Multiple Mediation Research Articles

Abstract PR002: Lymph node colonization reprograms lymphocyte responses to generate systemic tolerance and promote distant metastasis

Abstract The majority of cancer-associated deaths result from distant organ metastasis, yet the mechanisms that enable this process remain poorly understood. Colonization of locoregional or distant lymph nodes (LNs) typically precedes the formation of distant organ metastases, yet it has been unclear whether LN metastasis plays a functional role in disease progression. LNs are major sites of anti-tumor lymphocyte education, including in the context of immunotherapy, yet LN metastasis frequently correlates with further disease progression. By leveraging our mouse models of LN metastasis, we find that LN colonization represents a critical step in tumor progression by inducing tumor-specific immune tolerance in a manner that promotes further dissemination of tumors to distant organs. This promotion of distant seeding by LN metastases is reliant upon adaptive immunity and is tumor specific. Using flow cytometry and single-cell sequencing to perform comprehensive immune profiling, we identify multiple cellular mediators of tolerance. LN metastases evade NK cells, induce shifts in DC and B cell populations, and promote CD8 T cell exhaustion, but of particular importance, we find that regulatory T cells (Tregs) are enriched in the LNs of mice and patients with LN metastases. LN metastatic cells exhibit an enhanced capacity to induce Treg differentiation from naïve CD4 T cells, and ablation of Tregs using FoxP3-DTR mice eliminates the ability of LN metastases to promote distant metastasis. Furthermore, adoptive transfer of Tregs from the LNs of mice bearing LN metastases to naïve mice facilitates lung metastasis in a manner that Tregs from mice without LN metastases cannot. These Tregs are induced in a tumor antigen-specific manner and TCR recognition of tumors is required for the metastasis-promoting tolerance. Using photoconvertible mice, we track the trafficking dynamics of Tregs from tumor involved LNs and demonstrate their elevated trafficking to sites of distant metastasis prior to the formation of detectable metastases in those sites. Through bulk and single-cell TCR sequencing of the Treg repertoire we reveal how LN colonization alters the clonal architecture of the Treg compartment and demonstrate how the evolution of metastatic traits coincides with shifts in the Treg repertoire. Parallel analyses in patients with melanoma and head and neck cancer reveal similar CD4 T cell dynamics in the context of LN involvement. Together, these findings demonstrate a critical role for LN metastasis in promoting tumor-specific immune tolerance and metastatic progression. Citation Format: Cort B. Breuer, Norma A. Gutierrez, Zhewen Xiong, Amanda R. Kirane, John B. Sunwoo, Nathan E. Reticker-Flynn. Lymph node colonization reprograms lymphocyte responses to generate systemic tolerance and promote distant metastasis [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Tumor-body Interactions: The Roles of Micro- and Macroenvironment in Cancer; 2024 Nov 17-20; Boston, MA. Philadelphia (PA): AACR; Cancer Res 2024;84(22_Suppl):Abstract nr PR002.

The Development of Epilepsy Following CNS Viral Infections: Mechanisms.

This review examines the role of different viral infections in epileptogenesis, with a focus on Herpesviruses such as Human Herpesvirus 6 (HHV-6) and Epstein Barr Virus (EBV), Flaviviruses, Picornaviruses, Human Immunodeficiency Virus (HIV), Influenzavirus and Severe Acute Respiratory Syndrome CoronaVirus 2 (SARS-CoV-2). A growing literature on animal models, such as the paradigmatic Theiler's murine encephalomyelitis virus (TMEV) model, and clinical investigations in patients with epilepsy have started to elucidate cellular mechanisms implicated in seizure initiation and development of epilepsy following viral infections. A central role of neuroinflammation has emerged, with evidence of activation of the innate and adaptive immunity, dysregulation of microglial and astrocytic activity and production of multiple cytokines and other inflammatory mediators. Several chronic downstream effects result in increased blood-brain barrier permeability, direct neuronal damage, and modifications of ion channels ultimately leading to altered neuronal excitability and seizure generation. Key findings underscore the complex interplay between initial viral infection, neuroinflammation, and later development of epilepsy. Further research is needed to elucidate these mechanisms and develop targeted interventions.

