bluuebunny/crossref_metadata_2025_split huggingface dataset:
Immunomodulatory functions of the gut protist Pentatrichomonas hominis in health and disease
Authors: Soto Ariadna Soledad , Engel Clarisse , Sanchez Luzmariel Medina , Mehta Isha , Meisel Marlies , Das Jishnu , Hinterleitner Reinhard 
Published: August 2023

Abstract
Protists have been identified as part of the mammalian gut microbiome and are known to impact gut immunity and complex intestinal diseases such as inflammatory bowel disease (IBD). In humans, studies mainly describe host interactions with disease-causing species, while little is known about how commensal protists impact the immune system. Protists from the Parabasalid family, including Pentatrichomonas hominis (P. hominis), have been identified in about 30% of healthy individuals; however, the role of these non-pathogenic commensal Parabasalids remains unstudied. Our data shows that P. hominis promotes Treg differentiation in vitro. Interestingly, this ability was found to be contact-independent, as culture supernatant was sufficient to induce Tregs. Moreover, by doing de-novo genome and transcriptome assembly and high-resolution mass spectrometry we have identified immunomodulatory candidate pathways and metabolites that might be mediating this effect. Re-establishment of tolerance is a major therapeutic strategy for treating intestinal diseases. Hence, we were interested in studying P. hominis impact on the gut immune landscape. To that aim, we successfully and stably colonized mice with P. hominis in gnotobiotic housing conditions and under antibiotic regimen and we are testing P. hominis role under steady state and IBD mouse models. Altogether, our research will address a present gap in knowledge, potentiating the study of protists in the microbiome and their association with intestinal disorders.
Fumarylacetoacetate hydrolase (FAH): a candidate host gene associated with susceptibility to tuberculosis
Authors: Reijneveld Josephine F , Nieto-Caballero Victor E , Innocenzi Gabriel , Ruvalcaba Angel , Budzik Jonathan , Gutierrez-Arcelus Maria , Suliman Sara 
Published: August 2023

Abstract
Tuberculosis (TB) disease remains the leading cause of mortality from an infectious disease globally, with an estimated 1.6 million deaths in 2021. TB is caused by infection with Mycobacterium tuberculosis (Mtb), resulting in variable outcomes from asymptomatic latent infection to clinical TB disease. However, most individuals exposed to Mtb never develop clinical disease. We hypothesize that host factors, including metabolic pathways, determine the outcome of Mtb infection. Based on prior data from human cohorts we observed an association between impaired tyrosine metabolism and progression to TB disease. We then reanalyzed a public dataset of Mtb-infected monocyte derived dendritic cells (DCs) and found that stimulation with either live or heat-inactivated Mtb resulted in downregulation of FAH (fumarylacetoacetate hydrolase), which encodes the last enzyme in the tyrosine catabolism pathway. Next, we used gene editing of FAH in conditionally immortalized myeloid progenitors (CIM) from mice to test whether downregulation of the FAH gene is associated with higher susceptibility to Mtb. We generated three independent fah-edited CIM lines, with two lines showing editing efficiency above 90%. We infected wildtype and fah-edited CIMs with an H37Rv-lux Mtb strain and detected significantly higher Mtb growth in fah-edited CIMs compared to wildtype CIMs (p=0.004). We also successfully optimized CRISPR in primary human monocyte derived DCs and macrophages to define the role of FAH during infection in physiologically relevant myeloid cell types. Our data suggest that FAH deletion compromises immune control of Mtb. We are currently exploring the immunoregulatory roles of FAH during Mtb infection, including inflammasome activation.
MANGO: Inferring gene regulatory networks from single cell multiomics
Authors: Williams Mark Elliott , Scharer Christopher D 
Published: August 2023

Abstract
Transcription factors (TFs) and their target gene regulatory networks (GRNs) control immune cell fate decisions during differentiation and responses to environmental cues and signals. To better understand how GRN control immune outcomes and are dysregulated in disease settings, we developed MANGO (Multiomics Aided Neural Graph Ontology), a computational method that integrates single cell gene expression and chromatin accessibility data to infer genome-wide, cell-type specific GRN. MANGO harnesses graph neural networks to generate representations of gene and regulatory link behavior and uses existing interpretable methods, like UMAPs, to visualize the GRN and gather insights about functional neighborhoods of regulators or programs of regulation. By scoring each regulatory interaction and aggregating those with common sources, TF activity can be quantified and compared between networks. We applied MANGO to a human PBMC dataset to define GRN and identify key regulatory, cell-type specific TFs, despite sometimes having low changes in expression. Additionally, we show that MANGO can distinguish cells by regulation network at single cell resolution by feeding each cell’s expression and accessibility through its respective cell type’s regulation network and projecting the resulting embedding in lower dimensions with a UMAP. Finally, MANGO was used to uncover memory B and T cell GRNs that prime rapid secondary immune responses. Given the increase in single cell multiome datasets, we anticipate MANGO will provide unique insights into GRN in normal and diseased immune responses, and ultimately give rise to patient specific understanding of the immune system and precision medicine.
Supported by grants from NIH/NIAID (R01 AI148471) to CDS
MHC Ib-restricted T Cells Generate the Dominant Memory T Cell Response in Early Stages of Mycobacterium tuberculosis Infection
Authors: Cui Yongyong , Shang Shaobin , He Ying , Wang Chyung-Ru 
Published: August 2023

