Objective:Natural killer(NK)cells have gained considerable attention due to their potential in treating"cold tumors,"and are therefore considered as one of the new strategies for curing cancer,by using world...Objective:Natural killer(NK)cells have gained considerable attention due to their potential in treating"cold tumors,"and are therefore considered as one of the new strategies for curing cancer,by using worldwide development of their new possibilities and interventions with NK cell-related therapeutic products.Methods:We constructed a trispecific killer engager(TriKE)consisting of anti-CD16,IL-15,and anti-CD19.This TriKE was designed to attract CD19^(+)tumor cells to CD16^(+)NK cells,whereas IL-15 sustained the proliferation,development,and survival of NK cells.Results:Treatment with 161519 TriKE in the presence of CD19^(+)targets upregulated expression of CD69,CD107 a,TRAIL,IFN-γ,and TNF-α in NK cells,and significantly improved the proliferation and cytotoxicity of NK cells.NK cells"armed"with 161519 TriKE showed stronger cytolysis against CD19+targets compared with that of"unarmed"NK cells.A preclinical model of B-cell lymphoma in human peripheral blood mononuclear cell-reconstituted xenograft mice showed significant inhibition of tumor growth and prolonged overall survival after treatment with 161519 TriKE,when compared with that in control mice or mice treated with 1619 BiKE.Combined use of IL-2 was a more effective treatment with 1619 BiKE,when compared with that using 161519 TriKE.Conclusions:The newly generated 161519 TriKE enhanced the proliferation,activation,cytokine secretion,and cytotoxicity of NK cells in the presence of CD19+tumor cells.The 161519 TriKE aided inhibition of tumor growth and prolonged the overall survival of murine xenografts,and could be used to treat CD19-positive cancers.展开更多
Advancements in protein engineering have driven the continuous optimization of T-cell engagers(TCEs),resulting in remarkable clinical outcomes in the treatment of B-cell malignancies.Moreover,developing tri-or multisp...Advancements in protein engineering have driven the continuous optimization of T-cell engagers(TCEs),resulting in remarkable clinical outcomes in the treatment of B-cell malignancies.Moreover,developing tri-or multispecific TCEs has emerged as a promising strategy to address the challenges of tumor heterogeneity and antigen escape.However,considerable obstacles remain,primarily in format design.In this study,we engineered BAFF-based TCEs with various formats that incorporate anti-CD3 Fab or IgG domains fused with BAFF ligands to target BAFF recep tors(BAFFR,BCMA,and TACI).These constructs varied in valency and the presence or absence of long-acting ele ments such as Fc domains or the albumin binding domain consensus sequence(ABDCon).Although the inclusion of an Fc domain did not enhance sustained tumor eradication,variations in valency and spatial configuration profoundly influenced cytotoxicity.We identified TriBAFF/CD3/ABDCon as the optimal trifunctional construct,fea turing an anti-CD3 Fab backbone with BAFF and ABDCon fused to the C-termini of the heavy and light chains.This design facilitates optimal immune synapse formation between the target cells and T cells and effectively controls tumor burdens in various B-cell malignancy models with good tolerability.Notably,TriBAFF/CD3/ABDCon outper formed conventional therapies,including blinatumomab and BAFF-based CAR-T cells,in models of heterogeneous leukemia and aggressive lymphoma.These findings underscore the potential of using natural ligands as antibody-targeting modules and provide valuable insights into the design of the next generation of multispecific TCEs,which hold promise for improving treatment outcomes in a wide range of malignancies and beyond.展开更多
Bispecific killer cell engagers(BiKEs)are a powerful tool to incite the killing power of natural killer(NK)cells.Here,we posited that the BiKE technology could be utilized to deplete activated immune cells expressing ...Bispecific killer cell engagers(BiKEs)are a powerful tool to incite the killing power of natural killer(NK)cells.Here,we posited that the BiKE technology could be utilized to deplete activated immune cells expressing programmed death-1(PD-1^(+)cells),and hence treat autoimmune diseases since these cells drive the disorders.We designed and generated PD-1 BiKE that targets an activating NK cell receptor,CD16,and PD-1.PD-1 BiKE showed specific binding to PD-1^(+)cells and engaged CD16 simultaneously.PD-1 BiKE enhanced NK cell-mediated apoptosis and depletion of PD-1^(+)Raji cells,but not PD-1-Raji cells.Further,PD-1 BiKE induced apoptosis of primary PD-1^(+)T lymphocytes that are highly relevant to autoimmune disease progression.The BiKE depleted 42%of primary T cells that were stimulated in vitro.Importantly,those ablated primary T cells were activated cells.Meanwhile,naive T cells were spared by the BiKE treatment,supporting the crucial selectivity of PD-1 BiKE-directed cell depletion.Lastly,PD-1 BiKE is more effective than a conventional depleting antibody in the depletion of PD-1^(+)cells.The current work supports PD-1 BiKE is a selective,potent,and safe tool to deplete PD-1^(+)cells.展开更多
Cytokines exert powerful immunomodulatory effects that are critical to physiology and pathology in humans.The application of natural cytokines in clinical studies has not been clearly established,and there are often p...Cytokines exert powerful immunomodulatory effects that are critical to physiology and pathology in humans.The application of natural cytokines in clinical studies has not been clearly established,and there are often problems associated with toxicity or lack of efficacy.The key reasons can be attributed to the pleiotropy of cytokine receptors and undesired activation of off-target cells.With a deeper understanding of the structural principles and functional signals of cytokine-receptor interactions,artificial modification of cytokine signaling through protein engineering and synthetic immunology has become an increasingly feasible and powerful approach.Engineered cytokines are designed to selectively target cells.Herein,the theoretical and experimental evidence of cytokine engineering is reviewed,and the“supercytokines”resulting from structural enhancement and the“immunocytokines”generated by antibody fusion are described.Finally,the“engager cytokines”formed by the crosslinking of cytokines and bispecific immune engagers and other synthetic cytokines formed by nonnatural analogs are also discussed.展开更多
