bluuebunny/crossref_metadata_2025_split huggingface dataset:
Immature Dendritic Cell therapy in early life promotes peripheral tolerance of autoreactive T cells delaying onset and incidence of T1D.
Authors: Orozco Figueroa Stephanie , Reynolds Hayley , Bettini Matt 
Published: November 2024

Abstract
Type 1 Diabetes (T1D) is a complex autoimmune disease characterized by T cells mediating the destruction of insulin-secreting ß-cells in the pancreatic islets of Langerhans. Evidence suggests both central and peripheral T cell tolerance mechanisms fail in the development of T1D. The non-obese diabetic (NOD) mouse model is a spontaneous model of T1D that shares many characteristics to human disease. Studies in adult pre-diabetic NOD mice using immature dendritic cells (iDCs) as therapy result in delaying disease onset and, in some cases, lowering disease incidence. The mechanism by which DCs confer protection to diabetes is largely unknown, but is thought to occur in an antigen-independent manner; driven by tolerogenic cytokines. Broadly, DCs are also known to induce peripheral tolerance by activation induced cell death, anergy and inducing the development of regulatory T cells (iTregs). In the past twenty years, the existence of a neonatal window of tolerance has highlighted the importance of tolerogenic mechanisms to prevent autoimmunity. Therefore, we hypothesized DC therapy administered at a neonatal stage in NOD mice will result in protection to the development of T1D. Our studies treating NOD mice with iDCs from an early point in life demonstrate that donor iDCs migrate to the pancreatic draining lymph nodes, modulate the microenvironment diminishing islet T cell infiltration and T cell activation, culminating in a significant delay in the onset and incidence of T1D.
Trabectedin modulates the glioma innate and adaptive immune microenvironment in vivo
Authors: Nazzaro Matthew , Rajappa Prajwal , Currier Mark , Glaspell Andrea , Behbehani Gregory , Cripe Timothy 
Published: November 2024

Abstract
Low-grade gliomas (LGG) are the most common brain tumor in adolescents and young adults. LGG are neglected in the field of research due to their low relative risk compared to high-grade glioblastoma despite their potential to malignantly transform into fatal high-grade gliomas (HGG). Therefore, there is a necessity to investigate and develop novel therapeutics to combat the progression of glioma. Malignant progression of glioma is associated with an accumulation of immunosuppressive myeloid cells that impair anti-tumor T cell function. Trabectedin is an FDA approved chemotherapy used in the treatment of soft tissue sarcoma. Beyond its chemotherapeutic properties, Trabectedin has been shown to selectively deplete monocytes and macrophages, but its role in the modulating the brain TME has not yet been investigated. Here, we utilized mass cytometry (CyTOF) to investigate the impact of Trabectedin on the glioma immune TME as well as the global immune system in the immunocompetent, transgenic RCAS/t-va murine glioma model which recapitulates the progression of low to high-grade glioma. Trabectedin significantly reduced bone-marrow derived myeloid cells in the glioma TME as well as splenic macrophages and monocytes. Further, Trabectedin increased the proportion of tumor-infiltrating T cells. In conclusion, Trabectedin immunomodulates the glioma TME in vivo and could potentially enhance the efficacy of immunotherapies by overcoming myeloid-driven immunosuppressive resistance.
Microbial experience influences B16 melanoma tumor growth
Authors: Busalacchi Marlee , Bunda Nicholas , Pullen Johnna , Groeber Hanna , Morrison Cody , Renkema Kristin 
Published: November 2024

