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
Bispecific T-cell Engagers(BITEs)are a novel form of immunotherapy that overcome a deficiency of immune checkpoint inhibitors(ICI)by targeting a preidentified tumor associated antigen and redirecting a polyclonal popu...Bispecific T-cell Engagers(BITEs)are a novel form of immunotherapy that overcome a deficiency of immune checkpoint inhibitors(ICI)by targeting a preidentified tumor associated antigen and redirecting a polyclonal population of effector T-cells against the tumor.High grade serous ovarian cancer is a lethal disease in the recurrent setting and has not been amenable to ICI therapy.MUC16/CA125 is overexpressed in high grade serous ovarian cancer.BITEs targeting the tumor-retained portion of MUC16/CA125 have recently been described and are in early-phase clinical trials.To identify mechanisms of resistance to BITEs,we collected serum,peripheral blood mononuclear cells,and ascites samples from patients with disease progression on MUC16-directed bispecific antibodies.Analysis of these samples showed downregulation of MUC16/CA125,elevated secretion of VEGF,and epithelial-to-mesenchymal transition in tumor cells.Interestingly,hypoxia was determined to be a driver of these changes.These findings were prospectively validated in ovarian cancer cell lines with CRISPR/Cas9 knockout of MUC16/CA125 and VEGF.Peripheral blood mononuclear cells from patients with disease progression were capable of effective cytolysis ex vivo,suggesting that resistance to therapy was primarily tumor driven.Restoration of MUC16/CA125 expression did not restore cytotoxicity in the presence of increased VEGF secretion.Combination treatment with a VEGF inhibitor rescued cytotoxicity in hypoxia-conditioned ovarian cancer cell lines with preserved target antigen expression.Collectively,these data outline a link between hypoxia and the development of resistance to BITEs and posits inhibition of VEGF inhibition as a potentially important therapeutic intervention.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
Learning from the wisdom and insights of others remains one of the most effective paths to progress.This is the driving force behind our commitment to experience sharing.The March/April issue features three renowned i...Learning from the wisdom and insights of others remains one of the most effective paths to progress.This is the driving force behind our commitment to experience sharing.The March/April issue features three renowned international standardization experts who share their journeys,the strategic"hows and whys"of global participation,and the critical role of stakeholder engagement in shaping the future of the industry.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
When Sir Keir Starmer arrived in Beijing in late January,Britain marked its first prime-ministerial visit to China in eight years.The symbolism was unavoidable.Yet symbolism was not the point.The visit was about recal...When Sir Keir Starmer arrived in Beijing in late January,Britain marked its first prime-ministerial visit to China in eight years.The symbolism was unavoidable.Yet symbolism was not the point.The visit was about recalibrating economic engagement——carefully,and with numbers firmly in hand.展开更多
Land degradation,coupled with climate change impacts,poses serious threats to global land health and human well-being.Participatory scenario planning(PSP)has become a key tool for exploring these interconnected challe...Land degradation,coupled with climate change impacts,poses serious threats to global land health and human well-being.Participatory scenario planning(PSP)has become a key tool for exploring these interconnected challenges;however,its progress and effectiveness remain underexplored.This study reviews 46 papers,using PRISMA guidelines,to investigate how PSP supports sustainable land management and climate resilience.We document how PSP applications have evolved from a biophysical focus to one addressing broader environmental,societal,and economic challenges.Disparities in how participants engage across PSP phases document the need for more equitable and meaningful participation.Clustering future scenarios reveals the complex interconnections among ecological,social,and economic factors underpinning land management and climate resilience,underscoring the need for inclusive and integrated strategies.From the emerging trends,we identify opportunities to advance PSP implementation,including early engagement of decision-makers,balanced representation and equitable power dynamics,meaningful participation,cross-disciplinary collaboration,integration of human-nature relationships,and regular revision of future pathways.Overall,our review highlights PSP’s potential to co-create inclusive,equitable scenarios and actionable pathways towards sustainable and resilient land use futures.展开更多