By binding to multiple antigens simultaneously,multispecific antibodies are expected to substantially improve both the activity and long-term efficacy of antibody-based immunotherapy.Immune cell engagers,a subclass of...By binding to multiple antigens simultaneously,multispecific antibodies are expected to substantially improve both the activity and long-term efficacy of antibody-based immunotherapy.Immune cell engagers,a subclass of antibody-based constructs,consist of engineered structures designed to bridge immune effector cells to their target,thereby redirecting the immune response toward the tumor cells or infected cells.The increasing number of recent clinical trials evaluating immune cell engagers reflects the important role of these molecules in new therapeutic approaches for cancer and infections.In this review,we discuss how different immune cell types(T and natural killer lymphocytes,as well as myeloid cells)can be bound by immune cell engagers in immunotherapy for cancer and infectious diseases.Furthermore,we explore the preclinical and clinical advancements of these constructs,and we discuss the challenges in translating the current knowledge from cancer to the virology field.Finally,we speculate on the promising future directions that immune cell engagers may take in cancer treatment and antiviral therapy.展开更多
Introduction:The choice is no longer whether—but when and how!Today,organizations can no longer choose whether or not to engage with stakeholders;the only real decision is when and how to do it successfully.Engaging ...Introduction:The choice is no longer whether—but when and how!Today,organizations can no longer choose whether or not to engage with stakeholders;the only real decision is when and how to do it successfully.Engaging stakeholders is essential for any type of organization,public,private,or civil society.In fact,it is a fundamental part of effective governance,continuous improvement,and social responsibility.The principle behind stakeholder engagement is simple yet powerful:those who can influence or be affected by an organization's mission must be given the opportunity to express their views and contribute to shaping the decisions that impact them.展开更多
1.Introduction Speaking with an audience as a scientific expert should not be intimidating.I have done more than my share in a variety of roles,so Professors Zhigang Peng(Georgia Tech)and Xiaodong Song(Peking Universi...1.Introduction Speaking with an audience as a scientific expert should not be intimidating.I have done more than my share in a variety of roles,so Professors Zhigang Peng(Georgia Tech)and Xiaodong Song(Peking University)asked me to review pertinent lessons.展开更多
Objectives:Teachers are facing unprecedented new challenges leading them to face an increasing number of tasks that are not part of their job,as well as having to cope with the additional skills acquisition that comes...Objectives:Teachers are facing unprecedented new challenges leading them to face an increasing number of tasks that are not part of their job,as well as having to cope with the additional skills acquisition that comes with non-traditional forms of teaching and learning,and increased work pressure leading to an increase in the rate of teachers leaving the profession.Therefore,this study aims to explore the mechanism of the career calling on job burnout through career adaptability and work engagement.Methods:This study conducted a cross-sectional survey of 465 primary and secondary school teachers(PSST)in China's Mainland from the perspective of work adjustment and used structural equation modeling(SEM)to examine the mediating roles of career adaptability and work engagement in the relationship between teachers’career calling and job burnout.Results:The results show that PSSTs are above average in career calling,career adaptability,and work engagement,while job burnout is below average.A significant positive or negative correlation exists between career calling,career adaptability,work engagement,and job burnout.The result of path analysis indicates that career adaptability and work engagement exert an indirect influence on the job burnout of PSST through three paths:namely,the independent intermediary role of career adaptability(EV=−0.144),the independent intermediary role of work engagement(EV=0.172)and the chain intermediary role of the two(EV=0.176).Conclusion:This study emphasizes the importance of career adaptability and work engagement in teacher development in regulating career calling and job burnout.Therefore,on the one hand,we think that if managers want to reduce teachers’job burnout,they need to pay more attention to teachers’career adaptability and work engagement,rather than relying solely on teachers’career calling.On the other hand,it is to remind teachers not to rely on their adjustment to adapt to the work,but also to need outside help as much as possible.展开更多
Objective:This review aimed to identify the barriers and facilitators to equitable coronavirus disease 2019(COVID-19)vaccine distribution in Nigeria using the consolidated framework for implementation research(CFIR).M...Objective:This review aimed to identify the barriers and facilitators to equitable coronavirus disease 2019(COVID-19)vaccine distribution in Nigeria using the consolidated framework for implementation research(CFIR).Methods:A comprehensive search strategy was applied across five databases—Web of Science,MEDLINE,EMBASE,CAB Direct,and CINAHL.The search,conducted as part of a scoping review,yielded 2,751 citations.Seven studies met the inclusion criteria after screening.Data were extracted and analyzed using CFIR constructs to identify key barriers and facilitators to equitable vaccine distribution.Results:Six barriers were identified:limited physical and socioeconomic access,bribery,nepotism,and insufficient availability of translated information.Facilitators included community involvement as local monitoring agents,unannounced staff inspections,healthcare worker training tailored to community needs,and localized outreach strategies such as jingles and call-in programs.CFIR constructs,including Local Conditions,Tailoring Strategies,Available Resources,and Physical Infrastructure,provided a framework for analyzing the findings.Conclusion:This review highlights significant barriers and promising facilitators to equitable vaccine distribution in Nigeria.Targeted interventions,such as community engagement,anti-corruption measures,and culturally tailored strategies,are critical to addressing these challenges and improving access.These findings underscore the need for localized,equity-focused approaches to enhance vaccine distribution systems in Nigeria and other low-resource settings.展开更多