Abstract
Unconventional T cells, which recognize monomorphic MHC Ib molecules, such as Qa1, Qa2, M3, CD1, and MR1 have been implicated in the primary response to Mycobacterium tuberculosis (Mtb) infection. However, whether these T cells play a role and which MHC Ib molecules participate in the memory response against Mtb infection remains unknown. To determine the optimal immunization strategy, we vaccinated mice that lack MHC Ia (Kb−/−Db−/−) with an attenuated Mtb H37Rv strain via intravenous (IV) or subcutaneous (SC) injection. We found both routes of immunization induced a comparable MHC Ib-restricted CD8+ T cell response after virulent Mtb H37Rv re-challenge. Since bacteria were cleared through the SC but not the IV route, we selected SC as our primary route of immunization. MHC Ib-restricted CD8+ T cells in vaccinated mice produced multiple proinflammatory cytokines, expanded faster after Mtb challenge than those in unvaccinated mice, and recognized several Mtb protein antigens. Importantly, the memory response of MHC Ib-restricted CD8+ T cells was more dominant than that of MHC Ia-restricted CD8+ T cells at early stages of infection. We also observed an increased percentage and number of Qa1, Qa2 and M3-restricted CD8+ T cells in vaccinated mice in the early stages of infection, suggesting that these MHC Ib molecules can elicit MHC Ib-restricted memory CD8+ T cell response. While CD1d-restricted NKT cells did not differ significantly between vaccinated and non-vaccinated mice, the activation kinetics of MR1-restricted T cells was accelerated in vaccinated mice. Overall, we show that MHC Ib-restricted T cells memory response can play an important role at the early stages of Mtb infection thus should be included in subunit vaccine formulation.
Supported by grants from NIH (R01AI141083)
Subsecond release of catecholamines from CD4+ T lymphocytes
Authors: Seibold Jordan M , Ross Ashley 
Published: August 2023

Abstract
The neuroimmune system is complex and is regulated by small chemical messengers released from resident immune and neuronal cells. Catecholamines like dopamine and norepinephrine are important chemical messengers responsible for initiating and propagating messages between neurons and immune cells; however, the mechanism and dynamics of this signaling is relatively unknown. The presence of the intracellular machinery to synthesize and interact with catecholamines in T lymphocytes has been known for over a decade; however, direct measurement of catecholamine secretion in real time from immune cells has not been possible. Here, we have discovered that CD4+ T cells are capable of releasing catecholamines on a subsecond time scale. We have used a revolutionary technique, often used in the neuroscience field, called fast-scan cyclic voltammetry (FSCV) to measure subsecond fluctuations of catecholamines from isolated CD4+ T cells. This work provides direct evidence that T cells are capable of releasing catecholamines; potentially as a feedback communicator to resident sympathetic neurons in host immune organs. These results also prove that immune cells can signal on the same time scale as neurons . This work will hopefully open the door to enable more sophisticated studies at the neuron-immune synapse in the future.
National Institute of Health R01AI151552
Pre-activation of follicular B cells in old mice generates a hyper-response during germinal center reaction
Authors: Ticas Rodas Carlos J , Maul Robert W , Gearhart Patricia J 
Published: August 2023

