Direct Effect Research Articles

The melano-macrophage: The black leukocyte of fish immunity

Melanin and the process of melanin synthesis or melanogenesis have central roles in the immune system of insects, and production of melanin-synthesizing enzymes from their haemocytes may be induced following activation through danger signals. Melanin-containing macrophage-like cells have been extensively studied in amphibians and they are also present in reptiles. In fish, melano-macrophages are especially recognized with respect to melano-macrophage centres (MMCs), hypothesized to be analogues of germinal centres in secondary lymphoid organs of mammals and some birds. Melano-macrophages are in addition present in several inflammatory conditions, in particular melanised focal changes, or black spots, in the musculature of farmed Atlantic salmon, Salmo salar. Melanins are complex compounds that may be divided into different forms which all have the ability to absorb and scatter light. Other functions include the quenching of free radicals and a direct effect on the immune system. According to the common view held in the pigment cell community, vertebrate melanin synthesis with melanosome formation may only occur in cells of ectodermal origin. However, abundant information suggests that also myeloid cells of ectothermic vertebrates may be classified as melanocytes. Here, we discuss these opposing views and review relevant literature. Finally, we review the current status on the research concerning melanised focal muscle changes that represent the most severe quality problem in Norwegian salmon production, but also other diseases where melano-macrophages play important roles.

Abstract 6528: Integrin ɑvβ6 upregulation as a mechanism of T-cell evasion in head and neck squamous cell carcinoma

Abstract Head and neck squamous cell carcinoma (HNSCC) encompasses malignancies of the mucosal epithelium in the oral cavity, pharynx, and larynx. The lack of effective screening strategies and the typically late stage of detection are contributors to a considerable annual death toll of HNSCC. Additionally, the anatomical proximity of the malignancy to delicate structures of the head and neck leads to tremendous treatment-related morbidity. Therefore, there is great interest in developing life-saving therapies and strategies for treatment de-escalation. The immune checkpoint inhibitor pembrolizumab (αPD-1) has been approved for recurrent or metastatic HNSCC and as a frontline therapy for unresectable disease. However, only about a quarter of patients respond to αPD-1 therapy. The immunosuppressive effect of TGFβ has been widely described as relevant to the HNSCC tumor microenvironment. However, attempts to blockade TGFβ have failed mainly due to the widespread side effects of disrupting a highly promiscuous cytokine. Integrin αvβ6 is a major activator of the inert latent TGFβ into the active, immunosuppressive form. With its high relative specificity to HNSCC tissue, inhibition of αvβ6 could offer a safer approach for disrupting TGFβ to overcome resistance to immune checkpoint blockade. After screening ɑvβ6 expression levels of HNSCC cell lines via flow cytometry, cell lines FaDu and CAL27 were selected for further investigation due to high endogenous ITGB6 expression (FaDu 35.57% cells ITGB6+, CAL27 95.69% cells ITGB6+). The cell lines were transduced with a doxycycline-inducible short hairpin RNA (shRNA) knockdown of αvβ6 using a lentiviral system. Both knockdown and control shRNA cell lines were pretreated with 1 μg/mL of doxycycline for five days to induce the shRNA and subsequently co-cultured with TALL-104 T-cells. Quantitative fluorescence microscopy of the co-culture revealed that the knockdown of αvβ6 substantially increased T-cell killing over 24hrs (FaDu CTRL shRNA 6.72%±2.49 dead vs. FaDu ITGB6 shRNA 12.80%±3.16 dead, p<0.001). However, treatment of FaDu and CAL27 cell lines with active-TGFβ showed no change in PD-L1 expression via flow cytometric analysis. To determine whether the T cell evasive effect of αvβ6 is driven by other immune checkpoints on the cancer cells or by the direct effect that TGFβ has on immune cells, we show the generation of relevant mouse αvβ6 shRNA knockdown cells. These syngeneic in vivo studies will facilitate cytokine profiling to uncover the dynamics of tumor-immune cell interactions in response to αvβ6 inhibition. Citation Format: William J. MacDonald, Praveen R. Srinivasan, Maximilian Pinho-Schwermann, Shengliang Zhang, Vida Tajiknia, Connor Purcell, Jillian Strandberg, Nolan Stubbs, Wafik S. El-Deiry. Integrin ɑvβ6 upregulation as a mechanism of T-cell evasion in head and neck squamous cell carcinoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 6528.