How does contact valence and group salience affect outgroup attitudes in asynchronous computer mediated contact? Experiments on intergroup contact via social media posts

ABSTRACT The prejudice reduction potential of face-to-face intergroup contact is widely established, but we know much less about computer-mediated intergroup contact (online contact) specifically via social media where interactions are less controlled and mostly asynchronous. Additionally, much of the work on online contact has focused on positive, controlled contact, neglecting the effect of negative contact. We examined the effects of mediated contact via online posts with differing valence (positive, negative, and neutral) in three experimental studies, in an imaginary scenario (Study 1: N = 120) and a real intergroup scenario with South and North Indians (Study 2: N = 296, Study 3: N = 336). Main effects of One way and factorial ANOVA showed that contact valence significantly affected outgroup attitudes in Study 1 & 2 but was not replicated in Study 3, where quality and quantity of past contact and status differences emerged as significant predictors of attitudes. Multiple mediation analysis revealed that intergroup anxiety and quality of contact explained changes in attitudes, which was less affected by valence and more by regional identity and history of contact. Findings are discussed in light of the possibilities and limitations of asynchronous mediated contact on social media.

Understanding the Relationship Between Trait Mindfulness and Perceived Stress: The Serial Multiple Mediating Roles of Basic Psychological Needs Satisfaction and Psychological Flexibility.

Although research suggests that trait mindfulness has been negatively associated with perceived stress, an integrative examination of the underlying mechanisms is lacking. Consequently, the purpose of this study was to establish an integrative model within Monitor and Acceptance Theory (MAT). This model examined the relationship between trait mindfulness and perceived stress by assessing two important psychological resources: basic psychological needs satisfaction (BPNS) and psychological flexibility. A total of 679 young adults (Mage = 19.27 years, SD = 1.06) participated in this research. They completed a set of standardized instruments that assessed trait mindfulness, BPNS, psychological flexibility, and perceived stress. Serial multiple mediation analyses showed that trait mindfulness was associated with higher levels of BPNS and psychological flexibility, which in turn were associated with less perceived stress. Furthermore, the path coefficient of the serial multiple mediation was higher than other pathways. These findings demonstrate that BPNS and psychological flexibility are important mechanisms that underlie the relationship between trait mindfulness and perceived stress, particularly when they are synergistic.

The School Bullying Victimization in Adolescents With Non-Suicidal Self-Injury: The Role of Coping Strategies and Emotion Regulation.

The present study aimed to investigate the relationship between school bullying victimization and non-suicidal self-injury (NSSI) frequency, taking into consideration the mediating roles of coping strategies and emotional regulation. Participants were 12-18-year-old outpatients and inpatients who met the NSSI and depressive disorder criteria according to the DSM-5. Assessments included the Multidimensional Peer-Victimization Scale, Coping Style Scale for Middle School Students, Emotion Regulation Questionnaire for Children and Adolescents, and the Functional Assessment of Self-Mutilation to examine the bullying victimization, coping strategies, emotion regulation, and NSSI behaviour. Serial multiple mediation effects of coping strategies and emotion regulation between bullying victimization and NSSI frequency were analysed using the SPSS macro PROCESS programme. A total of 2335 participants were included in this study. Bullying victimization significantly predicted NSSI frequency (B=0.191, p<0.001). Both coping strategies and emotion regulation were important mediators in the relationship between bullying victimization and NSSI frequency. Bullying victimization indirectly affected NSSI through two serial mediation pathways: (1) bullying victimization → problem-focused coping → cognitive reappraisal → NSSI frequency, and (2) bullying victimization → emotion-focused coping→ expressive suppression → NSSI frequency. The study revealed a positive association between bullying victimization and the frequency of NSSI among adolescents with depressive disorder. Strategies of coping and emotional regulation significantly mediated the link between bullying victimization and the frequency of NSSI. The findings suggested that supporting adolescents in adopting effective coping and emotional regulation strategies could be a crucial approach to mitigate the impact of bullying victimization on the frequency of NSSI.

