4,244 LT performed from January 2015 to December 2019 were examined, including 3,498 primary liver transplantation (PLT) and 746 SLT recipients. Propensity score matching (PSM) analysis was used to minimize between-group imbalances. The overall survival (OS) and disease-free survival (DFS) between PLT and SLT in recipients fulfilling the Milan or Hangzhou criteria were compared based on the multivariate analysis, nomograms were plotted to further classify the SLT group into low- and high-risk groups. Results: In this study, the 1-, 3- and 5-year OS and DFS of SLT recipients fulfilling Milan criteria (OS, P=0.01; DFS, P<0.001) or Hangzhou criteria (OS, P=0.03; DFS, P=0.003) were significantly reduced when compared to that of PLT group after PSM analysis. Independent risk factors, including preoperative transarterial chemoembolization (TACE), alpha fetoprotein (AFP) level, tumor maximum size and tumor total diameter were selected to draw a prognostic nomogram. The low-risk SLT recipients (1-year, 95.34%; 3-year, 84.26%; 5-year, 77.20%) showed a comparable OS with PLT recipients fulfilling Hangzhou criteria (P=0.107). Conclusions: An optimal nomogram model for prognosis stratification and clinical decision guidance of SLT was established. The low-risk SLT recipients based on the nomograms showed comparable survival with those fulfilling Hangzhou criteria in PLT group.

Protein induced by vitamin K absence or antagonist II: Experience to date and future directions.

Hepatocellular carcinoma (HCC) is the most common type of primary liver cancer with high mortality. The realization of precision medicine in HCC relies upon efficient biomarkers. Protein induced by vitamin K absence or antagonist II (PIVKA-II) is an immature prothrombin with insufficient coagulation activity, overexpressing in HCC cells. Previous evidence confirmed the role of PIVKA-II in screening and diagnosing HCC. However, the increased PIVKA-II was observed not only in HCC, but also in non-HCC individuals such as vitamin K deficiency. The joint detection of PIVKA-II and other biomarkers could significantly improve diagnostic accuracy in HCC. Furthermore, PIVKA-II serves as a valuable prognostic predictor, transplantation eligibility, resectability, tumor recurrence, therapeutic efficacy, and malignant tumor behaviors. Additionally, PIVKA-II represents a potential target for agent development to establish new therapeutic strategies. Besides HCC, PIVKA-II also serves as a biomarker of vitamin K status. In this review, we assess the role of PIVKA-II in diagnosis, prediction, and treatment. Over the past decades, substantial progress has been achieved in the application of PIVKA-II. Exploration and innovation are required for further advances in the field of PIVKA-II investigation.

Incorporation of protein induced by vitamin K absence or antagonist-II into transplant criteria expands beneficiaries of liver transplantation for hepatocellular carcinoma: a multicenter retrospective cohort study in China.

INTRODUCTION: In order to maximize the utilization of precious donor liver, precisely determining potential hepatocellular carcinoma (HCC) candidates who will benefit from liver transplantation (LT) is essential. As a crucial diagnostic biomarker for HCC, protein induced by vitamin K absence or antagonist-II (PIVKA-II) has become one of the key indicators for assessing tumor recurrence risk after LT. This study aims to investigate the role of PIVKA-II in recipient selection and prognostic stratification. METHODS: The clinicopathologic data of HCC patients undergoing LT from 2015 to 2020 in six Chinese transplant centers were collected. Univariate and multivariate analyses were performed to determine risk factors for disease free survival (DFS). Based on these risk factors, survival analysis was made by Kaplan-Meier method and their value in prognostic stratification was assessed. RESULTS: A total of 522 eligible HCC patients with pre-LT PIVKA-II records were finally included in this study. Tumor burden>8 cm, α-fetoprotein>400 ng/ml, histopathologic grade III and PIVKA-II>240 mAU/ml were identified as independent risk factors for DFS. DFS of patients with PIVKA-II≤240 mAU/ml ( N =288) were significantly higher than those with PIVKA-II>240 mAU/ml ( N =234) (1-year, 3-year, and 5-year DFS: 83.2, 77.3, and 75.9% vs. 75.1, 58.5, and 50.5%; P <0.001). Compared with Hangzhou criteria ( N =305), incorporating PIVKA-II into Hangzhou criteria (including tumor burden, α-fetoprotein, and histopathologic grade) increased the number of patients with eligibility for LT by 21.6% but achieved comparable DFS and overall survival. CONCLUSIONS: Incorporating PIVKA-II into existing LT criteria could increase the number of eligible HCC patients without compromising post-LT outcomes.