Abstract 3841: Tumor-derived microRNA125a induces CART cell apoptosis and failure in B cell malignancies

Abstract Despite the remarkable efficacy of chimeric antigen receptor T -cell therapy (CART) for the treatment of B-cell malignancies, durable remission remains limited often due to tumor relapse. We have previously demonstrated that tumor-derived extracellular vesicles (EVs) induced CART cell failure in preclinical models. To characterize the impact of tumor EV induced CART cell dysfunction, we assessed microRNA (miRNA) profiles contained within tumor EVs from two independent patient cohorts and studied how they contributed to CART dysfunction. Our first cohort included patients with chronic lymphocytic leukemia (n=50). We previously showed that CLL patient derived EVs induce a state of CART cell dysfunction. To understand this dysfunction, we interrogated the miRNA cargo significantly enriched in CLL EVs and how their coculture impacts CART signaling by RNAseq. Here, we found a significant enrichment in miR-125a within CLL EVs as compared to healthy donor controls (p=.0001). CART cocultured with CLL EVs showed alterations in T cell activation pathways, where miR-125a targets TNFAIP3 and NFkB pathways were activated. These findings implicate miR-125a from CLL EVs in CART dysfunction. Next, we aimed to validate the impact of miRNA on CART cell outcomes in the clinic. We interrogated miRNA profiles from patients with diffuse large B cell lymphoma (DLBCL) treated with CART cell therapy (CART19-28ζ, axicabtagene ciloleucel). EV miRNA cargo was compared between responders (complete remission at 6 months, n=10) and non-responders (no response 1 month post CART19, n=10) to identify differentially enriched miRNAs across groups. miR-125a was again significantly upregulated in EVs of non-responders as compared to responders to CART19 treatment (fold change=3.28, padj=.018). To study the direct effect of miR-125a on CART cell functions, we generated and studied the effector functions of CART19-28z following transfection with miR-125a or negative miR control. CART19 cells transfected with miR-125a showed a dose dependent decrease in killing of lymphoma cells as compared to miR-control (p=.0001). miR-125a also significantly increased the rate of apoptosis in CART19 cells (fold change=1.95, p=.024) and decreased the level of CART proliferation (fold change=.71, p=.013) as compared to controls. Notably, miR-125a did not impact tumor cell growth, further verifying a direct CART effect. In summary, our studies demonstrate the impact of tumor derived miRNAs on CART cell outcomes. They identify that miR-125a is 1) associated with CLL EV induced CART dysfunction, 2) significantly elevated in non-responders to CART therapy in the clinic, and 3) able to decrease CART19 efficacy through reduced CART killing/proliferation and increased apoptosis. These results highlight a novel mechanism of CART19 failure induced through miRNA cargo delivery by tumor-derived EVs and the role of miR-125a in inducing CART19 dysfunction. Citation Format: Olivia Sirpilla, R. Leo Sakemura, Ismail Can, Truc N. Huynh, James H. GIrsch, Claudia Manriquez Roman, Carli M. Stewart, Kun Yun, Ekene J. Ogbodo, Long Mai, Omar Gutierrez Ruiz, Makena Rodriguez, Brooke Kimball, Hong Xia, Jose C. Villasboas, Stephen Ansell, Nora Bennani, Patrick B. Johnston, Jonas Paludo, Januario Castro, Mohamed Kharfandabaja, Sameer Parikh, Neil Kay, Yi Lin, Elizabeth Siegler, Saad Kenderian. Tumor-derived microRNA125a induces CART cell apoptosis and failure in B cell malignancies [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 3841.