The dynamics of student engagement and emotional states significantly influence learning outcomes.Positive emotions resulting from successful task completion stand in contrast to negative affective states that arise f...The dynamics of student engagement and emotional states significantly influence learning outcomes.Positive emotions resulting from successful task completion stand in contrast to negative affective states that arise from learning struggles or failures.Effective transitions to engagement occur upon problem resolution,while unresolved issues lead to frustration and subsequent boredom.This study proposes a Convolutional Neural Networks(CNN)based approach utilizing the Multi⁃source Academic Affective Engagement Dataset(MAAED)to categorize facial expressions into boredom,confusion,frustration,and yawning.This method provides an efficient and objective way to assess student engagement by extracting features from facial images.Recognizing and addressing negative affective states,such as confusion and boredom,is fundamental in creating supportive learning environments.Through automated frame extraction and model comparison,this study demonstrates reduced loss values with improving accuracy,showcasing the effectiveness of this method in objectively evaluating student engagement.Monitoring facial engagement with CNN using the MAAED dataset is essential for gaining insights into human behaviour and improving educational experiences.展开更多
This review interrogates empirical and theoretical research on agentic engagement in foreign language(FL)learning.Through synthesizing peer-reviewed studies from Web of Science and CNKI databases,it maps the theoretic...This review interrogates empirical and theoretical research on agentic engagement in foreign language(FL)learning.Through synthesizing peer-reviewed studies from Web of Science and CNKI databases,it maps the theoretical evolution,methodological innovations,key influencing factors and proposed suggestion for further research on student agency.Future research should prioritize,longitudinal studies,culturally comparative designs,validity constructs and ethical evaluations of artificial intelligence’s impact on learner autonomy.This review calls for a holistic approach to FL education,where agentic engagement bridges individual initiative,pedagogical innovation,and sociocultural responsiveness to empower learners in multilingual global contexts.展开更多
This study investigates whether and how exemplars can facilitate student engagement in self-assessment tasks.An intact class of 32 undergraduates majoring in Chinese-English translation participated in the study.After...This study investigates whether and how exemplars can facilitate student engagement in self-assessment tasks.An intact class of 32 undergraduates majoring in Chinese-English translation participated in the study.After some preliminary training,the students performed three translation self-assessment tasks,each involving comparison with authentic exemplars of varying quality and filling out a structured self-assessment report.Our analysis of multiple sources of data reveals the multi-dimensional nature of student engagement in self-assessment activities and the potential for using authentic exemplars of different qualities to enhance students’cognitive and behavioral engagement and mitigate negative emotions in the process.Pedagogical implications for implementing exemplars and self-assessment to promote student engagement and support student learning are discussed.展开更多
Background:With the rapid growth of digital learning environments,esports has emerged as a popular form of school-based activity that promotes teamwork,motivation,and engagement.However,limited research has examined h...Background:With the rapid growth of digital learning environments,esports has emerged as a popular form of school-based activity that promotes teamwork,motivation,and engagement.However,limited research has examined how participation in esports relates to students’psychological and academic development.To address this gap,the present study identified structural relationships between perceived psychological well-being,social support,academic engagement,and school-life satisfaction among students participating in school-based esports activities.Methods:We surveyed 588 students who competed in on-campus esports tournaments across 15 secondary schools in Gwangju Metropolitan City,South Korea.Psychological well-being,social support,academic engagement,and school-life satisfaction were measured using five-point Likert scales.Confirmatory factor analysis and structural equation modeling(SEM)were employed to test the hypotheses,and mediation effects were assessed via bootstrapping(1000 resamples,95%confidence interval)and competing model analysis.Results:The results showed that psychological well-being has significant positive effects on social support(β=0.899,p<0.001)and academic engagement(β=0.427,p<0.01).Social support positively predicted school-life satisfaction(β=0.804,p<0.001).Psychological well-being did not directly influence this outcome;instead,it exerted an indirect effect via social support(indirect effect=0.676,95%confidence interval[0.549,0.782]),indicating that social support functioned as a full mediator.Conclusion:Overall,the results demonstrate that school-based esports activities may serve as educational contexts that enhance students’overall satisfaction with school experiences through increased social support.Importantly,these findings highlight the unique psychosocial mechanisms of esports participation,including digital identity,online belonging,and virtual collaboration,which extend beyond traditional educational activities.Because the impact of academic engagement may depend on the quality of participation,future esports programs should incorporate support systems that foster autonomous and collaborative engagement and include digital-citizenship education.展开更多
Objective:To examine how emotional labor demands and strategies influence work engagement and occupational identity among Portuguese volunteer firefighters.Methods:Participants completed the Emotional Work Requirement...Objective:To examine how emotional labor demands and strategies influence work engagement and occupational identity among Portuguese volunteer firefighters.Methods:Participants completed the Emotional Work Requirements Scale,Emotional Labour Scale,Utrecht Work Engagement Scale,and Social Identity Scale.Multiple linear regression analyses were conducted to assess the predictive effects of emotional labor demands and strategies on work engagement and occupational identity.Results:Emotional labor explained 11.8%of the variance in work engagement and 10.9%in occupational identity.Positive emotion expression significantly predicted higher work engagement and a stronger occupational identity,while the suppression of negative emotions predicted a weaker occupational identity.Other emotional labor dimensions were not significant.Conclusions:Findings underscore the dual role of emotional labor—as a resource when positive emotions are expressed and as a strain when negative emotions are habitually suppressed.Targeted interventions to promote authentic positive expression and effective emotional processing may enhance firefighters’well-being,strengthen crisis team performance,and benefit the communities they serve.Further research is needed to deepen the understanding of emotional labor in crisis response contexts.展开更多