School Connectedness and Academic Burnout in Middle School Students: A Multiple Serial Mediation Model

Higher levels of school connectedness are associated with better study habits, but their relationship with academic burnout and the underlying mechanisms have not been revealed. We used a questionnaire to investigate the relationship between school connectedness and academic burnout and the mediating mechanisms of burnout in a sample of 394 Chinese middle school students, controlling for class, gender, and grade level. The results revealed that (1) school connectedness, autonomous motivation to learn, and core self-evaluations were significantly negatively related to academic burnout; and that (2) academic self-handicapping, core self-evaluations, and autonomous motivation to learn individually mediated the effects of school connectedness on academic burnout and mediated the effects of multiple factors. Therefore, educators should pay attention to the emotional needs of junior high school students, increase the level of school connectedness, consciously help students cultivate positive psychological factors such as autonomous motivation and core self-evaluations, reduce academic self-handicapping, increase their learning pleasure, and alleviate junior high school students’ academic burnout.

Suicidal risk among Chinese parents of autistic children and its association with perceived discrimination, affiliate stigma and social alienation

BackgroundCaring for autistic children becomes challenging and may lead to negative psychological outcomes, even increasing the suicide risk (SR). Researchers have studied the SR among parents of autistic children in Western nations, but little is known about it in China and how it relates to perceived discrimination (PD), affiliate stigma (AS), and social alienation (SA). The current study aimed to reveal the SR prevalence rate among Chinese parents of autistic children, and clarify whether AS and SA may play mediating roles in the association between SR and PD.MethodsA total of 645 Chinese parents of autistic children were recruited to complete a series of scales to evaluate SR, SA, AS, and PD using the Suicidal Behaviors Questionnaire-Revised (SBQ-R), Perceived Discrimination Scale for Parents of Children with Autism Spectrum Disorders (PDS-FP), Affiliate Stigma Scale (ASS), and General Social Alienation Scale (GSAS), respectively. Then, the SR prevalence rate among Chinese parents of autistic children was evaluated; and the multiple mediation analysis and structural equation modeling with the bootstrap method were conducted to test the mediating effects of AS and SA in the association between SR and PD.Results34.6% Chinese parents of autistic children had high SR. In particular, the incidence rate of suicide ideation, suicide plans, suicide attempts, and suicide likelihood during the previous year were 49.8%, 11.9%, 2.5%, and 13.8%, respectively. Additionally, PD was positively associated with SR (r = .40, p < .01); and AS and SA showed significant mediating effects on the association between PD and SR (p < .01).ConclusionsThe current study evaluated the SR prevalence rate among Chinese parents of autistic children, and clarified the mediating effects of AS and SA in the association between SR and PD. Findings might bring new insights and guidance for intervention of suicidality among Chinese parents of autistic children.

Adolescents’ perceptions of autonomy-supportive parents and social-emotional health: Serial multiple mediation of positive stress and mental toughness

Adolescence may bring some developmental challenges that affect social-emotional health. However, it is also possible to turn challenges into opportunities. Parental autonomy support, psychological stress, and mental toughness can contribute to adolescents having a healthy period. This study examined the mediating role of positive stress and mental toughness in the relationship between parental autonomy support and social-emotional health. The study included 441 (female 56.46%, male 43.54%) adolescents in Turkey enrolled in a high school. Self-report scales were used in this cross-sectional study. The results showed that positive stress and mental toughness were serial mediators of the relationship between adolescents’ perceptions of parental autonomy support and social-emotional health outcomes (indirect effect = 0.05 [0.03, 0.08]). These results extend the implications of self-determination and positive psychology theories. It guides parents, educators, and school counselors in strengthening adolescents’ social-emotional health. Adolescents’ socio-emotional health can be enhanced through workshops and counseling services that offer parental autonomy support, positive management of stress, and mental toughness.

Exploring the impact of student perceptions of Assessment for Learning on intrinsic motivation

Does student perception of Assessment for Learning (AfL) predict intrinsic motivation and is this relation mediated by the fulfillment of the needs for autonomy, relatedness, and competence? A total of 1658 students from junior vocational high schools completed a questionnaire assessing intrinsic motivation, need fulfillment for autonomy, relatedness, and competence, and perceptions of AfL practices. Structural equation modelling (SEM) was used to test the multiple mediation model of intrinsic motivation predicted by AfL through basic need fulfillment. Results indicated that AfL positively predicted intrinsic motivation, and this relation was fully mediated by fulfillment of needs for competence and relatedness, but not for autonomy. Perceived scaffolding predicted the fulfillment of all three basic needs and emerged as the primary predictor of intrinsic motivation. These findings indicate that fostering competence and relatedness through AfL practices may enhance student motivation.