Abstract 2125: The use of intestinal organoids as a preclinical screen to assess gastrointestinal (GI) toxicity and barrier integrity

Abstract Gastrointestinal (GI) toxicity is a common and often severe limiting factor in the development of antineoplastic drugs. Symptoms include diarrhoea, dehydration and ulceration which increase susceptibility to infection, partly due to damage of crypt and/or villus structures in the small intestine, impairing the barrier function. As novel targeted therapies are emerging, assessment of their potential GI toxicity remains crucial. Small intestinal (SI) organoids are 3D in vitro models of the epithelium which recapitulate the structure and function of the small intestine. We have further developed and validated the organoid model as a screening tool to predict GI toxicity and subsequent mucosal regeneration in four species: mouse, rat, dog and human. The culture conditions have been designed to mimic the stem cell niche and allow cell differentiation and proliferation to occur. All intestinal lineages were present in the organoids derived from each species and the epithelial hierarchy closely resembled that observed in vivo. The toxic effects of antineoplastic drugs on the organoids were assessed by quantification of the total cell viability upon treatment, coupled to morphometric analysis of the organoids (size, area, perimeter, and branching efficiency). Immunofluorescence and RNAseq can be used to identify the targeted cells and the toxicity mechanisms of the drugs. To further assess the effect of drugs on barrier integrity, we have developed transwell-grown cell monolayers derived from normal human small intestinal organoids. This model allows direct access to both apical and basal surfaces, which is not possible when using organoids where their geometry prevents access to the apical surface. The monolayer formation was followed by live imaging and Trans-Epithelial Electrical Resistance (TEER) measurements and treatments with toxic drugs were applied after TEER reached a plateau. The direct effect on barrier integrity was evaluated by TEER reduction, increased FITC-Dextran permeability and analysis of TJ proteins by immunofluorescence. Furthermore, effects on cell death were assessed by measuring the levels of Lactate Dehydrogenase (LDH) released into the medium by dying cells. In conclusion, our models provide an innovative in vitro solution to further study the toxic effects of drugs on the normal small intestine and to analyse direct effects on barrier integrity. The monolayer assay may also be useful for developing models of transient TJ impairment to improve the bioavailability of orally administered antineoplastic drugs. The model can be considered more representative of the normal intestine than transformed cell lines such as CaCo2. Citation Format: Valentina Ubertini, Sarah Hall, Frida Ponthan, James Wilson. The use of intestinal organoids as a preclinical screen to assess gastrointestinal (GI) toxicity and barrier integrity [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 2125.

Abstract 395: An alternating magnetic field suppresses tumor growth

Abstract Application of physical forces, ranging from ultrasound to electric field, is recommended in various clinical practice guidelines, including those for bone fracture or cancer treatment. However, mechanistic information for such treatments has been poorly provided, due to the lack of comprehensive study model. Here, we show an alternating magnetic field (AMF) per se exhibits direct anti-cancer effect through enhancing oxidative phosphorylation (OXPOHS) and thus metabolic reprograming. Proliferation of human glioblastoma cells (U87 and LN229), but not normal human astrocytes (NHA), was inhibited upon exposure to AMF within the narrow frequency range. Extracellular acidification rate was decreased while oxygen consumption was increased. These data indicated that AMF induced metabolic reprograming. This was accompanied by increased reactive oxygen species (ROS) production. Mouse models grafted with human glioblastoma cells showed that AMF exposure, 30 minutes per day for two weeks, suppressed the tumor growth and prolonged the overall survival. Our results suggest that the AMF exposure may be a simple strategy to inhibit cancer cell growth by utilizing oxidative stress via metabolic reprograming. Citation Format: Masanari Umemura, Taisuke Akimoto, Rafikul Islam, Kazuhito Kishi, Akane Nagasako, Rina Nakakaji, Takashi Yamaguchi, Yuto Mizuno, Soichiro Ishikawa, Tetsuya Yamamoto, Yoshihiro Ishikawa. An alternating magnetic field suppresses tumor growth [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 395.

