bluuebunny/crossref_metadata_2025_split huggingface dataset:
PENGARUH MODEL PEMBELAJARAN MAKE AND MATCH TERHADAP HASIL BELAJAR SISWA PADA MATA PELAJARAN IPA DI KELAS III SD NEGERI 89 PALEMBANG
Authors: Prasetyo Yogi Aditiya , Liza murniviyanti  , Eni Heldayani  
Published: August 2023

This study aims to determine the effect of the make and match learning model on student learning outcomes on energy sources in class III at SD Negeri 89 Palembang. The population of this study were all 39 students in class III and the sample used a saturated sample consisting of 2 classes, namely the experimental class, which consisted of 20 students and the control class, which consisted of 19 students. The author applies the make and match learning model in the experimental class through the direct learning model in the control class. The research instrument used by researchers is a multiple choice test. Based on the calculation of the hypothesis test, the posttest value for the experimental class and control class was 4.614 with a value of t_table = 1.687 and df = n - 2 where n = 39 so df = 37. So it can be concluded that t_count = 4.614 ≥ t_table = 1.687, thus H_0 is rejected and H_a is accepted or there is an influence of the make and match learning model on student learning outcomes in science subjects in class III SD Negeri 8 9 Palembang.
Keywords: Make And Match Learning, Learning Outcomes.
Me, myself and you: How self-consciousness influences time perception
Authors: Mioni Giovanna , Zangrossi Andrea , Cipolletta Sabrina 
Published: August 2023

AbstractSeveral investigations have shown that the processing of self-relevant information differs from processing objective information. The present study aimed to investigate the effect of social stimuli on subjective time processing. Here, social stimuli are images of an unknown male and female person and an image of participants’ self. Forty university students were tested with a time reproduction task in which they were asked to reproduce the duration of the stimulus previously presented. Images of others or themselves were used to mark the temporal intervals. Participants also performed questionnaires to evaluate the level of anxiety and depression as well as self-consciousness. A generalised linear mixed-effects model approach was adopted. Results showed that male participants with higher Private Self-Consciousness scores showed higher time perception accuracy than females. Also, female participants reported higher scores for the Public Self-Consciousness subscale than male participants. The findings are discussed in terms of social context models of how attention is solicited and arousal is generated by social stimuli, highlighting the effect of social context on subjective perception of time.
Novel advances in parainfluenza virus 3 neutralization through antibodies targeting hemagglutinin-neuraminidase
Authors: Miller Rose , Mousa Jarrod J 
Published: August 2023

Abstract
Parainfluenza virus 3 (PIV3) remains to be a global burden to infants, the elderly, and immunocompromised individuals. With no approved therapeutics or vaccines, PIV3 continues to cause a large portion of the lower respiratory illness hospitalizations in young children. Similar to other paramyxoviruses, PIV3 utilizes two structural proteins, the fusion (F) protein and the hemagglutinin-neuraminidase (HN) protein, for viral fusion and entry. Here, we characterize newly identified human monoclonal antibodies (mAbs) targeting HN on the PIV3 virion, with EC50 values ranging from 9ng/mL to 21ng/mL. The mAbs were tested for neutralization of PIV3 and all were determined to have an IC50 values ranging from 11ng/mL to 450ng/mL. Utilizing biolayer interferometry, we conducted a competitive epitope mapping study and found the mAbs targeted three major epitopes on the HN protein with some competitive binding between multiple sites, suggesting these epitopes are within close proximity of each other. mAbs binding to one particular site had significantly low IC50 values ranging from 11ng/mL to 120ng/mL. We have established a PIV3 infection model in Golden Syrian hamsters and are currently testing mAbs from each epitope for prevention of viral replication in the lungs and airways. Due to the similarities between the HN protein amongst different parainfluenza virus subtypes, we plan to study the potential cross-neutralizing capabilities of these mAbs against other parainfluenza virus subtypes.
Supported by grants from NIH (R01 AI143865)
Quantifying in vitro complement-dependent cytotoxicity (CDC) using advanced flow cytometry
Authors: McBain Kirsty A , Lovchik Julie , Bevan Nicola 
Published: August 2023