This study examines the impact of political polarization on youth engagement in Brazil,focusing on the intersection of historical legacies,cultural dynamics,and modern political influences.Tracing the evolution of pol...This study examines the impact of political polarization on youth engagement in Brazil,focusing on the intersection of historical legacies,cultural dynamics,and modern political influences.Tracing the evolution of polarization from the military dictatorship era to contemporary politics under Jair Bolsonaro,the study explores how polarized rhetoric,misinformation,and digital media have reshaped the political landscape for young Brazilians.Data for the study were collected through a survey of 159 college students aged 18-25 from public and private institutions across Brazil,complemented by 10 interviews with youth activists and party leaders from the Workers’Party(PT)and the Liberal Party(PL).These methods aimed to evaluate how polarization affects young people’s beliefs,political identities,behaviors,engagement levels,and ability to participate in constructive political discourse.The findings reveal that while polarization fosters hostility and deepens ideological divides,it also inspires youth activism by creating a sense of identity and belonging.Education,digital information channels,and the lack of representation in leadership roles emerge as key factors shaping youth engagement.Despite challenges,the research underscores hope:young Brazilians display resilience,critical awareness,and a shared desire for accountability and inclusivity.This study highlights the potential of youth to bridge divides and lead Brazil toward a more collaborative and democratic future.展开更多
This study examines the influence of land suitability and investment in facilities on tourism potential,with a particular focus on the mediating role of community engagement.While previous research has explored the im...This study examines the influence of land suitability and investment in facilities on tourism potential,with a particular focus on the mediating role of community engagement.While previous research has explored the impact of environmental and infrastructural factors on tourism development,few studies have examined the interactive effects of community engagement in maximizing these benefits.This study aims to fill this gap by providing empirical evidence from Huangma Village,Jiangxi Province,China.A quantitative research design was adopted,using Partial Least Squares-Structural Equation Modeling(PLS-SEM)in SmartPLS to test the hypothesized relationships.Data were collected from 231 respondents,including local residents,tourism business owners,government officials,and infrastructure developers,through a structured survey questionnaire.The results confirm that land suitability and infrastructure investment significantly enhance tourism potential,with community engagement playing a crucial mediating role.The findings suggest that tourism success depends not only on physical and economic factors but also on active local participation in tourism-related initiatives.This study contributes to the literature by integrating environmental,infrastructural,and social dimensions of tourism development.The findings offer practical insights for policymakers and tourism planners,emphasizing the need for sustainable land management,strategic infrastructure investment,and participatory tourism governance to maximize tourism potential.展开更多
Background Health promotion(HP)interventions delivered through sports clubs have demonstrated promising outcomes among men,but less is known about which aspects of the interventions work,for whom,and under what circum...Background Health promotion(HP)interventions delivered through sports clubs have demonstrated promising outcomes among men,but less is known about which aspects of the interventions work,for whom,and under what circumstances.This rapid realist review aimed to understand the contexts,mechanisms,and outcomes of HP interventions for men delivered through sports clubs.Methods A systematic literature search was conducted in February 2023 for studies published after 2013 in MEDLINE,Embase,and SPORTDiscus databases.Included studies:(a)were delivered by or in collaboration with sports clubs,(b)targeted men aged 18+years,and(c)reported 1 or more HP outcomes.A grey literature search was also performed.Studies were included in a realist synthesis based on richness and rigor.Hereafter,context-mechanism-outcome(CMO)configurations were developed.Results We identified and screened 3358 studies,finally including 59 studies describing 22 interventions.Most HP interventions were delivered in high income countries,included Caucasian men aged 35-65 years with overweight/obesity,and used professional sports clubs(mostly football)for recruitment and facilities.Quantitative HP outcomes were reported across 19 interventions.Of these 19 interventions,the majority reported on weight(n=18),physical activity(n=12),mental health(n=10),and diet(n=9).We identified 13 CMOs related to how HP interventions affected men's recruitment,engagement,and health behavior maintenance.Conclusion Our findings show that using sports clubs for HP interventions is effective for engaging men.Recruitment was facilitated by leveraging sports clubs’identity,addressing masculinity-related barriers,improving accessibility,and building trust.Engagement was enhanced through shared identity experiences,safe spaces,inclusive competition,and self-efficacy.However,there's limited evidence on behavior maintenance post-intervention,though involving community stakeholders seemed vital.In general,considerations should be made to avoid perpetuating traditional masculine norms,which may exclude some men and reinforce unhealthy behaviors.These findings can guide intervention development,emphasizing the need to harness men's perspectives in the process.展开更多