Abstract 279: Iatrogenic immunosuppression emplaces tacrolimus to drive squamous skin cancer progression and influence the microenvironment

Abstract One in thirteen organ transplant recipients (OTRs) develop post-transplant cutaneous squamous cell carcinoma (cSCC), leading to significant morbidity upon disease progression. Although chronic ultraviolet (UV) exposure primarily underlies keratinocyte carcinogenesis, long-term immunosuppression is a critical etiologic risk factor due to reduced systemic surveillance of dysplasia. Calcineurin inhibitors such as tacrolimus are commonly administered to suppress the immune system by blocking T-cell proliferation and preventing donor organ rejection. Contrarily, studies have evinced the off-target effects of immunosuppressives, namely azathioprine and cyclosporine, but not tacrolimus — the most widely used in all immunosuppression. In addition, the preclinical research literature has overlooked the contribution of stromal fibroblasts in the cSCC tumor microenvironment (TME). Hence, we hypothesize that tacrolimus exerts direct carcinogenic effects on keratinocytes and fibroblasts in the skin. We further postulate that tacrolimus enables a tumor-permissive microenvironment by activating dermal fibroblasts to cause aggressive and invasive keratinocyte carcinoma in OTRs. To examine this cellular crosstalk phenomenon, we used human keratinocytes, primary dermal fibroblasts and cSCC cells in mono- and co-cultures to mimic cutaneous and tumor complexities. Next, we assessed the molecular mechanisms utilized by tacrolimus to potentiate tumorigenesis pertinent to cell survival, proliferation and invasion. Herein, we show that tacrolimus promotes cell survival dose-dependently in cSCC cells. We also found that a fibroblast-cSCC spheroid co-culture significantly enhances cell invasion. In a wound-healing migration assay, tacrolimus increased the migratory capacity of normal keratinocytes and cSCC cells. However, cell proliferation remains nebulous due to cyclical dose-response effects in vitro. We then queried whether cell proliferation is affected in vivo using immunodeficient mice, and similar results were observed. We confirmed via immunoblotting that tacrolimus induced elevated expression of proliferation markers at distinct drug concentrations. Altogether, our findings illuminate keratinocyte-stroma interactions and particularly isolate the contributory role of tacrolimus in non-immune mediated cSCC pathogenesis. This knowledge suggests newer immunosuppressives that do not inhibit calcineurin activity may help relieve cutaneous malignancies in transplant recipients. Citation Format: Edwin Kumah, Yash Chhabra, Vania Wang, Agrani Dixit, Ashani Weeraratna, Kristin Bibee. Iatrogenic immunosuppression emplaces tacrolimus to drive squamous skin cancer progression and influence the microenvironment [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 279.

Linking Performance Appraisal and Government Employees’ Organizational Citizenship Behavior

This study investigates the relationship between performance appraisal (PA) and organizational citizenship behavior (OCB) among Korean government employees, integrating social exchange theory, prosocial values, and impression management perspectives. It analyzes how employees respond to PA’s perceived effectiveness, focusing on both direct and indirect effects of PA components alongside traditional OCB antecedents. Surveying 3,336 employees, the findings indicate positive correlations between performance feedback adequacy, PA fairness, and OCB, but a negative link with PA leniency. Organizational commitment emerged as a key mediator, especially between PA leniency, performance feedback frequency, and OCB. The study emphasizes the importance of a well-structured PA system to foster employee engagement in OCB.

An empirical evaluation of approximate and exact regression-based causal mediation approaches for a binary outcome and a continuous or a binary mediator for case-control study designs