Fatigue and Sleep-related Impairment as Predictors of the Effect of Nonpharmacological Therapies for Active duty Service Members With Chronic Pain: A Secondary Analysis of a Pragmatic Randomized Clinical Trial.

First-line treatments for chronic pain include selected complementary and integrative health therapies, including spinal manipulation, acupuncture, yoga, and massage; and standard rehabilitative care, including physical and occupational therapies. This study aimed to uncover critical factors that contribute to pain impact and the effectiveness of complementary and integrative health therapies and standard rehabilitative care among people with chronic pain, with a focus on the role of sleep-related impairment. We conducted a secondary analysis of data from a pragmatic randomized clinical trial of 280 U.S. active duty service members with chronic pain. Our study's multiple mediation analysis examined the indirect effect of complementary and integrative health therapies on pain impact through fatigue (β = - 0.43; 95% CI, -0.99 to -0.07). When stratified by sleep-related impairment, participants with T scores above the median of 62 demonstrated a significant negative indirect effect of complementary and integrative health therapies through fatigue (β = - 0.80; 95% CI, -2.31 to -0.14). This negative indirect effect was not significant for participants with sleep-related impairment T scores below the median (β = - 0.64; 95% CI, -1.48 to 0.07). These findings suggest that complementary and integrative health therapies are particularly effective in reducing pain impact for individuals with higher levels of sleep-related impairment, and that the effect of complementary and integrative health therapies is supported primarily by reducing fatigue.

Effect of mental state on sleep quality in patients receiving maintenance hemodialysis: A multiple mediation model of hope and family function.

The objective of this study was to investigate the current situation of sleep quality in patients receiving maintenance hemodialysis (MHD), and whether hope and family function play a mediating role between negative emotions and sleep quality. The Athens Insomnia Scale, Hospital Anxiety and Depression Scale, Herth Hope Index and Family Adaptation, Partnership, Growth, Affection and Resolve (APGAR) Index were used to investigate 227 MHD patients. The correlations among study variables were analyzed by Pearson correlation analysis. Structural equation model was used to construct and evaluate the mediation model. The sleep quality score of 227 patients receiving MHD was (7.57 ± 4.74), anxiety score was (4.36 ± 4.02), depression score was (5.91 ± 4.37), hope score was (34.64 ± 7.21), family function score was (6.21 ± 2.90). The negative emotions can directly predict sleep quality (β = 0.17, P = .046), positively predict sleep quality through hope (β = 0.12, P = .017), positively predict sleep quality through family function (β = 0.20, P < .001), and positively predict sleep quality through the chain mediating of hope and family function (β = 0.10, P < .001). The total effect size was 71.19%. It is concluded that negative emotions had a direct impact on the sleep quality of patients receiving MHD, and that improving the levels of family function and hope can help them sleep better.

Sequential multiple mediating effect of loneliness and family health on physical frailty and willingness to age at home in older adults: a national survey in China

BackgroundWith the rapid ageing of the global population, the number of older adults with physical frailty has been gradually increasing, making ageing at home a key strategy for coping with this demographic change. The opinions of older adults regarding their willingness to age at home deserve to be considered respectfully. As a result, this study aimed to investigate willingness to age at home and any associated underlying mechanisms involving physical frailty among older Chinese adults.MethodsThis study was a national cross-sectional survey. Stratified random and quota sampling were used before and after the individual level respectively. Willingness to age at home was compared between older adults with different characteristics using the Mann–Whitney U test and Kruskal–Wallis H test. A Spearman rank test was conducted to explore the correlations among physical frailty, loneliness, family health, and willingness to age at home. The path hypothesis that loneliness and family health influence the relationship between physical frailty and willingness to age at home among older adults was further tested through sequential multiple mediation analysis.ResultsA total of 3,837 older adults were included in this study. They returned a median score of 78 in terms of willingness to age at home. Physical frailty (β = − 0.044, P < 0.01) and loneliness (β = − 0.070, P < 0.001) were negatively associated, and family health (β = 0.275, P < 0.001) was positively associated with a willingness to age at home among older Chinese adults. Loneliness and family health played sequential multiple mediating role (β = − 0.018, Boot SE = 0.002, 95% CI = [–0.022, − 0.014]) between physical frailty and willingness to age at home.ConclusionsReducing physical frailty in older adults, reducing their sense of loneliness, and enhancing their family health is essential, as it can increase their levels of confidence with regard to ageing at home.