Insulin-induced gene 2 protects against hepatic ischemia-reperfusion injury via metabolic remodeling.

BACKGROUND: Hepatic ischemia-reperfusion (IR) injury is the primary reason for complications following hepatectomy and liver transplantation (LT). Insulin-induced gene 2 (Insig2) is one of several proteins that anchor the reticulum in the cytoplasm and is essential for metabolism and inflammatory responses. However, its function in IR injury remains ambiguous. METHODS: Insig2 global knock-out (KO) mice and mice with adeno-associated-virus8 (AAV8)-delivered Insig2 hepatocyte-specific overexpression were subjected to a 70% hepatic IR model. Liver injury was assessed by monitoring hepatic histology, inflammatory responses, and apoptosis. Hypoxia/reoxygenation stimulation (H/R) of primary hepatocytes and hypoxia model induced by cobalt chloride (CoCl2) were used for in vitro experiments. Multi-omics analysis of transcriptomics, proteomics, and metabolomics was used to investigate the molecular mechanisms underlying Insig2. RESULTS: Hepatic Insig2 expression was significantly reduced in clinical samples undergoing LT and the mouse IR model. Our findings showed that Insig2 depletion significantly aggravated IR-induced hepatic inflammation, cell death and injury, whereas Insig2 overexpression caused the opposite phenotypes. The results of in vitro H/R experiments were consistent with those in vivo. Mechanistically, multi-omics analysis revealed that Insig2 is associated with increased antioxidant pentose phosphate pathway (PPP) activity. The inhibition of glucose-6-phosphate-dehydrogenase (G6PD), a rate-limiting enzyme of PPP, rescued the protective effect of Insig2 overexpression, exacerbating liver injury. Finally, our findings indicated that mouse IR injury could be attenuated by developing a nanoparticle delivery system that enables liver-targeted delivery of substrate of PPP (glucose 6-phosphate). CONCLUSIONS: Insig2 has a protective function in liver IR by upregulating the PPP activity and remodeling glucose metabolism. The supplementary glucose 6-phosphate (G6P) salt may serve as a viable therapeutic target for alleviating hepatic IR.

ATRA sensitized the response of hepatocellular carcinoma to Sorafenib by downregulation of p21-activated kinase 1.

BACKGROUND: Sorafenib resistance greatly reduces the efficacy of treatments in advanced hepatocellular carcinoma (HCC) patients, but the underlying mechanisms are not thoroughly understood. All-trans retinoic acid (ATRA), an anti-leukaemia agent, has attracted considerable attention due to its role in sensitizing cells to other anticancer treatments. We aimed to investigate the combined effect of ATRA and Sorafenib on HCC and the underlying mechanisms. METHODS: CCK-8, cell sphere formation, trans-well migration, and wound-healing assays were used to analyse the biological behaviours of HCC cells in vitro. Western blotting and qRT-PCR analysis were conducted to measure the expression of p21 activated kinase 1 (PAK1) and phospho-p21 activated kinase 1 (pPAK1). Xenograft models were established to confirm the synergistic effects of ATRA and Sorafenib in vivo. TUNEL assays and immunohistochemistry were utilized to determine apoptosis, proliferation, PAK1 and pPAK1 levels in tumour tissues. RESULTS: We observed that PAK1 was overexpressed in HCC, and its expression was negatively correlated with the survival of patients. PAK1 promoted the proliferation, self-renewal and epithelial-mesenchymal transition of HCC cells. Correlation analysis indicated that the IC50 of Sorafenib was positively correlated with the level of pPAK1 in HCC cell lines. ATRA inhibited the progression of HCC and sensitized HCC response to Sorafenib by downregulation of PAK1, as shown by the calculated coefficient of drug interaction and the data obtained from xenograft models. CONCLUSIONS: Our findings indicated that instead of treatment with Sorafenib alone, the combination of ATRA and Sorafenib provides a more effective treatment for HCC patients. Video Abstract.