Abstract
Cancer immunity research is traditionally conducted with specific pathogen-free (SPF) mice, which mimic the immune system of a human newborn. This poses a challenge for research aimed at understanding immune responses relevant to humans. We utilized a mouse model to investigate microbial experience impacts on immune population dynamics and responses. By cohousing SPF C57Bl/6 mice with pet store mice, we generated a cohoused (CoH) mouse that more accurately reflects the impact of microbial experience on the human immune system. We hypothesized that CoH mice would mount a more effective anti-tumor response when compared to SPF mice. We challenged the mice with sub-cutaneous B16 melanoma to measure both tumor growth and immune responses. Interestingly, CoH tumor grew more slowly, and tumor weights were significantly reduced when compared to SPF mice on days 7 and 10 post-injection. We investigated CD8+ T cell and monocyte/macrophage phenotypes in various tissues, including the tumors. Control of tumor growth may be related to the observed differences in CD8+ T cell activation profiles and monocyte/macrophage differentiation found in CoH mice. Collectively, our results indicate that microbial experience influences anti-tumor immunity and that cohoused mouse models may prove to have valuable translational applications for future cancer immunity research.
Modulating the epigenetic interplay in exhausted CD8 T cells for effective immunotherapy
Authors: Yousif Amir , Saadey Abbey , Lowin Ava , Castillo Chelsea , Saini Ankita , Chan Wing , Alinari Lapo , Webb Amy , Oltz Eugene , Ghoneim Hazem 
Published: November 2024

Abstract
Epigenetic imprinting of terminal exhaustion in chronically stimulated CD8 T cells is a major impediment to T cell immunotherapies during chronic viral infections or cancer. Foundational work establishes that exhausted CD8 T cells (TEX) acquire heritable DNA methylation programs that silence genes critical for T cell stemness/function, restraining responses to immune checkpoint blockade (ICB). However, the molecular interplay between histone post-translational modifications and de novo DNA methylation during the progression to terminal exhaustion remains poorly understood. To address this, we employ our novel in vitro model of human T cell dysfunction and the chronic LCMV infection model to reveal a temporal linkage in which progressive histone changes prime the acquisition of de novo DNA methylation in TEX. Via a selective inhibitor or CRISPR editing in human CD8 T cells, we identify specific histone-modifying enzymes as key epigenetic drivers that orchestrate DNA methylation programming during terminal exhaustion. Notably, targeting the histone-modifying enzymes reinvigorated effector function and cytotoxicity in dysfunctional human T cells. Moreover, combined epigenetic therapy and anti-PD-L1 enhanced the ICB responses of both progenitor and cytolytic TEX during chronic viral infection. Collectively, our findings reveal novel epigenetic drivers of CD8 T cell dysfunction, supporting therapeutic potential of targeting the epigenetic crosstalk underpinning T cell exhaustion.
Crispr-Cas9 screen identifies potential novel regulators of CD8+ T cell dysfunction.
Authors: Holcomb Erin , Jiang Long , Tate Akshay , Pearson Ashley , Wang Zhuwen , Elaimy Ameer , James Jadyn , Huber Amanda , Green Michael 
Published: November 2024

Abstract
CD8+ T cells directly target and kill cancer cells and are required for effective antitumor immunity. However, CD8+ T cells may become dysfunctional when exposed to chronic antigen stimulation during cancer. Dysfunction is characterized by reduced proliferation, increased expression of inhibitory receptors, and impaired effector function, yet the genetic mechanisms controlling dysfunction remain poorly understood. To address this gap, we have developed an ex vivo restimulation model that recapitulates features of CD8+ T cell dysfunction seen within the tumor microenvironment. By coupling this system with genome-wide CRISPR-Cas9 loss of function screening, we have identified eIF4G2, a non-canonical protein translation factor, which may play a novel role in the progression of CD8+ T cells to a dysfunctional state. Deletion of eIF4G2 restored CD8+ T cell survival and proliferation during chronic restimulation conditions in vitro. Transcriptomic and flow cytometric analyses revealed that eIF4G2 controls expression of genes contributing to oxidative stress and a dysfunctional phenotype in vitro. Future studies will focus on characterizing the mechanistic and functional roles of this protein translation factor in vivo, as well as translating this model to primary human CD8+ T cells. In summary, we have uncovered eIF4G2 as a novel potential regulator of CD8+ T cell dysfunction and targeting eIF4G2 may improve antitumor immunity and immunotherapy efficacy.
The regulatory role of the transcription factor HEB in Myc-overexpressing T-cell Acute Lymphoblastic Leukemia
Authors: Tousinas Georgios , Lewis Cody , Tracy Melissa , Arnovitz Stephen , Emmanuel Akinola Olumide , Khazaie Khashayarsha , Bergsagel Leif , Gounari Fotini 
Published: November 2024