Insomnia severity and obesity mediated by health behaviors in adolescents.

Sleep difficulties in youth have been associated with numerous negative outcomes, such as higher risk of obesity. Though the relationship between sleep and obesity is not well clarified, past research has shown that modifiable health behaviors, such as diet, physical activity, and screen time, may explain this relationship. The purpose of this study was to simultaneously examine these health behaviors as mediators of the relationship between insomnia severity and obesity among a sample of adolescents aged 12-18years. English-speaking parents/legal guardians of adolescents were invited to participate in an online survey focused on pediatric sleep patterns, health behaviors, and weight. Parents/guardians (N = 599) reported on their adolescent's diet (i.e., consumption of fruits/vegetables, fast food, and breakfast), physical activity, screen time, and BMI. A multiple mediation analysis was run to test these health behaviors as mediators of the relationship between insomnia severity and BMI, after controlling for sex, age, race, and poverty. While insomnia was related to most health behaviors, screen time was the only significant mediator of the relationship between insomnia and BMI, after controlling for the effects of the other mediators and all covariates, ab = .04, 95% CrI [.01, .09]. Screen time has implications for both adolescents' sleep health and weight. Pediatric clinicians should systematically assess for, and provide, recommendations on ways to improve sleep and screen time use, in addition to providing traditional dietary and physical activity recommendations.

Mechanism for developing brand equity of higher education institutes using intangible resources: a serial-multiple mediation analysis

PurposeThis study aims to build a comprehensive model for developing higher education institutes (HEIs) brand equity by examining the impact of HEIs intangible resources, brand management aspects, attachment strength and student’s contemporary citizenship behavior (CCB).Design/methodology/approachData were gathered through a self-administered questionnaire from Indian students and alumni (n = 703). The study examines the proposed comprehensive model through serial and multiple mediation analysis.FindingsThe study unfolded “service quality? brand image? attachment strength? word-of-mouth? brand equity” as the most significant path to develop HEI’s brand equity.Research limitations/implicationsThis study pioneers an empirically validated mechanism for developing brand equity in HEIs, addressing gaps identified by previous studies and offering a theoretical framework that elucidates how HEIs can leverage intangible resources through strategic brand management to foster attachment and influence positive student behaviors, thereby contributing to the development of HEI brand equity.Practical implicationsHEIs need to understand that relying solely on tangible aspects leads to short-lived effects. To maintain a lasting competitive advantage, HEIs should focus on crafting a rich historical narrative, retaining talented faculty and staff and earning respect from the public to build a lasting reputation.Originality/valueThis study develops the mechanism for developing brand equity of HEIs using its valuable, rare and inimitable intangible resources. Along with the introduction of novel constructs like competence, heritage and word-of-mouth to existing study, the proposed conceptual model is premised on the theory of self-congruence, social-exchange theory and CCB.

Effects and Mechanisms of TikTok on Self-Rated Health of Older Adults in China During the COVID-19 Pandemic: A Mediation Analysis

Background/Objectives: During the COVID-19 pandemic, TikTok emerged as a significant app for entertainment and information acquisition for the general public, gradually extending its reach to the older population. Digital technology, exemplified by TikTok, has become an indispensable part of older adults’ lives. However, while prior studies have extensively focused on the impact of internet use on older adults’ health, research on the impact of TikTok during the COVID-19 pandemic remains insufficient. Methods: Utilizing data from the China Family Panel Studies (CFPS) 2020, this study explored the impact of TikTok use on older adults’ self-rated health and its underlying mechanisms through multiple regression and mediation analysis. Results: The study found that (1) TikTok use had a significant positive effect on the self-rated health of older adults; (2) while TikTok use increased the exercise frequency of older adults, exercise frequency did not affect their self-rated health; and (3) TikTok use boosted older adults’ protein intake, contributing substantially to their self-rated health, accounting for 38.7% of the total effect. Conclusions: It is advisable to actively promote the popularity of short video apps such as TikTok among older adults, as they serve as an effective tool for disseminating health information and encouraging healthier lifestyles and behaviors.