Abstract
Complement dependent cytotoxicity (CDC) is a key Fc mediated function of monoclonal antibody (mAb) therapeutics. mAb binding to antigen triggers a complex molecular cascade with sequential recruitment of serum proteins, eventuating in target cell lysis. Here we demonstrate CDC quantification in a streamlined, in vitro, advanced flow cytometry assay.
Anti-CD20 mAbs were incubated with target cell lines in 96- or 384-well plates. Human serum (15%) was then added to induce CDC. Cells were labeled with iQue® Cell Membrane Integrity (R/Red) Dye to enable assessment of cell death using the iQue® Advanced Flow Cytometry Platform.
Induction of CDC by anti-CD20 mAbs correlated with target cell CD20 expression, with most cell death observed with high-CD20 expressing Ramos cells. Maximal Ramos cell death induced by Rituximab and Truxima® was 68% and 70%, respectively. Comparatively, cell death of mid-CD20 expressing Raji cells was lower at 34% and 24%. No CDC was induced with CD20 negative Jurkat cells. Another anti-CD20-IgG1 mAb was compared against two isotype mutants: IgG1fut (non-fucosylated) and IgG1NQ (non-glycosylated). Their activity was profiled towards three previously described effector functions: antibody-dependent cellular cytotoxicity (ADCC); antibody-dependent cellular phagocytosis (ADCP) and CDC. CDC induction was comparable between the three mAbs, however their ADCC and ADCP activity differed. The IgG1NQ did not exert ADCP or ADCC activity, whilst the IgG1fut showed more ADCC and less ADCP than the native.
These data exemplify the use of advanced flow cytometry to quantify Fc function of mAbs towards a range of effector mechanisms, highlighting the potential to profile libraries of novel therapeutics in minimal time.
Novel Strategy to Regulate PD-L1 Expression and Enhance Anti-Tumor Effect
Authors: Sredni Benjamin , Chaouat Abigael , Hay Ophir , Manoim Julia , Nadler Ronia , Kalechman Yona 
Published: August 2023

Abstract
The programmed death 1/PD ligand 1(PD-1/PD-L1 axis is a major player in the tumor immune evasion strategy. We show that the immunomodulatory small tellurium molecules, AS101 [ammonium trichloro(dioxoethylene-o, o′)tellurate] and SAS [octa-O-bis-(R,R)-tartarate ditellurane], suppress PD-L1 expression on a variety of human and mouse malignant cells by inhibition of the α4β1 VLA-4 (very late antigen-4) integrin activity. As a consequence, pAkt and its downstream effector pNFκB are inhibited. VLA-4/pAkt/pNFκB signaling blockade was found crucial for decreasing PD-L1 expression. Moreover, the tellurium compounds had physiological effects. SAS augmented killing of human and mouse malignant cells by stimulated syngeneic splenocytes or CD8+ T cells. Furthermore, SAS prevented the development of chemoresistance in malignant cells. IL-10 production by tumor cells, the inhibition of which by AS101 we showed suppressed chemoresistance, is shown here to be closely associated with inhibition of VLA-4 and PD-L1 expression suggesting that AS101 and SAS compounds may, at least partially, induce chemosensitivity by virtue of inhibition of the VLA-4/IL-10/PD-L1 pathway. AS101 or SAS treatment of B16 melanoma-bearing mice decreased tumor cell PD-L1 expression, led to increased CD8+ T-cell infiltration into the tumors and tumor shrinkage. Combined treatment with αPD-1 antibody and either of the tellurium compounds significantly increased antitumor effects. These results collectively suggest that VLA-4 integrin signaling serves as a critical component of cancer evasion and is a potential target for cancer treatment. Furthermore, AS101 or SAS may be suitable for effective combinatorial cancer immunotherapy with αPD-1.
The Potential of Therapeutic Targeting of the TWEAK-Fn14 pathway in Atopic Dermatitis
Authors: Gupta Rinkesh Kumar , Fung Kai , Figueroa Daniela , Miller Jacqueline , Ay Ferhat , Croft Michael 
Published: August 2023