Abstract
Acute Lymphoblastic Leukemia (ALL) is the most common cancer among children in the US. Approximately 5% of T-cell ALL (T-ALL) cases involve acquired focal chromosomal duplications encompassing a region downstream of the Myc oncogene, characterized as a Notch1-dependent Myc enhancer (N‑Me). The lack of mouse models with such N‑Me duplications has limited our ability to study the molecular mechanisms of the disease. We found that mouse leukemias resulting from conditional aberrant activation of β-catenin with simultaneous ablation of the transcription factor HEB in CD4+CD8+ double positive thymocytes bear N‑Me duplications. The ablation of HEB fundamentally changes the mechanism of leukemogenesis induced by the simple activation of β-catenin, which is characterized by TCRα-Myc/Pvt1 reciprocal translocations. Based on the finding that HEB binds N-Me at a site that overlaps Notch-1 binding and the conserved motifs of other regulators, we propose that HEB has a central regulatory role in the oncogenic process. We hypothesize that HEB binding regulates the access of transcription regulators to N-Me, rationing Myc expression. Loss of HEB in the context of activated β-catenin enables access of these regulators to N-Me, and triggers super-enhancer properties and changes in chromatin conformation, leading to excessive Myc expression and leukemogenesis. Ultimately, the proposed study aspires to determine the role of HEB in the initiation, progression, and treatment of human T-ALL
High throughput assay for detection of antibodies targeting multiple subunit membrane proteins of human neuron synapse in vitro
Authors: Li Quanzhen , Yang Shuwei , Muellner Julius , Lin Dan , Feng Feifei , Xie XiaoXia , Mai Zihao 
Published: November 2024

Abstract
Synapses are essential to the transmission of nervous impulses from one neuron to another. There are more than 1000 multiple-subunit membrane proteins in synapse. Some of them are drug targets and/or autoantigens. Most autoantibodies against synapse membrane proteins recognize conformation of extracellular domains. Based on known structures and predicted structures by chatGPT, we used N-methyl-D-aspartate (NMDA)receptor as model for quantitative assay in vitro. In order to keep the native form of the extracellular domains of NMDA receptor, we modified some amino acids in transmembrane domains and intracellular domains, establishing a stable cell line expressing cluster NMDA receptor used to sensitively detect autoantibody in human serum and cerebrospinal fluid. We also prepared stable NMDA receptor tetramer complex from the stable cell line and prepared monoclonal antibodies (mAB) against subunit GluN1 and GluN2. Based on tetramer complex and mABs, we established a method to quantitatively detect antibodies from clinical samples.
Selective small-molecule PKC-theta inhibitors effectively block TCR-mediated activation of naïve peripheral blood and tissue resident memory T cells
Authors: Whitener Robert , Harden Jamie , Hofland Hans , Patel Jeegar 
Published: November 2024

Abstract
Immune mediated inflammatory diseases constitute a diverse set of illnesses in which an aberrant immune response damages self-tissue. While progress has been made in treating these conditions, there continues to be room for improvement. Patients diagnosed with T cell mediated disorders (TMDs) such as atopic dermatitis, rheumatoid arthritis and inflammatory bowel disease often respond well to broadly-acting immunosuppressive drugs, most of which come with significant side-effects, further highlighting the need for more targeted approaches. Compared to other family members, the protein kinase c - theta isoform (PKCt) expression is highly restricted to T cells, is critical to downstream signaling of the TCR complex, and represents an attractive therapeutic target for TMDs. Here, we report results from novel small molecule inhibitors (SMIs) which are highly specific for PKCt. In an in-vitro model of TCR-mediated activation of human PBMCs, our SMIs potently prevented activation of both CD4 and CD8 T cells without affecting cellular viability. Similarly, in in-vitro models of whole primary human skin biopsies under Th1, Th2, and Th17 inducing conditions, tissue resident memory T cells failed to activate and release pro-inflammatory cytokines after PKCt inhibition. Taken together, we have identified multiple novel SMIs of PKCt which are highly potent and highly selective, representing a potential new therapeutic strategy for patients with T-cell mediated inflammatory disease.
Variation in the single cell epigenomic and transcriptomic profiles in response to seasonal influenza vaccination: A comparison between healthy young and older adults
Authors: Ravichandran Sathyabaarathi , Ucar Duygu , Marches Radu , Chaussabel Damien , A. Kuchel George , Banchereau Jacques 
Published: November 2024