Targeting macrophagic PIM-1 alleviates osteoarthritis by inhibiting NLRP3 inflammasome activation via suppressing mitochondrial ROS/Cl- efflux signaling pathway.

BACKGROUND: Osteoarthritis (OA), in which macrophage-driven synovitis is considered closely related to cartilage destruction and could occur at any stage, is an inflammatory arthritis. However, there are no effective targets to cure the progression of OA. The NOD-, LRR-,and pyrin domain-containing protein 3 (NLRP3) inflammasome in synovial macrophages participates in the pathological inflammatory process and treatment strategies targeting it are considered to be an effective approach for OA. PIM-1 kinase, as a downstream effector of many cytokine signaling pathways, plays a pro-inflammatory role in inflammatory disease. METHODS: In this study, we evaluated the expression of the PIM-1 and the infiltration of synovial macrophages in the human OA synovium. The effects and mechanism of PIM-1 were investigated in mice and human macrophages stimulated by lipopolysaccharide (LPS) and different agonists such as nigericin, ATP, Monosodium urate (MSU), and Aluminum salt (Alum). The protective effects on chondrocytes were assessed by a modified co-culture system induced by macrophage condition medium (CM). The therapeutic effect in vivo was confirmed by the medial meniscus (DMM)-induced OA in mice. RESULTS: The expression of PIM-1 was increased in the human OA synovium which was accompanied by the infiltration of synovial macrophages. In vitro experiments, suppression of PIM-1 by SMI-4a, a specific inhibitor, rapidly inhibited the NLRP3 inflammasome activation in mice and human macrophages and gasdermin-D (GSDME)-mediated pyroptosis. Furthermore, PIM-1 inhibition specifically blocked the apoptosis-associated speck-like protein containing a CARD (ASC) oligomerization in the assembly stage. Mechanistically, PIM-1 inhibition alleviated the mitochondrial reactive oxygen species (ROS)/chloride intracellular channel proteins (CLICs)-dependent Cl- efflux signaling pathway, which eventually resulted in the blockade of the ASC oligomerization and NLRP3 inflammasome activation. Furthermore, PIM-1 suppression showed chondroprotective effects in the modified co-culture system. Finally, SMI-4a significantly suppressed the expression of PIM-1 in the synovium and reduced the synovitis scores and the Osteoarthritis Research Society International (OARSI) score in the DMM-induced OA model. CONCLUSIONS: Therefore, PIM-1 represented a new class of promising targets as a treatment of OA to target these mechanisms in macrophages and widened the road to therapeutic strategies for OA.

P-21 Activated Kinases in Liver Disorders.

The p21 Activated Kinases (PAKs) are serine threonine kinases and play important roles in many biological processes, including cell growth, survival, cytoskeletal organization, migration, and morphology. Recently, PAKs have emerged in the process of liver disorders, including liver cancer, hepatic ischemia-reperfusion injury, hepatitis, and liver fibrosis, owing to their effects in multiple signaling pathways in various cell types. Activation of PAKs promotes liver cancer growth and metastasis and contributes to the resistance of liver cancer to radiotherapy and chemotherapy, leading to poor survival of patients. PAKs also play important roles in the development and progression of hepatitis and other pathological processes of the liver such as fibrosis and ischemia-reperfusion injury. In this review, we have summarized the currently available studies about the role of PAKs in liver disorders and the mechanisms involved, and further explored the potential therapeutic application of PAK inhibitors in liver disorders, with the aim to provide a comprehensive overview on current progress and perspectives of PAKs in liver disorders.