Abstract
Atopic dermatitis (AD) is a chronic skin inflammatory condition exhibiting a markedly thickened epidermis. Keratinocytes, the major cells of the epidermis, are a key target of inflammation and several cytokines including IL-13 and IL-22 have receptors expressed on these cells. Because Fn14 (TNFRSF12A), the receptor for the TNF family cytokine TWEAK (TNFSF12), is also expressed on keratinocytes, we examined the inflammatory potential of TWEAK alone, and together with IL-13 and IL-22, in controlling AD-signature gene expression in using RNA-seq. Transcriptomic analysis showed that TWEAK strongly upregulated many AD genes in human keratinocytes, which partially overlapped with those induced by IL-13 and IL-22. TWEAK also acted synergistically with IL-13 and IL-22 to exaggerate induction of AD-related genes. Correspondingly, cKO mice lacking Fn14 only in keratinocytes were protected from developing pronounced allergen-induced AD-like skin inflammation. Furthermore, mice treated therapeutically with anti-TWEAK exhibited a significantly reduced AD phenotype including less epidermal thickening combined with a strongly reduced Th2 response in the skin. Moreover, the therapeutic efficacy of TWEAK inhibition was similar to that resulting from blockade of IL-13. The data suggest that TWEAK shares pathogenic activity with IL-13 and IL-22 and can be considered as a potential therapeutic target in AD similar to IL-13.
Nil
Use of CD122+ natural killer cell precursors for superior anti-leukemia response
Authors: Krieg Carsten , Guglietta Silvia 
Published: August 2023

Abstract
Acute Myeloid Leukemia (AML) is an aggressive blood cancer in adults. Intensive induction therapy successfully induces a complete response in up to 80% of the adult patients but a fraction of them is refractory or relapses. The fraction of non-responsive or relapsing patients is especially high amongst medically unfit and older patients, who cannot undergo aggressive chemotherapy treatment. Therefore, offering patients failing on first line intensive chemotherapy and medically unfit and older patients an effective treatment option for long-term control or even cure of disease represents a significant yet unmet clinical need.
As a component of the innate immunity, NK cells have recently shown great promise for the treatment of patients with different malignancies. Here, we show that injection of human interleukin-2 (IL-2) complexes (IL-2cx) induce the de novo generation and massive expansion of NK cell precursors in vivo. Furthermore, IL-2cx-expanded NK cells exert effector functions with the capacity to control the growth of non-self MHC class I-deficient RMA-S lymphoma cells in vivo, while remaining tolerant towards MHC class-expressing self RMA cells.
In an experimental setup mimicking the clinical case of refractory patients after intensive AML induction therapy, IL-2cx treatment mediated strong anti-AML responses following haploidentical bone marrow transplantation without the need for adoptive transfer of donor-derived or in vitro autologous expanded NK cells. Thus, this study demonstrates that IL-2cx immunotherapy allows the in vivo generation and expansion of functionally mature NK cells to achieve long-term response in AML paving the way to an effective treatment option.
We are sponsored partly by the Cell Evaluation & Therapy Shared Resource, Hollings Cancer Center, Medical University of South Carolina (P30 CA138313), and an ACS-IRG to CK.
High Throughput Screening Identifies CDK Inhibitors as Inflammasome-Activating Vaccine Adjuvants
Authors: Weiss Adam M , Rosenberger Matthew G , Kim Jeremiah Y , Lopez Marcos A , Rowan Stuart J , Esser-Kahn Aaron P 
Published: August 2023

Abstract
Several FDA-approved adjuvant formulations, such as saponins and lipid nanoparticles, have been shown to mediate their adjuvant effects in part through the NLRP3 inflammasome. These formulations are among the most potent adjuvants in use, but they are limited by poor synthetic control and immunotoxic side effects. New small molecule adjuvants targeting the NLRP3 inflammasome would allow broader implementation of subunit- and nucleotide-based vaccines against poorly immunogenic antigens. In this work, we leverage high throughput screening of immunomodulatory compounds to identify cyclin dependent kinase (CDK) inhibitors as a novel class of inflammasome-activating small molecule adjuvants. CDK inhibitors are FDA-approved anti-cancer drugs which block cell cycle progression to prevent tumor proliferation. When co-administered with a Toll-like receptor (TLR) agonist, we observe that these inhibitors induce robust NLRP3- and Caspase-dependent IL-1β secretion in primary murine and human dendritic cells. When formulated with a TLR4 agonist and ovalbumin for use in vaccination, these compounds were found to enhance antibody production and antigen-specific CD8+ T cell proliferation relative to formulation controls. While greater work is needed to formulate and optimize these adjuvants, understanding the mechanism of CDK inhibitors’ adjuvanticity will both enhance our understanding of these compounds and expand their use case to vaccination.
Supported by grants from NIH (75N93019C00041, T32 GM008720) and DTRA (1-18-1-0052).
Characterization of a novel therapeutic antibody targeting peptide/HLA-E
Authors: Upchurch-Ange Katherine Christine , Oter Gizem , Gimlin Susanne , Weidanz Debra Wawro , Weidanz Jon 
Published: August 2023