BackgroundIn the causal mediation analysis framework, several parametric regression-based approaches have been introduced in past years for decomposing the total effect of an exposure on a binary outcome into a direct effect and an indirect effect through a target mediator. In this context, a well-known strategy involves specifying a logistic model for the outcome and invoking the rare outcome assumption (ROA) to simplify estimation. Recently, exact estimators for natural direct and indirect effects have been introduced to circumvent the challenges prompted by the ROA. As for the approximate approaches relying on the ROA, these exact approaches cannot be used as is on case-control data where the sampling mechanism depends on the outcome.MethodsConsidering a continuous or a binary mediator, we empirically compare the approximate and exact approaches using simulated data under various case-control scenarios. An illustration of these approaches on case-control data is provided, where the natural mediation effects of long-term use of oral contraceptives on ovarian cancer, with lifetime number of ovulatory cycles as the mediator, are estimated.ResultsIn the simulations, we found few differences between the performances of the approximate and exact approaches when the outcome was rare, both marginally and conditionally on variables. However, the performance of the approximate approaches degraded as the prevalence of the outcome increased in at least one stratum of variables. Differences in behavior were also observed among the approximate approaches. In the data analysis, all studied approaches were in agreement with respect to the natural direct and indirect effects estimates.ConclusionsIn the case where a violation of the ROA applies or is expected, approximate mediation approaches should be avoided or used with caution, and exact estimators favored.

Investigating links between teacher leadership, collective efficacy and teacher commitment in Egyptian schools: a mediated-effects analysis

PurposeResearch investigating the impact of school leadership on teachers’ emotions and practices has mostly focused on the leadership behaviors of school principals, thus ignoring the potential leadership qualities of other school members, especially teachers. The current study aimed to bridge this gap by providing further insight into the link between teacher leadership and teacher outcomes in Egyptian schools. Specifically, the study examined the mediating role of collective teacher efficacy in the relationship between teacher leadership and teacher commitment.Design/methodology/approachThe study employed structural equation modeling and bootstrapping to analyze survey data collected from 497 teachers in primary and middle schools in Damietta city, Egypt.FindingsThe results supported our proposition that teachers’ leadership practices have more indirect than direct effects on teacher commitment through collective teacher efficacy. That is, teacher leadership practices positively affect teachers’ efficacy beliefs, which, in turn, increase their sense of commitment to school.Originality/valueThe study adds a new aspect to the literature by investigating the potential role of teacher leadership in promoting positive teacher attitudes that can have a positive impact on student learning. This is significant given the growing emphasis that educational systems place on enhancing school effectiveness. Specifically, understanding the factors that contribute to teacher commitment can inform strategies for retaining effective teachers and improving the overall quality of the teaching workforce. Additionally, since most of the empirical research on teacher leadership has been produced in Western contexts, it is important to enrich the field with studies conducted in other societies, especially in the Arab region.

Leading in times of crisis and remote work: perceived consideration leadership behavior and its effect on follower work engagement

Based on the job-demands resources theory, we examine whether leadership behavior affects followers' work engagement in the context of remote work during times of crisis, and how this effect can be explained. We focus on consideration leadership and its impact on followers' engagement under conditions of enforced remote work during the COVID-19 pandemic. Therein, we examine the role of optimism as a potential mediator. To better understand how the impact of consideration leadership behavior unfolds during crises, we examine whether being new to remote work and feeling personally impacted by COVID-19 amplified the proposed relationship between consideration leadership and followers' engagement. A sample of 729 German employees participated in a three-wave study across 6 weeks in May and June 2020. Longitudinal structural equation modeling uncovered direct positive effects of consideration leadership on changes in followers' work engagement in the second time lag (T2 to T3), while optimism did not mediate this effect. Multigroup comparisons revealed that employees who worked from home were particularly responsive to consideration leadership. No moderating effects were found for whether the COVID-19 pandemic personally impacted employees. The discussion highlights the critical role of leadership in followers' motivation and wellbeing in times of crisis and remote work.

UV-filter benzophenones suppress human, pig, rat, and mouse 11β-hydroxysteroid dehydrogenase 1: Structure-activity relationship and in silico docking analysis