A mixed blessing for liver transplantation patients - Rapamycin.

BACKGROUND: Liver transplantation (LT) is an effective treatment option for end-stage liver disease. Mammalian target of rapamycin (mTOR) inhibitors, such as rapamycin, are widely used post LT. DATA SOURCES: In this review, we focused on the anti-cancer activities and metabolic side effects of rapamycin after LT. The literature available on PubMed for the period of January 1999-September 2022 was reviewed. The key words were rapamycin, sirolimus, liver transplantation, hepatocellular carcinoma, diabetes, and lipid metabolism disorder. RESULTS: Rapamycin has shown excellent effects and is safer than other immunosuppressive regimens. It has exhibited excellent anti-cancer activity and has the potential in preventing hepatocellular carcinoma (HCC) recurrence post LT. Rapamycin is closely related to two long-term complications after LT, diabetes and lipid metabolism disorders. CONCLUSIONS: Rapamycin prevents HCC recurrence post LT in some patients, but it also induces metabolic disorders. Reasonable use of rapamycin benefits the liver recipients.

Using ISU-GAN for unsupervised small sample defect detection.

Surface defect detection is a vital process in industrial production and a significant research direction in computer vision. Although today's deep learning defect detection methods based on computer vision can achieve high detection accuracy, they are mainly based on supervised learning. They require many defect samples to train the model, which is not compatible with the current situation that industrial defect sample is difficult to obtain and costly to label. So we propose a new unsupervised small sample defect detection model-ISU-GAN, which is based on the CycleGAN architecture. A skip connection, SE module, and Involution module are added to the Generator, enabling the feature extraction capability of the model to be significantly improved. Moreover, we propose an SSIM-based defect segmentation method that applies to GAN-based defect detection and can accurately extract defect contours without the need for redundant noise reduction post-processing. Experiments on the DAGM2007 dataset show that the unsupervised ISU-GAN can achieve higher detection accuracy and finer defect profiles with less than 1/3 of the unlabelled training data than the supervised model with the full training set. Relative to the supervised segmentation models UNet and ResUNet++ with more training samples, our model improves the detection accuracy by 2.84% and 0.41% respectively and the F1 score by 0.025 and 0.0012 respectively. In addition, the predicted profile obtained using our method is closer to the real profile than other models used for comparison.

Targeting the Hepatic Microenvironment to Improve Ischemia/Reperfusion Injury: New Insights into the Immune and Metabolic Compartments.

Hepatic ischemia/reperfusion injury (IRI) is mainly characterized by high activation of immune inflammatory responses and metabolic responses. Understanding the molecular and metabolic mechanisms underlying development of hepatic IRI is critical for developing effective therapies for hepatic IRI. Recent advances in research have improved our understanding of the pathogenesis of IRI. During IRI, hepatocyte injury and inflammatory responses are mediated by crosstalk between the immune cells and metabolic components. This crosstalk can be targeted to treat or reverse hepatic IRI. Thus, a deep understanding of hepatic microenvironment, especially the immune and metabolic responses, can reveal new therapeutic opportunities for hepatic IRI. In this review, we describe important cells in the liver microenvironment (especially non-parenchymal cells) that regulate immune inflammatory responses. The role of metabolic components in the diagnosis and prevention of hepatic IRI are discussed. Furthermore, recent updated therapeutic strategies based on the hepatic microenvironment, including immune cells and metabolic components, are highlighted.

Shyness and depressive symptoms: a multiple mediation model involving core self-evaluations and sense of security.