The dynamic characteristics of the track system can directly affect its service performance and failure process.To explore the load characteristics and dynamic response of the track system under the dynamic loads from...The dynamic characteristics of the track system can directly affect its service performance and failure process.To explore the load characteristics and dynamic response of the track system under the dynamic loads from the rack vehicle in traction conditions,a systematic test of the track subsystem was carried out on a large-slope test line.In the test,the bending stress of the rack teeth,the wheel-rail forces,and the acceleration of crucial components in the track system were measured.Subsequently,a detailed analysis was conducted on the tested signals of the rack railway track system in the time domain and the time-frequency domains.The test results indicate that the traction force significantly affects the rack tooth bending stress and the wheel-rail forces.The vibrations of the track system under the traction conditions are mainly caused by the impacts generated from the gear-rack engagement,which are then transferred to the sleepers,the rails,and the ballast beds.Furthermore,both the maximum stress on the racks and the wheel-rail forces measured on the rails remain below their allowable values.This experimental study evaluates the load characteristics and reveals the vibration characteristics of the rack railway track system under the vehicle’s ultimate load,which is very important for the load-strengthening design of the key components such as racks and the vibration and noise reduction of the track system.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
Introduction:From rules to participation Today,standardization is no longer just about unifying technical terms or setting measurements.It has become a strategic tool to build trust,strengthen competitiveness,and driv...Introduction:From rules to participation Today,standardization is no longer just about unifying technical terms or setting measurements.It has become a strategic tool to build trust,strengthen competitiveness,and drive sustainable economic growth.As industries grow more complex and new technologies and regulations emerge,it is more important than ever to involve all key players:manufacturers,suppliers,consumers,academics,and regulators.Their shared knowledge and input help shape the standards and policies that guide markets,protect consumers,and ensure product quality and safety.展开更多
The 15th Five-Year Plan will begin in 2026,amid heightened global technological competition and rapid supply chain changes.At this pivotal moment,the low-altitude economy and commercial aerospace,once seen as futurist...The 15th Five-Year Plan will begin in 2026,amid heightened global technological competition and rapid supply chain changes.At this pivotal moment,the low-altitude economy and commercial aerospace,once seen as futuristic,are quickly transitioning from strategic concepts to large-scale manufacturing industries.These sectors now drive China’s high-quality development and support a new framework for international engagement.展开更多
Dear editor,Bispecific T-cell engagers(also referred to as BiTEs)are bi/multispecific antibodies that are a clinically used cancer immunotherapy,which enforce formation of an immunological synapse between T-cells and ...Dear editor,Bispecific T-cell engagers(also referred to as BiTEs)are bi/multispecific antibodies that are a clinically used cancer immunotherapy,which enforce formation of an immunological synapse between T-cells and tumour cells by antigenic engagement on the respective cells,resulting in cancer cell apoptosis.1,2 Tumour heterogeneity,however,is a major challenge for identifying the most appropriate cancer target antigen for each patient.Discovery of new tumour targets outweighs new BiTE approval,calling for rapid screening tools to evaluate novel targets and BiTE combinational formats.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
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 the Nile Albright Research Foundation(O.O.Y.)The Flatley Foundation(O.O.Y.)+2 种基金The Worden Family Foundation(O.O.Y.)The Barshad Family(O.O.Y.)the Vincent Memorial Hospital Foundation(S.K.B.).
文摘Bispecific T-cell Engagers(BITEs)are a novel form of immunotherapy that overcome a deficiency of immune checkpoint inhibitors(ICI)by targeting a preidentified tumor associated antigen and redirecting a polyclonal population of effector T-cells against the tumor.High grade serous ovarian cancer is a lethal disease in the recurrent setting and has not been amenable to ICI therapy.MUC16/CA125 is overexpressed in high grade serous ovarian cancer.BITEs targeting the tumor-retained portion of MUC16/CA125 have recently been described and are in early-phase clinical trials.To identify mechanisms of resistance to BITEs,we collected serum,peripheral blood mononuclear cells,and ascites samples from patients with disease progression on MUC16-directed bispecific antibodies.Analysis of these samples showed downregulation of MUC16/CA125,elevated secretion of VEGF,and epithelial-to-mesenchymal transition in tumor cells.Interestingly,hypoxia was determined to be a driver of these changes.These findings were prospectively validated in ovarian cancer cell lines with CRISPR/Cas9 knockout of MUC16/CA125 and VEGF.Peripheral blood mononuclear cells from patients with disease progression were capable of effective cytolysis ex vivo,suggesting that resistance to therapy was primarily tumor driven.Restoration of MUC16/CA125 expression did not restore cytotoxicity in the presence of increased VEGF secretion.Combination treatment with a VEGF inhibitor rescued cytotoxicity in hypoxia-conditioned ovarian cancer cell lines with preserved target antigen expression.Collectively,these data outline a link between hypoxia and the development of resistance to BITEs and posits inhibition of VEGF inhibition as a potentially important therapeutic intervention.
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Learning from the wisdom and insights of others remains one of the most effective paths to progress.This is the driving force behind our commitment to experience sharing.The March/April issue features three renowned international standardization experts who share their journeys,the strategic"hows and whys"of global participation,and the critical role of stakeholder engagement in shaping the future of the industry.