Benzophenone chemicals (BPs) have been developed to prevent the adverse effects of UV radiation and they are widely contaminated. 11β-Hydroxysteroid dehydrogenase 1 (11β-HSD1) catalyze the conversion of inactive glucocorticoid to active glucocorticoid, playing critical role in many physiological function. However, the direct effect of BPs on human, pig, rat, and mouse 11β-HSD1 remains unclear. In this study, we screened the inhibitory strength of 12 BPs on 4 species, and performed the structure-activity relationship (SAR) and in silico docking analysis. The inhibitory potency of BPs was: for human 11β-HSD1, BP6 (IC50 = 18.76 μM) > BP8 (40.84 μM) > BP (88.89 μM) > other BPs; for pig 11β-HSD1, BP8 (45.57 μM) > BP6 (59.44 μM) > BP2 (65.12 μM) > BP (135.56 μM) > other BPs; for rat 11β-HSD1, BP7 (67.17 μM) > BP (68.83 μM) > BP8 (133.04 μM) > other BPs; and for mouse 11β-HSD1, BP8 (41.41 μM) > BP (50.61 μM) > other BPs. These BP chemicals were mixed/competitive inhibitors of these 11β-HSD1 enzymes. The 2,2′-dihydroxy substitutions in two benzene rings play a key role in enhancing the effectiveness of inhibiting 11β-HSD1, possibly via increasing hydrogen bond interactions. Docking analysis shows that these BPs bind to NADPH/glucocorticoid binding sites and forms hydrogen bonds with catalytic residues Ser and/or Tyr. In conclusion, this study demonstrates that BP chemicals can inhibit 11β-HSD1 from 4 species, and there are subtle species-dependent difference in the inhibitory strength and structural variations of BPs.

Spatiotemporal characteristics and driving factor analysis of embodied CO2 emissions in China's building sector

Since the embodied emissions of the building sector play a pivotal role in the total emission profile of developing countries, represented by China, it is crucial to uncover its emission characteristics and the underlying drivers. Most existing studies focus on building operational emissions, and there is a lack of in-depth studies on embodied emissions, especially in spatiotemporal heterogeneity and spatial correlation. Thus, this study calculates embodied emissions of the building sector in China's 29 provinces during 2011–2020 and develops an innovative factor analysis model that integrates the extended STIRPAT model, network analysis, and spatial Durbin model to explore the influence mechanisms of various factors on emissions from local, spillover, overall and temporal perspectives. The empirical results reveal notable spatiotemporal differences and spatial dependence across regions. The area has consistently been the most crucial driver. The building performance demands are increasingly influencing emissions through direct and spillover effects. The slowdown decarbonization of the material industry diminishes its impact. Limited technical improvement and regional shifts of carbon-intensive enterprises have weakened the technological emission reduction effects. Therefore, regulating ineffective construction, discouraging excessive building performance, implementing demand-side material efficiency strategies, bolstering interregional coordination, and developing low-carbon technologies are keys to cutting emissions.

COVID-19 and the Heart: Lessons Learned and Future Research Directions

It has become evident that acute COVID-19 infection can lead to cardiovascular complications. While the exact mechanisms by which COVID-19 affects the cardiovascular system have yet to be fully elucidated, several mechanisms have been proposed, including direct myocardial effects on the virus and systemic inflammation as an indirect result. The cardiovascular complications of COVID-19 have been characterized and described using noninvasive cardiac imaging. The impact of COVID-19 on the cardiovascular system extends beyond the acute phase of the infection and well beyond recovery or the convalescent period. However, the underlying mechanisms of post-viral long-COVID symptoms have yet to be elucidated. It is evident that COVID-19 has become endemic and is here to stay. Future studies are needed (1) to understand the long-term effects of the cardiovascular complications of COVID-19, future cardiovascular events and the impact of mutating variants on cardiovascular complications through data collection and analysis, (2) to identify the most important diagnostic criteria for prognosis of COVID-19 and to understand the disease mechanism through biomarkers and advanced cardiac imaging, including echocardiography and (3) to develop novel strategies to manage and treat these cardiovascular complications using the knowledge gained.