Abstract
Immune cells acquire a variety of defects that accumulate overtime in a process known as Immunosenescence. To study any innate defects that B lymphocytes may acquire during aging, we have developed an adoptive transfer system using follicular B cells from young (FOY, 8–12 weeks) and old (FOO, &gt;22 mo.) mice into a μMT B cell-deficient mouse. This model reveals that FOO cells, compared to their young counterparts, produce a higher amount of activated germinal center (GC) B cells in the presence of the common antigen NP-CGG after 14 days of immunization. However, these cells do not produce antigen-specific antibodies while showing a significant decrease in NP+ λ+ antigen-specificity. To study this change in phenotype further, we performed single cell RNA sequencing using both young and old populations of naïve, and day 14 GC B cells. Comparison of the naïve populations by PCA showed only minor differences between populations. Interestingly, Ccr6 is being upregulated in FOO cells but has a decreased expression in the old population of GCs. This change in expression suggests that FOO cells are pre-activated before transfer to μMT mice and antigen encounter. Analysis of the immunoglobulin repertoire in these cells showed that FOO cells also have decreased use of the canonical NP-specific IgH V-gene 1–72 and fail to include the CDR2 W33L mutation that is known to increase antibody affinity 10-fold. Taken together, these findings show that old mice produce pre-activated and hyper-responsive cells that cause a lack of proper selection and affinity maturation during the GC reaction.
This research was supported in part by the Intramural Research Program of the NIH, National Institute on Aging.
Spatial Profiling of Glioblastoma Microenvironments and Response to Immunotherapy
Authors: Garcia-Rivera Lizmarie , Chen Dan , Kaech Susan 
Published: August 2023

Abstract
Glioblastoma (GBM) is the most common adult brain cancer. Recent therapeutic advances, including immunotherapies that enhance anti-tumor immune responses, have failed to significantly improve survival. To address these failures, deeper studies on the cellular interactions that orchestrate whether GBM resists or regresses during immunotherapy are needed. Our group recently discovered that anti-CTLA-4 therapy initiated a novel microglia-CD4 T cell partnership. Following anti-CTLA-4, tumor-bearing mice showed a significant increase in survival and enhanced tumor regression. Further investigation showed that CD4 T cells, not cytotoxic CD8 T cells, were necessary for this response and that microglia were responsible for both sustaining tumoricidal CD4 T cell activity via MHC-II antigen presentation and phagocytosing debilitated tumor cells. With the rise of spatial profiling platforms, such as NanoString’s CosMx, we can now capture snapshots of the cellular dynamics that lead to a successfully mounted anti-tumor response in a continually evolving tumor microenvironment. Using both murine models and human GBM specimens, we are exploring the cellular networks that support beneficial CD4 T cell-microglia interactions and tumor regression. Conversely, we are also examining the role of regulatory T cells in the periphery and tumor microenvironment, and how these cells may interact with other immune suppressive niches, including GBM-associated microglia and infiltrating macrophages, to support GBM progression. Through this work, we are mapping the GBM cellular niches that support or suppress anti-tumor responses, with the goal of exposing vulnerabilities that can be exploited with better tailored immunotherapies.
Supported by grants from NIH (R01 CA240909, R01 CA230275)
Determining mechanisms of T cell leukemogenesis using E2A−/− mice
Authors: Parriott Geoffrey R , Bartom Elizabeth T , Kee Barbara L 
Published: August 2023

Abstract
T cell acute lymphoblastic leukemia (T-ALL) is a hematological malignancy caused by the transformation of T-lymphocytes during their development. 60% of pediatric T-ALLs have ectopic expression of Tal1, a gene that promotes leukemogenesis in part by altering the function of E2A. Consistent with this, mice with germline deletion of E2A develop T-ALL that mirrors human Tal1+ T-ALL. In this study, we used mice that delete E2A at different stages in T cell development to investigate the mechanisms causing T-ALL. Mice carrying a VavCre transgene and floxed alleles of E2A (VcKO) delete E2A early in T cell development, have reduced numbers of thymocytes prior to transformation, and develop T-ALL with an average latency of 18 weeks. Mice with an LckCre transgene (LcKO) delete E2A later than VcKO mice, have replete thymi, and rarely develop T-ALL. From this, we hypothesized that 1) E2A regulates a gene program in early T cell development that is antagonistic to transformation, or 2) Having a replete, competitive thymus suppresses transformation. Pre-leukemic VcKO thymocytes showed significantly more differentially expressed genes than LcKO thymocytes, including Notch1 and Myc, and are enriched for cancer associated pathways. To determine if the lack of competition in the VcKO thymus contributes to leukemogenesis, we reconstituted VcKO thymi by transplanting wild type bone marrow into sublethally irradiated VcKO mice. BM transplant significantly increased the number and frequency of DP thymocytes and increased leukemia latency. Together, these data suggest that intrinsic loss of E2A promotes leukemogenesis by changing the gene program of early developing thymocytes and by creating a non-competitive environment that supports transformation.
Robust eIF4B levels undermine invasive growth and immune evasion mechanisms in murine triple negative breast cancer models
Authors: Barbi Joseph J , Smith Randall , Diba Leila Zabihi , Srinivasan Aravind , Ossevoort Thomas , Zollo Robert , He Qian , Venkatesh Meera , Arora Aayush P , Washington Deschana , Yao Song , Walker Sarah E 
Published: August 2023