BACKGROUND: Depression is one of the most common mental health disorders among Chinese university students. Some depressed students are observed to be shy. Therefore, the current study aimed to verify the association of shyness and depression symptoms and explore how shyness is positively associated with depressive symptoms. According to Blatt's model of depression, the current study explores the mediating roles of core self-evaluation and sense of security, as an affective factor and a cognitive factor, in the relationship between shyness and depressive symptoms. METHODS: The participants (543 Chinese college students) completed the Revised Henderson Undergraduate Shyness Scale, Core Self-Evaluations Scale, Self-Rating Depression Scale, and Security Questionnaire. The bivariate correlations between variables andthe multiple mediation model were tested by correlation analysis and structural equation model respectively. RESULTS: Shyness was significantly and positively correlated with depressive symptoms; shyness and depressive symptoms were significantly and negatively correlated with sense of security and core self-evaluations; and sense of security was significantly and positively correlated with core self-evaluations. Core self-evaluations and sense of security played complete mediating effects in the relationship between shyness and depressive symptoms parallelly and sequentially. LIMITATIONS: The cross-sectional design we used limited causal interpretations. Besides, the sample was restricted to college students, and the generalizability of the results is thus limited. CONCLUSIONS: Shyness increases the risk ofdepression by reducing the sense of security and core self-evaluation, as well as by the sequential mediating effects of sense of security and core self-evaluations.

The Effect of Shyness on Adolescent Network Problem Behavior: The Role of Gender and Loneliness.

With the latest, rapid developments of the Internet, young people have become the main group in the online world. Congruently, Internet problem behaviors have shown a significant growth trend among adolescents. The present paper explores the factors affecting adolescents' problem network behavior from the perspective of their shyness, gender, and loneliness, and provides suggestions for guiding these young people toward using the network rationally. The study surveyed 5,130 teenagers from Shandong province in China to investigate the moderating effect of gender on the relationship between shyness and problem network behavior, and the mediating effect of loneliness on the moderating effect. The results indicated that the level of shyness among girls was significantly higher than that among boys, whereas the prevalence of cyberbullying, pathological Internet use, and Internet gaming disorder was significantly lower for girls than for boys. The relationship among shyness, cyberbullying, and Internet gaming disorder was found to be moderated by gender, and the problems of cyberbullying and Internet gaming disorder faced by shy boys were greater than those faced by shy girls. In addition, the moderating effect of gender on cyberbullying and Internet gaming disorder was found to occur through the mediating factor of loneliness. The paper concludes with a discussion of the theoretical significance and generalizability of our research results.

The effects of violent video games and shyness on individuals' aggressive behaviors.

The general aggression model (GAM) has suggested that the interaction between person factors (e.g., personality variables) and situation factors (e.g., playing violent video games [VVGs]) can increase individuals' aggressive behaviors through their cognition (e.g., hostile attributions), affect (e.g., negative affect), and/or arousal. The present study employed a modified competitive reaction time task to test the effects of shyness, violent (vs. nonviolent) gameplay, and shyness on individuals' positive-negative affect, hostile attributions, and aggressive behaviors. In addition, the present study also employed structural equation modeling (SEM) to test the mediation (by cognition and affect) and moderation (by shyness). Results showed that playing a VVG increased aggressive behaviors, negative affect, and hostile attributions primarily among shy participants. In addition, the results of SEM also revealed that this moderating role was mediated by negative affect and hostile attributions. The present study supported GAM and showed that individuals' aggressive behaviors are differentially susceptible to VVGs, depending on their level of shyness in a "for bad and for worse" manner.

Associations among shyness, interpersonal relationships, and loneliness in college freshmen: A longitudinal cross-lagged analysis.

This short-term longitudinal study examined the reciprocal associations among shyness, interpersonal relationships, and loneliness in a sample of 361 Chinese college freshmen (138 male students, mean age = 18.57 years). A fully cross-lagged panel design was used in which shyness, interpersonal relationships, and loneliness were assessed at three time points separated by 8 months. The results indicated that the associations among shyness, interpersonal relationships, and loneliness were dynamic and bidirectional. The self-report scores and the pattern of cross-lagged associations among shyness, interpersonal relationships, and loneliness were the same for male and female students at all three times. Implications for loneliness interventions and future research directions are provided.