Background:Work engagement(WE)is critical to quality primary healthcare delivery.However,limited research has explored its levels and determinants among healthcare professionals in low-and middle-income countries.This...Background:Work engagement(WE)is critical to quality primary healthcare delivery.However,limited research has explored its levels and determinants among healthcare professionals in low-and middle-income countries.This study assessed the levels and correlates of work engagement among physician assistants(PAs)in Ghana.Methods:A cross-sectional study was conducted among 439 PAs from October to December 2024.Participants were recruited via emails,social media platforms,and posters featuring study links and scannable questionnaire codes.WE was measured using the validated Utrecht Work Engagement Scale questionnaire.Results:Overall,WE levels were average,with similar trends across the three subdomains.In the bootstrapped multivariate linear regression model,anxiety was negatively associated with WE(β=-0.49,95%confidence interval[CI]:-0.77 to-0.21).Conversely,working in an urban area(β=0.36,95%CI:0.05 to 0.67),holding the rank of PA/Senior PA(β=0.27,95%CI:0.03 to 0.52),reporting good self-rated health(β=0.54,95%CI:0.19 to 0.88),and working at health centers(β=0.86,95%CI:0.22 to 1.50)were positively associated with WElevels.Conclusion:WE levels are average in the study sample,highlighting the need for strategic interventions to improve and sustain the healthcare workforce's motivation and performance.Addressing workplace stressors,enhancing professional development opportunities,and fostering supportive work environments could improve engagement among PAs and healthcare professionals in general.Strengthening WE is essential for ensuring resilient quality primary healthcare systems and achieving the goals of universal health coverage.展开更多
基金supported by grants from the National Key R&D Program of China(Grant No.2019YFA0508502)the CAMS Innovation Fund for Medical Sciences(Grant No.2019-I2M-5-073)the National Natural Science Foundation of China(Grant Nos.81788101,81972679,and 81821001)。
文摘Objective:Natural killer(NK)cells have gained considerable attention due to their potential in treating"cold tumors,"and are therefore considered as one of the new strategies for curing cancer,by using worldwide development of their new possibilities and interventions with NK cell-related therapeutic products.Methods:We constructed a trispecific killer engager(TriKE)consisting of anti-CD16,IL-15,and anti-CD19.This TriKE was designed to attract CD19^(+)tumor cells to CD16^(+)NK cells,whereas IL-15 sustained the proliferation,development,and survival of NK cells.Results:Treatment with 161519 TriKE in the presence of CD19^(+)targets upregulated expression of CD69,CD107 a,TRAIL,IFN-γ,and TNF-α in NK cells,and significantly improved the proliferation and cytotoxicity of NK cells.NK cells"armed"with 161519 TriKE showed stronger cytolysis against CD19+targets compared with that of"unarmed"NK cells.A preclinical model of B-cell lymphoma in human peripheral blood mononuclear cell-reconstituted xenograft mice showed significant inhibition of tumor growth and prolonged overall survival after treatment with 161519 TriKE,when compared with that in control mice or mice treated with 1619 BiKE.Combined use of IL-2 was a more effective treatment with 1619 BiKE,when compared with that using 161519 TriKE.Conclusions:The newly generated 161519 TriKE enhanced the proliferation,activation,cytokine secretion,and cytotoxicity of NK cells in the presence of CD19+tumor cells.The 161519 TriKE aided inhibition of tumor growth and prolonged the overall survival of murine xenografts,and could be used to treat CD19-positive cancers.
基金supported by Shenzhen Medical Research Fund(B2402027)the National Natural Science Foundation of China(32171464)+3 种基金Shenzhen Fundamental Research Program(Natural Science Foundation)-Key Basic Research Project(JCYJ20241202125200001)the National Key R&D Program of China(2019YFA0904200 and 2019YFA0906100)Shenzhen Nanshan District Health System Science and Technology Major Project(NSZD2023018)This study is a Nanshan District medical key discipline construction financial support project.
文摘Advancements in protein engineering have driven the continuous optimization of T-cell engagers(TCEs),resulting in remarkable clinical outcomes in the treatment of B-cell malignancies.Moreover,developing tri-or multispecific TCEs has emerged as a promising strategy to address the challenges of tumor heterogeneity and antigen escape.However,considerable obstacles remain,primarily in format design.In this study,we engineered BAFF-based TCEs with various formats that incorporate anti-CD3 Fab or IgG domains fused with BAFF ligands to target BAFF recep tors(BAFFR,BCMA,and TACI).These constructs varied in valency and the presence or absence of long-acting ele ments such as Fc domains or the albumin binding domain consensus sequence(ABDCon).Although the inclusion of an Fc domain did not enhance sustained tumor eradication,variations in valency and spatial configuration profoundly influenced cytotoxicity.We identified TriBAFF/CD3/ABDCon as the optimal trifunctional construct,fea turing an anti-CD3 Fab backbone with BAFF and ABDCon fused to the C-termini of the heavy and light chains.This design facilitates optimal immune synapse formation between the target cells and T cells and effectively controls tumor burdens in various B-cell malignancy models with good tolerability.Notably,TriBAFF/CD3/ABDCon outper formed conventional therapies,including blinatumomab and BAFF-based CAR-T cells,in models of heterogeneous leukemia and aggressive lymphoma.These findings underscore the potential of using natural ligands as antibody-targeting modules and provide valuable insights into the design of the next generation of multispecific TCEs,which hold promise for improving treatment outcomes in a wide range of malignancies and beyond.
基金supported by the HCI Melanoma Center Grant,the National Institutes of Health AI139535 grant,and the National Multiple Sclerosis Society GR-1807-31630 grant to Mingnan Chen(USA)supported by the HCI Melanoma Center Grant,the National Institutes of Health AI139535 grant,and the National Multiple Sclerosis Society GR-1807-31630 grant to Mingnan Chen(USA).
文摘Bispecific killer cell engagers(BiKEs)are a powerful tool to incite the killing power of natural killer(NK)cells.Here,we posited that the BiKE technology could be utilized to deplete activated immune cells expressing programmed death-1(PD-1^(+)cells),and hence treat autoimmune diseases since these cells drive the disorders.We designed and generated PD-1 BiKE that targets an activating NK cell receptor,CD16,and PD-1.PD-1 BiKE showed specific binding to PD-1^(+)cells and engaged CD16 simultaneously.PD-1 BiKE enhanced NK cell-mediated apoptosis and depletion of PD-1^(+)Raji cells,but not PD-1-Raji cells.Further,PD-1 BiKE induced apoptosis of primary PD-1^(+)T lymphocytes that are highly relevant to autoimmune disease progression.The BiKE depleted 42%of primary T cells that were stimulated in vitro.Importantly,those ablated primary T cells were activated cells.Meanwhile,naive T cells were spared by the BiKE treatment,supporting the crucial selectivity of PD-1 BiKE-directed cell depletion.Lastly,PD-1 BiKE is more effective than a conventional depleting antibody in the depletion of PD-1^(+)cells.The current work supports PD-1 BiKE is a selective,potent,and safe tool to deplete PD-1^(+)cells.