Elevating teachers’ performance through locus of control, leadership style, environmental factors, and work motivation

The roles of teachers as educators are to impart knowledge and skills to students, as well as develop their mental character. Therefore, this study aims to analyze the influence of locus of control, leadership style, environmental factors, and work motivation on teachers’ performance in guiding students toward a higher level of education. A sample size of 720 high school teachers was used to explore the perceptions of locus of control, leadership style, environmental factors, and work motivation on performance. Furthermore, the data were analyzed using the Smart-Partial Least Square software. The results showed a direct effect of locus of control, leadership style, and environmental factors on work motivation. Moreover, there was an effect of locus of control, environmental factors, and work motivation on teachers’ performance. These results highlight the necessity for qualified teachers, which the government of Indonesia needs to fulfill in order to achieve a better education across the country.

Ethical and preventive legal technology

AbstractPreventive Legal Technology (PLT) is a new field of Artificial Intelligence (AI) investigating the intelligent prevention of disputes. The concept integrates the theories of preventive law and legal technology. Our goal is to give ethics a place in the new technology. By explaining the decisions of PLT, we aim to achieve a higher degree of trustworthiness because explicit explanations are expected to improve the level of transparency and accountability. Trustworthiness is an urgent topic in the discussion on doing AI research ethically and accounting for the regulations. For this purpose, we examine the limitations of rule-based explainability for PLT. Hence, our Problem Statement reads: to what extent is it possible to develop an explainable and trustworthy Preventive Legal Technology? After an insightful literature review, we focus on case studies with applications. The results describe (1) the effectivity of PLT and (2) its responsibility. The discussion is challenging and multivariate, investigating deeply the relevance of PLT for LegalTech applications in light of the development of the AI Act (currently still in its final phase of process) and the work of the High-Level Expert Group (HLEG) on AI. On the ethical side, explaining AI decisions for small PLT domains is clearly possible, with direct effects on trustworthiness due to increased transparency and accountability.

Life course socioeconomic status, chronic pain, and the mediating role of allostatic load: findings from the midlife in the United States.

Low socioeconomic status (SES) has been linked to chronic pain (CP); however, the mechanisms by which SES over the life course influences downstream CP outcomes remain unclear. This study utilizes data from the Midlife in the United States (MIDUS) survey, a prospective sample of community-dwelling individuals (N=781), to investigate the chain of risk additive model of SES in relation to CP. Additionally, the study examines the mediating role of allostatic load (AL) in the relationship between life course SES and CP. Confirmatory factor analysis was employed to capture the multidimensionality of life course SES and path analysis was used to examine the direct and indirect effects on CP. AL was computed by quartile-based summation and by latent class analysis. Results indicated lower SES in MIDUS 2 was associated with greater high-interference CP odds in MIDUS 3 (OR=1.069, 95% CI=1.006-1.136, P < 0.05) and no association was found between distal SES and levels of CP interference. Similarly, no significant relationship was observed between SES and the number of CP locations. Additionally, no additive effects of SES were found, and AL did not present mediation effects on the association between life course SES and CP. The present study emphasizes the importance of directly proximal effects of SES on CP, underscoring the need for equitable distribution of health resources and the implementation of policies focused on diminishing socioeconomic inequalities. Further research is needed to examine alternative pathways by which proximal SES impact CP.

Major Depressive Disorder as a Driver of Dual Systems Model Development During Adolescence and Emerging Adulthood Among Justice-Involved Youth: Is Salience Age-Graded?

The dual systems model is a psychological framework centered on differential development of sensation-seeking and impulse control during adolescence and emerging adulthood with implications for understanding antisocial behavior. However, there is a dearth of research which has examined mental illness as a driver of differential development of these constructs. This study examined major depressive disorder as a risk factor for elevated sensation-seeking and diminished impulse control and tested to determine whether the salience differed by age. The Pathways to Desistance data were analyzed. Mixed effects models examined the direct effect of major depressive disorder on dual systems outcomes and test for moderation by age. Findings indicated that major depressive disorder at baseline was associated with increased sensation-seeking and diminished impulse control. Relationships did not differ in salience based on age. Results suggest that treatment effective for addressing depression may have relevance for mitigating the impact of the disorder on cognition.