Susceptibility of Shy Students to Internet Addiction: A Multiple Mediation Model Involving Chinese Middle-School Students.

Recent studies found that some personality traits (e.g., impulsivity, sensation seeking) are frequently related to Internet addiction. In line with previous studies, this study aimed to determine whether shy students readily develop Internet addiction and to identify the causes of their developing Internet addiction. Specifically, this study examined the mediating roles of cognitive flexibility, self-regulation, and self-inconsistency in linking shyness and Internet addiction. A total of 1301 middle-school students in Shandong Province, East China, completed the relevant scales. Correlation analysis revealed that shyness was positively correlated with self-inconsistency and Internet addiction and negatively correlated with self-regulation and self-inconsistency. Cognitive flexibility, self-regulation, and self-inconsistency played fully mediating roles in the relationship between shyness and Internet addiction. The results indicate the significance of shyness-sensitivity for Internet addiction and suggest that cognitive and coping abilities as well as social adjustment factors should be considered when designing interventions to help shy students overcome Internet addiction.

Relationship Between Shyness and Generalized Pathological Internet Use Among Chinese School Students: The Serial Mediating Roles of Loneliness, Depression, and Self-Esteem.

The present study aimed to explore the mediating effects of loneliness, depression, and self-esteem on the association between shyness and generalized pathological Internet use (GPIU). A total of 5215 school students completed questionnaires regarding shyness, loneliness, depression, self-esteem, and GPIU (aged 11-23 years old, M = 16.19, SD = 3.10). The self-reported scores for GPIU, shyness, loneliness, depression, and self-esteem were tested in students from elementary schools to universities. The results of a variance analysis indicated that senior high school students had the greatest prevalence of GPIU of all the study stages. With the study stages resolved, the results of a structural equation model revealed that: (a) shyness positively predicted GPIU; (b) shyness/loneliness/depression predicted GPIU through self-esteem; (c) shyness predicted GPIU through loneliness/depression → self-esteem; and (d) shyness predicted GPIU through loneliness → depression → self-esteem. In conclusion, these results provided significant implications for preventing or reducing GPIU in Chinese school students.

Shyness and Learning Adjustment in Senior High School Students: Mediating Roles of Goal Orientation and Academic Help Seeking.

Learning maladjustment is a common phenomenon in the context of examination-oriented education system in china, especially among high school students who experience intense pressure when preparing for the national college entrance examination. Previous literature suggests that shyness may negatively affect ones' cognition, emotion, and behavioral performance and lead to academic and social maladjustment. Therefore, learning adjustment among shy high school students is a critical and practical point of inquiry. With a sample of 677 Chinese senior high school students, this study aims to assess the association between shyness and learning adjustment and related mechanisms of goal orientation (i.e., mastery-approach goals, mastery-avoid goals, performance-approach goals, and performance-avoid goals) and academic help seeking (i.e., instrumental help seeking from teacher, instrumental help seeking from classmate, executive help seeking, and avoidance of help seeking). Self-report measures were adopted to collect information on: demographic characteristics, the level of shyness, goal orientation, academic help seeking, and learning adjustment. Results indicated that shyness was negatively correlated with learning adjustment, and this association was mediated by the dimensions of goal orientation and dimensions of academic help seeking. Specifically, shyness not only predicted learning adjustment through mastery-approach goals, and instrumental help seeking (teachers) but also predicted learning adjustment through the multiple mediating effects of the dimensions of goal orientation and the dimensions of academic help seeking (i.e., mastery-approach goals and instrumental help seeking from teachers, mastery-approach goals and executive help seeking, mastery-avoid goals and instrumental help seeking from classmates, mastery-avoid goals and executive help seeking, and performance-avoid goals and executive help seeking). Identifying these mediators further enables us to work out effective measures to promote shy high school students' learning adjustment.