基金supported by the Shenzhen Institute of Synthetic Biology Scientific Research Program(ZTXM20214003)Natural Science Foundation of China(82122055,81872318)Natural Science Foundation of Anhui Province(2108085J13).
文摘Cytokines exert powerful immunomodulatory effects that are critical to physiology and pathology in humans.The application of natural cytokines in clinical studies has not been clearly established,and there are often problems associated with toxicity or lack of efficacy.The key reasons can be attributed to the pleiotropy of cytokine receptors and undesired activation of off-target cells.With a deeper understanding of the structural principles and functional signals of cytokine-receptor interactions,artificial modification of cytokine signaling through protein engineering and synthetic immunology has become an increasingly feasible and powerful approach.Engineered cytokines are designed to selectively target cells.Herein,the theoretical and experimental evidence of cytokine engineering is reviewed,and the“supercytokines”resulting from structural enhancement and the“immunocytokines”generated by antibody fusion are described.Finally,the“engager cytokines”formed by the crosslinking of cytokines and bispecific immune engagers and other synthetic cytokines formed by nonnatural analogs are also discussed.
基金CR is supported by a grant from the National Research Fund Luxembourg(FNR),Doctoral Training Unit"i2TRON",PRIDE19/14254520,project 20200831.
文摘By binding to multiple antigens simultaneously,multispecific antibodies are expected to substantially improve both the activity and long-term efficacy of antibody-based immunotherapy.Immune cell engagers,a subclass of antibody-based constructs,consist of engineered structures designed to bridge immune effector cells to their target,thereby redirecting the immune response toward the tumor cells or infected cells.The increasing number of recent clinical trials evaluating immune cell engagers reflects the important role of these molecules in new therapeutic approaches for cancer and infections.In this review,we discuss how different immune cell types(T and natural killer lymphocytes,as well as myeloid cells)can be bound by immune cell engagers in immunotherapy for cancer and infectious diseases.Furthermore,we explore the preclinical and clinical advancements of these constructs,and we discuss the challenges in translating the current knowledge from cancer to the virology field.Finally,we speculate on the promising future directions that immune cell engagers may take in cancer treatment and antiviral therapy.
文摘Introduction:The choice is no longer whether—but when and how!Today,organizations can no longer choose whether or not to engage with stakeholders;the only real decision is when and how to do it successfully.Engaging stakeholders is essential for any type of organization,public,private,or civil society.In fact,it is a fundamental part of effective governance,continuous improvement,and social responsibility.The principle behind stakeholder engagement is simple yet powerful:those who can influence or be affected by an organization's mission must be given the opportunity to express their views and contribute to shaping the decisions that impact them.
文摘1.Introduction Speaking with an audience as a scientific expert should not be intimidating.I have done more than my share in a variety of roles,so Professors Zhigang Peng(Georgia Tech)and Xiaodong Song(Peking University)asked me to review pertinent lessons.
基金funded by Humanities and Social Sciences Foundation and Natural Science Foundation of Nanjing University of Posts and Telecommunications(NYY222055,NY224176)General Subject of Educational Science Planning in Jiangsu Province(C/2024/01/76)National Natural Science Foundation of China(62307025).
文摘Objectives:Teachers are facing unprecedented new challenges leading them to face an increasing number of tasks that are not part of their job,as well as having to cope with the additional skills acquisition that comes with non-traditional forms of teaching and learning,and increased work pressure leading to an increase in the rate of teachers leaving the profession.Therefore,this study aims to explore the mechanism of the career calling on job burnout through career adaptability and work engagement.Methods:This study conducted a cross-sectional survey of 465 primary and secondary school teachers(PSST)in China's Mainland from the perspective of work adjustment and used structural equation modeling(SEM)to examine the mediating roles of career adaptability and work engagement in the relationship between teachers’career calling and job burnout.Results:The results show that PSSTs are above average in career calling,career adaptability,and work engagement,while job burnout is below average.A significant positive or negative correlation exists between career calling,career adaptability,work engagement,and job burnout.The result of path analysis indicates that career adaptability and work engagement exert an indirect influence on the job burnout of PSST through three paths:namely,the independent intermediary role of career adaptability(EV=−0.144),the independent intermediary role of work engagement(EV=0.172)and the chain intermediary role of the two(EV=0.176).Conclusion:This study emphasizes the importance of career adaptability and work engagement in teacher development in regulating career calling and job burnout.Therefore,on the one hand,we think that if managers want to reduce teachers’job burnout,they need to pay more attention to teachers’career adaptability and work engagement,rather than relying solely on teachers’career calling.On the other hand,it is to remind teachers not to rely on their adjustment to adapt to the work,but also to need outside help as much as possible.