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When Sir Keir Starmer arrived in Beijing in late January,Britain marked its first prime-ministerial visit to China in eight years.The symbolism was unavoidable.Yet symbolism was not the point.The visit was about recalibrating economic engagement——carefully,and with numbers firmly in hand.
基金supported by the Royal Thai Government Scholarship in Science and Technologythe Faculty of Environment and Resource Studies, Mahidol University, Thailand (FERS, Mahidol University)
文摘Land degradation,coupled with climate change impacts,poses serious threats to global land health and human well-being.Participatory scenario planning(PSP)has become a key tool for exploring these interconnected challenges;however,its progress and effectiveness remain underexplored.This study reviews 46 papers,using PRISMA guidelines,to investigate how PSP supports sustainable land management and climate resilience.We document how PSP applications have evolved from a biophysical focus to one addressing broader environmental,societal,and economic challenges.Disparities in how participants engage across PSP phases document the need for more equitable and meaningful participation.Clustering future scenarios reveals the complex interconnections among ecological,social,and economic factors underpinning land management and climate resilience,underscoring the need for inclusive and integrated strategies.From the emerging trends,we identify opportunities to advance PSP implementation,including early engagement of decision-makers,balanced representation and equitable power dynamics,meaningful participation,cross-disciplinary collaboration,integration of human-nature relationships,and regular revision of future pathways.Overall,our review highlights PSP’s potential to co-create inclusive,equitable scenarios and actionable pathways towards sustainable and resilient land use futures.
基金supported by the National Natural Science Foundation of China(No.52388102)the Sichuan Science and Technology Program(No.2024NSFTD0011)the Fundamental Research Funds for the State Key Laboratory of Rail Transit Vehicle System of Southwest Jiaotong University(No.2023TPL-T11).
文摘The dynamic characteristics of the track system can directly affect its service performance and failure process.To explore the load characteristics and dynamic response of the track system under the dynamic loads from the rack vehicle in traction conditions,a systematic test of the track subsystem was carried out on a large-slope test line.In the test,the bending stress of the rack teeth,the wheel-rail forces,and the acceleration of crucial components in the track system were measured.Subsequently,a detailed analysis was conducted on the tested signals of the rack railway track system in the time domain and the time-frequency domains.The test results indicate that the traction force significantly affects the rack tooth bending stress and the wheel-rail forces.The vibrations of the track system under the traction conditions are mainly caused by the impacts generated from the gear-rack engagement,which are then transferred to the sleepers,the rails,and the ballast beds.Furthermore,both the maximum stress on the racks and the wheel-rail forces measured on the rails remain below their allowable values.This experimental study evaluates the load characteristics and reveals the vibration characteristics of the rack railway track system under the vehicle’s ultimate load,which is very important for the load-strengthening design of the key components such as racks and the vibration and noise reduction of the track system.
基金Support was provided by NSF(grant No.EAR-2041892)
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.
文摘Introduction:From rules to participation Today,standardization is no longer just about unifying technical terms or setting measurements.It has become a strategic tool to build trust,strengthen competitiveness,and drive sustainable economic growth.As industries grow more complex and new technologies and regulations emerge,it is more important than ever to involve all key players:manufacturers,suppliers,consumers,academics,and regulators.Their shared knowledge and input help shape the standards and policies that guide markets,protect consumers,and ensure product quality and safety.
文摘The 15th Five-Year Plan will begin in 2026,amid heightened global technological competition and rapid supply chain changes.At this pivotal moment,the low-altitude economy and commercial aerospace,once seen as futuristic,are quickly transitioning from strategic concepts to large-scale manufacturing industries.These sectors now drive China’s high-quality development and support a new framework for international engagement.
基金supported by the Novo Nordisk Foundation Grant,CEMBID(Center for Multifunctional Biomolecular Drug Design,Grant Number:NNF17OC0028070)the National Key Research and Development Programme(2024 YFA0918600)+1 种基金Venus Project from China-Japan Union Hospital of Jilin University(Funding No.:XHQMX20242)the Science and Technology Development Plan Project of Jilin Province(Grant No.:20230402040GH).
文摘Dear editor,Bispecific T-cell engagers(also referred to as BiTEs)are bi/multispecific antibodies that are a clinically used cancer immunotherapy,which enforce formation of an immunological synapse between T-cells and tumour cells by antigenic engagement on the respective cells,resulting in cancer cell apoptosis.1,2 Tumour heterogeneity,however,is a major challenge for identifying the most appropriate cancer target antigen for each patient.Discovery of new tumour targets outweighs new BiTE approval,calling for rapid screening tools to evaluate novel targets and BiTE combinational formats.
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.