Abstract
T-cell receptor mimic antibodies (TCRm) have become an attractive therapeutic modality group as they allow for the targeting of intracellular proteins presented by HLA, which may allow for a large potential of new targets. However, the polymorphic nature of classical HLA class I and findings of HLA downregulation in cancer cells might limit the use of these agents for cancer treatment. An alternative approach would be to target peptides presented by HLA-E, a highly monomorphic molecule often found upregulated in cancer cells. Thus, we aimed to generate a TCRm against HLA-E presenting the leader sequence peptide from HLA-G since both HLAs are often expressed in multiple cancer types. An antibody was identified from a naïve human phage library and further affinity matured using yeast display. The final clone, ABX-001, had an affinity constant (KD) of 7.9nM. Specificity studies using both peptide-loaded cells and tumor cell lines showed that ABX-001 only bound when both HLA-E and HLA-G were present. Extensive profiling was done on immune cells to also confirm that they did not bind ABX-001. Finally, ABX-001 was assessed for its ability to direct killing of target-positive tumor cell lines. We observed that cytotoxicity in CD8+ T cells was enhanced with the addition of an ABX-001-CD3 T cell engager. We also observed that ABX-001 can act as a checkpoint inhibitor by blocking the interaction of HLA-E with NKG2A in cytotoxicity experiments using NK cells. These data indicate that we can effectively target peptide/HLA-E and highlights its potential therapeutic applications in cancer treatment.
Functional DKK1 antibodies demonstrate antagonistic and tumor suppression activities
Authors: Wang Linya , Peterson Sean Michael , Lujan Ana , Chan Kara Y , Hu Cameron , Villalta Mouna , Yuan Tom Z , Han Zhen , Yang Marisa , Prabhu Vishwaas , Htoy Tammy , VanDyke Paul , Holliday Carson , Franco Hector , Wadhwa Hansika , Giang Hoa , Stafford Ryan , Axelrod Fumiko , Sato Aaron 
Published: August 2023

Abstract
Wnt signaling plays an important role in embryonic development and tumorigenesis. These biological effects are exerted by activation of the β-catenin/TCF transcription complex and consequent regulation of a set of downstream genes. DKK1 has been shown to be a potent inhibitor of Wnt signaling via competing Wnt binding to LRP5/6. DKK1 is tumorigenic in multiple cancer types and also immunosuppressive via MDSCs and NK cells. Emerging evidence indicates that DKK1 has been involved in T cell differentiation and induction of cancer evasion of immune surveillance by accumulating MDSCs. Consequently, DKK1 has become a promising target for cancer immunotherapy, and the mechanisms of DKK1 affecting cancers and immune cells have received great attention. With Twist’s precision DNA writing technologies, we have created phage display libraries with diversity greater than 1e10, and utilized machine learning model for optimal discovery. In this study, we discovered anti-DKK1 antibodies blocking the binding of DKK1 to the receptor. The in vitro functional assays showed that the interaction of Wnt to its receptor was restored in the presence of anti-DKK1 antibodies, resulting in TCF/LEF signaling upregulation. Moreover, anti-DKK1 antibodies induced immune cell activation, and led to tumor cell cytotoxicity. In addition, anti-DKK1 antibodies binding to different domains of DKK1 led to different functional effect. In vivo study indicated anti-DKK1 antibodies is potent in tumor regression. Our anti-DKK1 leads shows promising efficacy in cancer immunotherapy.
Canonical BAF Complex activity licenses CD8+ T cell effector fates
Authors: McDonald Bryan , Chick Brent , Ahmed Nasiha , Hargreaves Diana , Kaech Susan 
Published: August 2023

Abstract
CD8+ T cells provide a critical layer of host protection against all manner of pathogens and malignancies. Chromatin remodeling is a critical component of differentiation and acquisition of cytotoxic functions in activated CD8+ T cells, but the mechanisms by which remodeling is achieved in a site-specific way to promote appropriate effector cell fates are poorly understood. Here we identified a role for the ARID1A-containing canonical BAF (cBAF) complex in regulating chromatin accessibility and differentiation of antiviral effector CD8+ T cells. Arid1a was required for CD8+ T cell differentiation into terminal effector and tissue-resident memory cells, but was not required for the formation of long-lived circulating memory cells. Mechanistically, cBAF acted to promote chromatin accessibility at thousands of loci bound by important effector-associated TFs including BHLHE40, T-bet, and BATF. Understanding how chromatin remodeling is regulated in differentiating effector CD8+ T cells will yield insight into optimizing vaccines and adoptive cell therapies for cancer.
Supported by grants from NIH (F99 CA274688, R37 AI066232, R01 AI151123)
Inhibition of distinct glycolytic enzymes produces differential effects on CD4 T cell function
Authors: Godfrey Wesley H , Cho Kaho , Shanmukha Shruthi , Deng Jodie , Kornberg Michael 
Published: August 2023