文摘Objective:This review aimed to identify the barriers and facilitators to equitable coronavirus disease 2019(COVID-19)vaccine distribution in Nigeria using the consolidated framework for implementation research(CFIR).Methods:A comprehensive search strategy was applied across five databases—Web of Science,MEDLINE,EMBASE,CAB Direct,and CINAHL.The search,conducted as part of a scoping review,yielded 2,751 citations.Seven studies met the inclusion criteria after screening.Data were extracted and analyzed using CFIR constructs to identify key barriers and facilitators to equitable vaccine distribution.Results:Six barriers were identified:limited physical and socioeconomic access,bribery,nepotism,and insufficient availability of translated information.Facilitators included community involvement as local monitoring agents,unannounced staff inspections,healthcare worker training tailored to community needs,and localized outreach strategies such as jingles and call-in programs.CFIR constructs,including Local Conditions,Tailoring Strategies,Available Resources,and Physical Infrastructure,provided a framework for analyzing the findings.Conclusion:This review highlights significant barriers and promising facilitators to equitable vaccine distribution in Nigeria.Targeted interventions,such as community engagement,anti-corruption measures,and culturally tailored strategies,are critical to addressing these challenges and improving access.These findings underscore the need for localized,equity-focused approaches to enhance vaccine distribution systems in Nigeria and other low-resource settings.
文摘The dynamics of student engagement and emotional states significantly influence learning outcomes.Positive emotions resulting from successful task completion stand in contrast to negative affective states that arise from learning struggles or failures.Effective transitions to engagement occur upon problem resolution,while unresolved issues lead to frustration and subsequent boredom.This study proposes a Convolutional Neural Networks(CNN)based approach utilizing the Multi⁃source Academic Affective Engagement Dataset(MAAED)to categorize facial expressions into boredom,confusion,frustration,and yawning.This method provides an efficient and objective way to assess student engagement by extracting features from facial images.Recognizing and addressing negative affective states,such as confusion and boredom,is fundamental in creating supportive learning environments.Through automated frame extraction and model comparison,this study demonstrates reduced loss values with improving accuracy,showcasing the effectiveness of this method in objectively evaluating student engagement.Monitoring facial engagement with CNN using the MAAED dataset is essential for gaining insights into human behaviour and improving educational experiences.
文摘This review interrogates empirical and theoretical research on agentic engagement in foreign language(FL)learning.Through synthesizing peer-reviewed studies from Web of Science and CNKI databases,it maps the theoretical evolution,methodological innovations,key influencing factors and proposed suggestion for further research on student agency.Future research should prioritize,longitudinal studies,culturally comparative designs,validity constructs and ethical evaluations of artificial intelligence’s impact on learner autonomy.This review calls for a holistic approach to FL education,where agentic engagement bridges individual initiative,pedagogical innovation,and sociocultural responsiveness to empower learners in multilingual global contexts.
文摘This study investigates whether and how exemplars can facilitate student engagement in self-assessment tasks.An intact class of 32 undergraduates majoring in Chinese-English translation participated in the study.After some preliminary training,the students performed three translation self-assessment tasks,each involving comparison with authentic exemplars of varying quality and filling out a structured self-assessment report.Our analysis of multiple sources of data reveals the multi-dimensional nature of student engagement in self-assessment activities and the potential for using authentic exemplars of different qualities to enhance students’cognitive and behavioral engagement and mitigate negative emotions in the process.Pedagogical implications for implementing exemplars and self-assessment to promote student engagement and support student learning are discussed.
文摘Background:With the rapid growth of digital learning environments,esports has emerged as a popular form of school-based activity that promotes teamwork,motivation,and engagement.However,limited research has examined how participation in esports relates to students’psychological and academic development.To address this gap,the present study identified structural relationships between perceived psychological well-being,social support,academic engagement,and school-life satisfaction among students participating in school-based esports activities.Methods:We surveyed 588 students who competed in on-campus esports tournaments across 15 secondary schools in Gwangju Metropolitan City,South Korea.Psychological well-being,social support,academic engagement,and school-life satisfaction were measured using five-point Likert scales.Confirmatory factor analysis and structural equation modeling(SEM)were employed to test the hypotheses,and mediation effects were assessed via bootstrapping(1000 resamples,95%confidence interval)and competing model analysis.Results:The results showed that psychological well-being has significant positive effects on social support(β=0.899,p<0.001)and academic engagement(β=0.427,p<0.01).Social support positively predicted school-life satisfaction(β=0.804,p<0.001).Psychological well-being did not directly influence this outcome;instead,it exerted an indirect effect via social support(indirect effect=0.676,95%confidence interval[0.549,0.782]),indicating that social support functioned as a full mediator.Conclusion:Overall,the results demonstrate that school-based esports activities may serve as educational contexts that enhance students’overall satisfaction with school experiences through increased social support.Importantly,these findings highlight the unique psychosocial mechanisms of esports participation,including digital identity,online belonging,and virtual collaboration,which extend beyond traditional educational activities.Because the impact of academic engagement may depend on the quality of participation,future esports programs should incorporate support systems that foster autonomous and collaborative engagement and include digital-citizenship education.
基金funded by national funds through FCT-Fundação para a Ciência e a TecnologiaI.P.(Foundation for Science and Technology,I.P.) under project UIDB/05037/2020.
文摘Objective:To examine how emotional labor demands and strategies influence work engagement and occupational identity among Portuguese volunteer firefighters.Methods:Participants completed the Emotional Work Requirements Scale,Emotional Labour Scale,Utrecht Work Engagement Scale,and Social Identity Scale.Multiple linear regression analyses were conducted to assess the predictive effects of emotional labor demands and strategies on work engagement and occupational identity.Results:Emotional labor explained 11.8%of the variance in work engagement and 10.9%in occupational identity.Positive emotion expression significantly predicted higher work engagement and a stronger occupational identity,while the suppression of negative emotions predicted a weaker occupational identity.Other emotional labor dimensions were not significant.Conclusions:Findings underscore the dual role of emotional labor—as a resource when positive emotions are expressed and as a strain when negative emotions are habitually suppressed.Targeted interventions to promote authentic positive expression and effective emotional processing may enhance firefighters’well-being,strengthen crisis team performance,and benefit the communities they serve.Further research is needed to deepen the understanding of emotional labor in crisis response contexts.