Abstract
Older adults exhibit reduced responses to influenza vaccines than young adults. However, the underlying immunological features responsible for this age-related decline remains limited. In our study, we recruited 35 older (&gt;65 years) and 7 young (26-39 years) adults, administered standard or high-dose seasonal influenza vaccines in 2017 and 2018. We assessed antibody responses to H1N1, H3N2, and Influenza B strains using a hemagglutination inhibition(HAI) assay at baseline and on Day35 post-vaccination. We then performed scRNAseq and snATACseq on 10 healthy older and 7 young adults on Day1, Day7, and Day35 to probe innate and adaptive immune responses. Post-vaccination, significant increases in HAI antibody titers were observed for all strains in both age groups, albeit with variability in responses among healthy older adults. Analyses of scRNAseq and snATACseq data revealed distinct innate and adaptive immune signatures in healthy young and older adults, reflecting age-related differences in influenza vaccine responses. Previously, we identified a unique baseline immune phenotype associated to weak Prevnar™ responses in older adults, suggesting it might serve as an aging signature. This baseline phenotype feature is characterized by increased expression of CYTOX genes, increased CD16+ NK and TH17 cell frequency, and decreased TH1 cell frequency. We further assessed the relevance of these characteristics in the context of age-related influenza vaccine responses.
Ubiquitination of Hemocyanin Mediated by a Mitochondrial E3 Ubiquitin Ligase Regulates Immune Response in Penaeus vannamei
Authors: Zhang Xiaojun , Zhang Zhaoxue , Zheng Zhihong , Yao Defu , Zhao Yongzhen , Liu Qingyun , Lin Zhongyang , Zhang Yueling 
Published: November 2024

Abstract
Ubiquitination is a critical posttranslational modification that regulates host immune responses to pathogens. In this study, we investigated the ubiquitination of hemocyanin (PvHMC [Penaeus vannamei hemocyanin]) mediated by the mitochondrial E3 ubiquitin ligase (PvMulan) in shrimp Penaeus vannamei. We characterized distinct ubiquitination patterns of PvHMC in response to different pathogen challenges, both in vitro and in vivo. Specifically, we found that Vibrio parahaemolyticus infection led to an increase in PvMulan, which resulted in K48-linked ubiquitination and subsequent proteasomal degradation of PvHMC. In contrast, PvMulan primarily enhanced the SUMOylation of PvHMC, bolstering its immune functions against white spot syndrome virus challenges. Inhibition of PvMulan-mediated PvHMC ubiquitination significantly affected the proliferation of V. parahaemolyticus and the survival rate of infected shrimps. This study sheds light on the role of hemocyanin ubiquitination in immune regulation, illustrating its dual function in response to distinct pathogens.
Disability research in African Network for Evidence-to-Action in Disability affiliated countries
Authors: Kahonde Callista K. , Mji Gubela 
Published: November 2024