The Role of Multiple Mediation with Contextual Neighborhood Measures in Ovarian Cancer Survival..

BackgroundMediation by multiple agents can affect the relation between neighborhood deprivation and segregation indices and ovarian cancer survival. In this paper, we examine a variety of potential clinical mediators in the association between deprivation indices (DIs) and segregation indices (SIs) with all-cause survival among women with ovarian cancer in the African American Cancer Epidemiology Study (AACES). MethodsWe use novel Bayesian multiple mediation structural models to assess the joint role of mediators (stage at diagnosis, histology, diagnostic delay) combined with the DIs and SIs (Yost, ADI, Kolak’s URB, ICE-income) and a set of confounders with survival. The confounder set is selected in a preliminary step, and each DI or SI is included in separate model fits. ResultsWhen multiple mediators are included, the total impact of DIs and SIs on survival is much reduced. Unlike the single mediator examples previously reported, the Yost, ADI and ICE-income indices do not display significant direct effects. This suggests that when important clinical mediators are included, the impact of neighborhood SES indices is significantly attenuated. It is also clear that certain behavioral and demographic measures such as physical activity, smoking, or adjusted family income do not have a significant role in survival when mediated by clinical factors. ConclusionMultiple mediation via clinical and diagnostic-related measures reduces the contextual effects of neighborhood measures on ovarian cancer survival. The robust association of the Kolak URB index on survival may be due to its relevance to access to care, unlike SES-based indices whose impact was significantly reduced when important clinical mediators were included.

The analysis of a causal model of learning organization on sustainable organizational performance of public IT companies in China: Knowledge management practices and innovation capability as multiple mediators

This research aims to empirically examine the role of learning organization practices in enhancing sustainable organizational performance, utilizing knowledge management and innovation capability as mediating variables. The study was conducted in public IT companies across China, which is a vital sector for driving innovation and economic growth. A mixed-methods approach was employed, with quantitative methods accounting for 70% and qualitative methods for 30% of the research. Purposive sampling was utilized to distribute questionnaires to 546 employees from 10 public IT companies. Statistical analysis was conducted using Structural Equation Modeling (SEM). The findings indicate that learning organization practices significantly influence knowledge management practices (β = 0.785, p &lt; 0.001) and innovation capability (β = 0.405, p &lt; 0.001). Furthermore, knowledge management practices positively contribute to sustainable organizational performance (β = 0.541, p &lt; 0.001), while innovation capability also has a positive effect (β = 0.143, p &lt; 0.001). Moreover, knowledge management practices partially mediate the relationship between learning organization practices and sustainable performance, with a total effect of 0.788 (p &lt; 0.001). The mediating role of innovation capability is also significant, with a total effect of 0.422 (p = 0.045). The study further includes qualitative in-depth interviews with 20 managers from 10 IT companies across five regions in China: East, South, West, North, and Central. Senior managers were selected through a stratified sampling method to ensure comprehensive representation by including both the largest and smallest companies in each region. These findings underscore the critical role of learning organizations in promoting sustainability through effective knowledge management and innovation capabilities within the IT sector.