文摘This study examines the impact of political polarization on youth engagement in Brazil,focusing on the intersection of historical legacies,cultural dynamics,and modern political influences.Tracing the evolution of polarization from the military dictatorship era to contemporary politics under Jair Bolsonaro,the study explores how polarized rhetoric,misinformation,and digital media have reshaped the political landscape for young Brazilians.Data for the study were collected through a survey of 159 college students aged 18-25 from public and private institutions across Brazil,complemented by 10 interviews with youth activists and party leaders from the Workers’Party(PT)and the Liberal Party(PL).These methods aimed to evaluate how polarization affects young people’s beliefs,political identities,behaviors,engagement levels,and ability to participate in constructive political discourse.The findings reveal that while polarization fosters hostility and deepens ideological divides,it also inspires youth activism by creating a sense of identity and belonging.Education,digital information channels,and the lack of representation in leadership roles emerge as key factors shaping youth engagement.Despite challenges,the research underscores hope:young Brazilians display resilience,critical awareness,and a shared desire for accountability and inclusivity.This study highlights the potential of youth to bridge divides and lead Brazil toward a more collaborative and democratic future.
文摘This study examines the influence of land suitability and investment in facilities on tourism potential,with a particular focus on the mediating role of community engagement.While previous research has explored the impact of environmental and infrastructural factors on tourism development,few studies have examined the interactive effects of community engagement in maximizing these benefits.This study aims to fill this gap by providing empirical evidence from Huangma Village,Jiangxi Province,China.A quantitative research design was adopted,using Partial Least Squares-Structural Equation Modeling(PLS-SEM)in SmartPLS to test the hypothesized relationships.Data were collected from 231 respondents,including local residents,tourism business owners,government officials,and infrastructure developers,through a structured survey questionnaire.The results confirm that land suitability and infrastructure investment significantly enhance tourism potential,with community engagement playing a crucial mediating role.The findings suggest that tourism success depends not only on physical and economic factors but also on active local participation in tourism-related initiatives.This study contributes to the literature by integrating environmental,infrastructural,and social dimensions of tourism development.The findings offer practical insights for policymakers and tourism planners,emphasizing the need for sustainable land management,strategic infrastructure investment,and participatory tourism governance to maximize tourism potential.
基金supported by the 5 Steno Diabetes Centers in Denmark,which are partly funded by the Novo Nordisk Foundation.
文摘Background Health promotion(HP)interventions delivered through sports clubs have demonstrated promising outcomes among men,but less is known about which aspects of the interventions work,for whom,and under what circumstances.This rapid realist review aimed to understand the contexts,mechanisms,and outcomes of HP interventions for men delivered through sports clubs.Methods A systematic literature search was conducted in February 2023 for studies published after 2013 in MEDLINE,Embase,and SPORTDiscus databases.Included studies:(a)were delivered by or in collaboration with sports clubs,(b)targeted men aged 18+years,and(c)reported 1 or more HP outcomes.A grey literature search was also performed.Studies were included in a realist synthesis based on richness and rigor.Hereafter,context-mechanism-outcome(CMO)configurations were developed.Results We identified and screened 3358 studies,finally including 59 studies describing 22 interventions.Most HP interventions were delivered in high income countries,included Caucasian men aged 35-65 years with overweight/obesity,and used professional sports clubs(mostly football)for recruitment and facilities.Quantitative HP outcomes were reported across 19 interventions.Of these 19 interventions,the majority reported on weight(n=18),physical activity(n=12),mental health(n=10),and diet(n=9).We identified 13 CMOs related to how HP interventions affected men's recruitment,engagement,and health behavior maintenance.Conclusion Our findings show that using sports clubs for HP interventions is effective for engaging men.Recruitment was facilitated by leveraging sports clubs’identity,addressing masculinity-related barriers,improving accessibility,and building trust.Engagement was enhanced through shared identity experiences,safe spaces,inclusive competition,and self-efficacy.However,there's limited evidence on behavior maintenance post-intervention,though involving community stakeholders seemed vital.In general,considerations should be made to avoid perpetuating traditional masculine norms,which may exclude some men and reinforce unhealthy behaviors.These findings can guide intervention development,emphasizing the need to harness men's perspectives in the process.
文摘Background:Work engagement(WE)is critical to quality primary healthcare delivery.However,limited research has explored its levels and determinants among healthcare professionals in low-and middle-income countries.This study assessed the levels and correlates of work engagement among physician assistants(PAs)in Ghana.Methods:A cross-sectional study was conducted among 439 PAs from October to December 2024.Participants were recruited via emails,social media platforms,and posters featuring study links and scannable questionnaire codes.WE was measured using the validated Utrecht Work Engagement Scale questionnaire.Results:Overall,WE levels were average,with similar trends across the three subdomains.In the bootstrapped multivariate linear regression model,anxiety was negatively associated with WE(β=-0.49,95%confidence interval[CI]:-0.77 to-0.21).Conversely,working in an urban area(β=0.36,95%CI:0.05 to 0.67),holding the rank of PA/Senior PA(β=0.27,95%CI:0.03 to 0.52),reporting good self-rated health(β=0.54,95%CI:0.19 to 0.88),and working at health centers(β=0.86,95%CI:0.22 to 1.50)were positively associated with WElevels.Conclusion:WE levels are average in the study sample,highlighting the need for strategic interventions to improve and sustain the healthcare workforce's motivation and performance.Addressing workplace stressors,enhancing professional development opportunities,and fostering supportive work environments could improve engagement among PAs and healthcare professionals in general.Strengthening WE is essential for ensuring resilient quality primary healthcare systems and achieving the goals of universal health coverage.