Background: The African Network for Evidence-to-Action in Disability (AfriNEAD) is a leading role player in Africa promoting evidence-informed policies and practices for disability inclusion on the continent. This article presents findings of a desktop review that explored trends of disability research in the AfriNEAD affiliated countries.Objectives: The review explored trends of research that has been published by members of the disability research community who are contributing to AfriNEAD Conferences.Method: A Google scholar search was conducted using names of researchers who presented articles at the first six AfriNEAD Conferences, recording peer-reviewed journal publications by each author according to the eight AfriNEAD research focus areas. This was followed by a hand search of all articles published in the African Journal of Disability from AfriNEAD affiliated countries.Results: There is an exponential increase in the number of peer reviewed journal publications from AfriNEAD affiliated countries over the last two decades. Collaborations are common among authors within the same African country. International collaborations are common among authors from Africa with authors from the Global North.Conclusion: African researchers need to network and collaborate more across Africa, to promote disability research in countries where research is scarce and to focus more on research areas that are not receiving attention.Contribution: The desktop exploration is a first step for AfriNEAD to get a baseline understanding of published disability research in the countries affiliated to the network. Further research is required to understand these trends and to provide evidence necessary to address the identified gaps.
A sociotheological interpretation of Genesis 50:25 in a Zimbabwean context
Authors: Mwandayi Canisius 
Published: November 2024

Migration to foreign lands is as old as the biblical stories of Abraham leaving his native land, Ur of the Chaldeans to go to a land that God was to show him. Concomitant with migration, however, is the possibility of death in the new habitat and oftentimes important decisions are made on how to fund the funerals. In the case of Zimbabwean diasporas, this has seen the rise in popularity of funeral insurance companies such as Diaspora Insurance and the GoFundMe initiatives. While the issue of funding funerals appears to be the primary thing that people are seized with when a funeral strikes, the most salient aspects would be issues of religion and culture. This article endeavours to show how, despite the challenging economic environment, the costly repatriation of dead relatives can best be appreciated through a sociotheological interpretation of Genesis 50:25. In other words, Genesis 50:25 can be used as a mirror to understand the value people place on issues of religion and culture. It is thus my argument that the religious background of the actors as well as their socio-cultural setting are critical in making important decisions regarding the place of interment as well as influencing the funding logistics to take the corpse to the desired resting place.Contribution: As the death toll continues to rise of diasporas who would have gone offshore in search of a reprieve from the economic challenges that have become almost an indelible mark of Zimbabwe, issues around the values of traditional religion and culture continue to come to the fore. This research adds a voice to the ongoing religious and political dialogue in Zimbabwe in so far as it seeks to explain and understand the underlying reasons behind the costly repatriation of deceased relatives through a sociotheological reading of Genesis 50:25.
Evaluating factors influencing youth participation in agricultural enterprises: Implications for food security and agribusiness
Authors: Giwu Ongama , Mdoda Lelethu , Ntlanga Samuel S. , Loki Olwethu 
Published: November 2024

Background: Agriculture is crucial for economic growth, yet youth engagement in agricultural enterprises is declining due to concerns related to perceived profitability, resource access, and social stigmas. Understanding these determinants is vital for fostering youth interest in agriculture and promoting sustainable rural development and food security.Aim: This study examines the factors affecting youth engagement in agricultural enterprises in Umzimvubu Local Municipality, South Africa, and their implications for food security and agribusiness.Setting: Addressing youth unemployment and enhancing agriculture’s contribution to gross domestic product (GDP) require understanding barriers to youth participation. This study was conducted in Umzimvubu Local Municipality, South Africa.Methods: A structured questionnaire was administered to 210 youths through stratified random sampling. Descriptive statistics and a univariate probit regression model were used for analysis.Results: Findings indicate male dominance in agriculture, with educational background positively correlating with participation. Single youths showed greater interest than married counterparts. Challenges like land availability and a lack of financial support hinder engagement. Significant determinants include age, education, farming skills, social group membership, and household revenue, while factors like household size, gender, and limited access to credit negatively impact willingness to participate.Conclusion: Addressing financial barriers through improved access to loans is essential to enhance youth involvement. Policies should cater to youth-specific traits and environmental challenges to build a resilient agricultural sector driven by young innovators.Contribution: The study emphasises the need for a comprehensive policy framework collaboratively developed by the government, the Department of Agriculture, and non-governmental organisations.