Abstract

Introduction
When T cells are activated, they upregulate glycolysis and take on a requisite Warburg phenotype. In this study, we evaluated the effect of inhibiting two distinct glycolytic enzymes, GAPDH and PGAM, on CD4 T cell differentiation.

Methods/Results
Using the GAPDH inhibitor heptelidic acid, we found that GAPDH inhibition produces a potent anti-inflammatory phenotype in Th1 cells, significantly reducing IFNγ expression. We further showed that GAPDH inhibition produces the anti-inflammatory metabolite methylglyoxal, which is necessary for its anti-inflammatory effect. GAPDH inhibition also produced anti-inflammatory effects in vivo, as heptelidic acid significantly reduced disease severity and altered immune subsets in a therapeutic treatment paradigm in the MOG35–55 EAE model of multiple sclerosis. Furthermore, we showed that GAPDH inhibition enhances Treg polarization, while inhibiting PGAM, a downstream glycolytic enzyme, potently blocked Treg polarization. Additionally, we found that inhibition of PGAM increases serine biosynthesis and subsequently alters 1-carbon metabolism. We also found that PGAM gene expression is associated with Treg differentiation and response to immunotherapy in lung cancer patients.

Conclusion
Overall, our in vitro and in vivo results indicate that targeting the glycolytic enzyme GAPDH produces an anti-inflammatory phenotype via the methylglyoxal pathway, while targeting the downstream enzyme PGAM produces an opposite effect via regulation of serine synthesis. Our findings suggest that the functional consequences of glycolysis inhibition depend on the specific enzymes targeted, which represent promising novel therapeutic targets for immunological disease.

This work was supported by NIH/NINDS grant K08NS104266 and Conrad N. Hilton Foundation Marilyn Hilton Bridging Award for Physician Scientists grant 17316 to MDK. WHG was supported by NIH MSTP Grant T32 GM136577 and the American Association of Immunologists’ Careers in Immunology Fellowship Program.
Antioxidation protein Nrf2 modulates glutamine metabolism to regulate activation-driven expansion of CD4+T-cells
Authors: Tripathi Aprajita , Pant Anil , Bugbee Ashlyn , Choi Ben H , Pyaram Kalyani 
Published: August 2023

Abstract
Nutrient metabolism governs the effector functions like activation, expansion, and subset differentiation of CD4+T-cells, the orchestrators of adaptive immunity. The levels of reactive oxygen species (ROS), the metabolic byproducts of cellular metabolism are regulated by the antioxidation pathway, which is composed of Keap1 and Nrf2 proteins. We observed that, the expression of Nrf2 is temporally regulated post-activation in CD4+T-cells (high on day 1 and low on days 2 and 3) indicating its role in CD4+T-cell effector functions. It is yet unknown if and how the antioxidation pathway crosstalks with cellular metabolism to shape CD4+T-cell effector responses. Here, using mice with T-cell specific deletion of Keap1 (Keap1-KO) or Nrf2 (Nrf2-KO) we deciphered the effects of high and low levels of Nrf2 (antioxidation) levels, respectively in CD4+T-cells. Upon activation in vitro, Keap1-KO CD4+T-cells with constitutively high levels of Nrf2 showed higher proliferation, increased expression of early activation markers and elevated TCR-mediated signaling compared to wildtype (WT) cells. In contrast, decreased proliferation and lower TCR-mediated signaling was noted in activated Nrf2-KO CD4+T-cells. To dissect the underlying mechanisms, we performed metabolite analyses and activation in nutrient-limiting conditions. Interestingly, activated Keap1-KO CD4+T-cells show upregulated glutamine metabolism as measured by metabolic intermediates and rely on glutamine for optimum activation and increased expansion. Together, our findings identify a mechanism by which antioxidation protein Nrf2 metabolically reprograms CD4+T-cells and modulates their metabolic dependencies to support their activation and expansion.