The Influence of Transformational Leadership on Work Motivation Has an Impact on Teacher Performance in Senior High Schools in Southwest Sumba Regency

The quality of learning is influenced by many aspects, the most important of which is the teacher's ability. This research to analyze and explain the impact of transformational leadership and work motivation on teacher performance. Quantitative research was carried out on high school teachers in the West Sumba district. The number of teachers was 726 people. Determining the number of illustrations using a random sampling method, Morgan's recipe was corrected with Warwich's and Lininge's recipes. The results obtained were 300 respondents. The collection uses a closed-type questionnaire with 5 options. The analysis uses the multivariate Structural Equation Modeling (PLS-SEM) method. The research results are: (1) transformational leadership has an important positive direct influence on the encouragement of activity, experimental facts, T-Statistics is 2.517, P-Values is 0.012 (2) leadership has an important positive direct effect on teacher ability T-Statistics experimental fact is 2,795 P-Values is 0.008( 3) encouragement of activities has a direct positive influence on the teacher's ability T-Statistics experimental fact is 14.448 P-Values is 0.000(4) leadership Transformational leadership indirectly influences teacher ability through activity encouragement as proven by experiments. T-Statistics is 2.461. P-Values are 0.014. Research findings show that transformational leadership and activity encouragement have an important influence and are predictors of increasing teacher ability.

The Impact of Economic Integration on Income Inequality in the EU: A Panel Data Analysis of the EU Members from 2002-2020

This paper investigates the relation between economic integration and income inequality for the 27 current EU members from 2002 to 2020. The Gini coefficient is the dependent variable in a panel data regression analysis, and is expressed as a function of indicators related to economic integration (total trade, intra-EU trade, foreign direct investment (FDI) inflow and outflow) and a set of control variables. Although much research points to a significant relationship between inequality and integration, there is no consensus on the sign and magnitude of the effect. In this paper, four random effects panel models are estimated with robust standard errors to uncover this relationship. The results show that in the context of the EU, intra-EU trade is associated with decreased income inequality, while overall trade and FDI in- or outflow seem to have no direct effect on the income gap. In addition, the level of economic development seems to moderate the effect of intra-EU trade: for countries with a below-average gross domestic product (GDP) per capita, the reducing effect of integration on Gini is weaker than for richer countries. Additionally, market capitalisation, the presence of natural resources and government spending on social benefits are associated with reduced inequality, while unemployment and population size seem to drive income disparities. These results are consistent with a major part of the existing literature and lead to interesting conclusions for policy makers. The originality of this work differentiating it from prior research is twofold: (1) the region of examination is the EU, which is not often the subject of similar analyses, and (2) an interaction effect is examined that differs from the conventional measures for less developed economies.

Analysis of risk factors and interactions for pain in temporomandibular disorder: A cross-sectional study.

Risk factors for temporomandibular disorder (TMD) pain remain unclear. This study aimed to identify risk factors for TMD pain using a biopsychosocial model and to investigate interactions between potential risk factors-oral behaviours (OBs), psychological factors and sleep quality-and their direct and indirect effects on TMD pain. This was a cross-sectional study of 488 patients with TMDs (422 women; 30.8 ± 9.4 years). Pain was assessed using the Numerical Rating Scale. Demographic, behavioural, psychological and biomedical data were collected through clinical examination, face-to-face interviews and questionnaires. Multiple linear regression analysis was used to identify factors associated with TMD pain. Mediation and moderation analysis were used to evaluate interactions between variables. Significant mediation ('0' not included in the 95% confidence interval (CI)) and moderation (p < .05) effects on TMD pain were identified. Marital status, diagnosis subgroup, previous medication use, depression and sleep quality were significant risk factors for TMD pain (p < .05). Significant mediation effects were observed as follows: depression and sleep quality mediated the association between OBs and pain; sleep quality mediated the association between somatization, depression, anxiety and pain; and depression mediated the association between sleep quality and pain (all 95% CI did not contain '0'). (1) Marital status, diagnosis subgroup, previous medication use, depression and sleep quality were associated with TMD pain. (2) OBs can exacerbate pain by promoting depression and reducing sleep quality. Psychological factors and sleep quality can interact to exacerbate pain.