Natural killer cells are required for the recruitment of CD8+ T cells and the efficacy of immune checkpoint blockade in melanoma brain metastases

BackgroundBrain metastases (BrM) affect up to 60% of patients with metastatic melanoma and are associated with poor prognosis. While combined immune checkpoint blockade of programmed death-1 (PD-1) and cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) demonstrates intracranial efficacy in a proportion of patients with melanoma, the responses are rarely durable, particularly in patients with symptomatic BrM. The brain is an immune-specialized organ and immune responses are regulated differently to the periphery.MethodsUsing our previously established two-site model of melanoma BrM with concomitant intracranial and extracranial tumors, in which clinically observed efficacy of the combined PD-1/CTLA-4 (PC) blockade can be reproduced, we here explored the role of natural killer (NK) cells in BrM, using functional studies, immunophenotyping and molecular profiling.ResultsWe demonstrate that NK cells are required for the intracranial efficacy of PC blockade. While both perforin and interferon gamma were necessary for the PC blockade-dependent control of intracranial tumor growth, NK cells isolated from intracranial tumors demonstrated only a limited cancer cell killing ability, and PC blockade did not alter the abundance of NK cells within tumors. However, the depletion of NK cells in PC blockade-treated mice led to tumor molecular profiles reminiscent of those observed in intracranial tumors that failed to respond to therapy. Furthermore, the depletion of NK cells resulted in a strikingly reduced abundance of CD8+ T cells within intracranial tumors, while the abundance of other immune cell populations including CD4+ T cells, macrophages and microglia remained unaltered. Adoptive T cell transfer experiments demonstrated that PC blockade-induced trafficking of CD8+ T cells to intracranial tumors was chemokine-dependent. In line with this, PC blockade enhanced intratumoral expression of several T cell-attracting chemokines and we observed high expression levels of cognate chemokine receptors on BrM-infiltrating CD8+ T cells in mice, as well as in human BrM. Importantly, the depletion of NK cells strikingly reduced the intratumoral expression levels of T cell attracting chemokines and vascular T cell entry receptors that were upregulated following PC blockade.ConclusionOur data demonstrate that NK cells underpin the efficacy of PC blockade in BrM by orchestrating the "responder" molecular profile in tumors, and by controlling the intratumoral abundance of CD8+ T cells through regulation of multiple key molecular mediators of T cell trafficking.

Can Transportation Networks Contribute to the Sustainable Development of Urban Agglomeration Spatial Structures?

The advancements in global urbanisation have significantly elevated the configuration of transportation networks for the sustainable development of urban agglomeration spatial structures (UASS). Using a comprehensive panel dataset covering 140 counties and districts in the Chengdu-Chongqing Economic Circle from 2014 to 2023, this study empirically examines the impact of transportation networks on the sustainability of UASS. It elucidates the underlying mechanisms using spatial Durbin, spatial spillover and multiple mediation effect models. The findings reveal that transportation networks considerably enhance the sustainability of UASS and generate substantial positive spatial spillover effects. The decay boundary of the spatial spillover effects exhibits a transition from positive to negative, eventually approaching ineffectiveness. The heterogeneity analysis indicates significant variations in terms of transportation network expansion and regional functional division on the sustainability of UASS across regions with various levels of economic development. This outcome suggests that regional development policies should carefully consider regional economic development disparities. The mechanism analysis further reveals that transportation networks enable the sustainability of UASS by accelerating regional hierarchical systems and regional connectivity.

Maternal support in preschool and child behavior problems: The mediating role of childhood emotion knowledge.

Children's emotion knowledge encompasses abilities to recognize and label emotions in the service of positive adaptation. Drawing on a sociodemographically diverse sample of 250 children (50% female sex assigned at birth; Mage_W1 = 49.02 months, SD = 2.99) and their maternal caregivers (55.6% Latina; 37.6% poverty), this study evaluated a multiple mediation model to integrate heretofore distinct bodies of research examining (a) parenting effects on the development of emotion knowledge and (b) emotion knowledge effects on socioemotional adaptation. Observations of maternal supportive presence at age 4 predicted increases in children's emotion recognition and labeling from ages 4 to 8. However, only emotion labeling skills explained children's behavioral adjustment outcomes with a significant pathway from supportive parenting at age 4 to fewer externalizing and internalizing behavior problems at age 10 via improved emotion labeling skills. These findings suggest that emotion knowledge, particularly labeling skills, partially explains the protective impact of supportive parenting on behavioral adaptation across childhood. Prevention and intervention efforts should target both supportive parenting practices and emotion knowledge skill development to support children's socioemotional functioning and reduce behavior problems. (PsycInfo Database Record (c) 2024 APA, all rights reserved).