Abstract
Dysregulated protein synthesis is seen in many aggressive cancers, including metastatic breast cancer. However, the specific contributions of certain translation initiation factors to in vivo disease remain undefined. This is particularly true of eIF4B, an RNA-binding protein and cofactor of the RNA helicase eIF4A and associated eIF4F cap-binding complex. While eIF4A, eIF4G, and eIF4E are known to contribute to the progression of many cancer types, the role played by eIF4B in breast cancer remains relatively unclear. We therefore explored how naturally divergent and experimentally modulated eIF4B levels impact tumor growth and progression in murine triple negative breast cancer (TNBC) models. Surprisingly, we found that higher eIF4B levels in mouse and human breast cancers were associated with less aggressive phenotypes. shRNA-mediated eIF4B knockdown in TNBC lines failed to markedly alter proliferation and global translation in cells grown in vitro and only modestly hindered primary mammary tumor growth in mice. However, eIF4B knockdown significantly enhanced invasive growth in vitro and exacerbated both tumor burden and mortality relative to nontargeting shRNA controls in a model of metastatic disease. Deposited patient data reinforced a link between high eIF4B levels and better outcomes. Interestingly, in vitro and in vivo studies associated low eIF4B expression with more formidable immune evasion. These findings suggest that eIF4B levels impact metastatic disease in part through immunomodulatory mechanisms beyond the factor’s traditional role supporting eIF4/F directed translation. Future studies should explore the impact of these findings for personalizing treatment decisions and developing future therapies.
Targeting the NKG2A axis with a TCR mimic antibody containing an active Fc domain promotes anti-tumor immunity
Authors: Ghaffari Soroush , Weidanz Jon 
Published: August 2023

Abstract
The NKG2A axis is an emerging immune checkpoint. Blocking antibodies to the NKG2A receptor in combination with cancer vaccines and PD-(L)1 antibodies have been found to enhance anti-tumor immunity in murine models and cancer patients. The ligand for the NKG2A receptor is the non-classical major histocompatibility (MHC) class Ib molecule, Qa-1b in mice (HLA-E in humans), loaded with leader peptides from classical MHC class Ia molecules to form Qa-1b/Qdm peptide complexes. Here, we explore the therapeutic value of targeting the NKG2A ligand, not done previously, using our recently described single-domain T-cell receptor mimic (TCRm) antibody, EXX-1. Two syngeneic murine tumor models (A20 and CT26) were used to evaluate the therapeutic potential of EXX-1 and its mode(s) of action. The initial study done showed EXX-1 Fc active (mIgG2a) displayed optimal tumor growth inhibition and prolonged survival time in mice compared to a modified form of EXX-1 containing an inactive Fc domain. These findings suggested that in addition to blocking the NKG2A pathway, EXX-1 Fc active antibody likely induces tumor cell death via antibody dependent cellular cytotoxicity (ADCC). Moreover, mice treated with EXX-1 antibody as single agent therapy showed significantly better survival outcomes compared to the cohort of mice treated with blocking antibody to the NKG2A receptor. This implies that there might be potential benefits of targeting the NKG2a ligand over the NKG2A receptor though this will require further investigation. Additionally, combination therapy using EXX-1 Fc active and PD-(L)1 blocking antibodies revealed markedly improved rates of tumor-free mice compared to mice receiving treatment with EXX-1 Fc active or anti-PD-(L)1 antibody alone.
Analisis Dan Visualisasi Data Body Performance Menggunakan Tiga Tools Visualisasi
Authors: Husna Lailatul , Prasetyo Utomo Pradita Eko 
Published: August 2023

Artikel ini membahas tentang Analisa dan visualitasasi data dari data body performance .dimana nanntinya hasil Analisa penulis akan dicantumkan dibagian hasil dan pembahasan.dari artikel ini kita dapat melihat keuntungan memvisualisasikan data yang ada.dengan adanya beragam tools visualisasi data akan mempermudah kita dalam menganalisis dan memvisualisasikan data yang diinginkan.berikut tiga tools yang digunakan dalam artikel ini yaitu : Microsoft Power BI, Google Colab, dan Tableau Public.Adanya visualisasi data akan mempermudah mengambil keputusan.Dalam melakukan visualisasi data harus memperhatikan beberapa hal seperti data apa yang akan digunakan , apa yang ingin divisualisasikan , dan dugaan apa yang ingin dibuktikan.
Kata kunci—analisis dan visualiasi data, Tableau Public, Microsoft Power Bi, Google Colab.
Pengaruh Kualitas Produk, Harga dan Promosi terhadap Keputusan Pembelian Sepeda Motor Merek Honda (Studi Kasus di Kecamatan Batu)
Authors: Alfiah Alfiah 
Published: August 2023

The market share of Honda motorcycles in Indonesia is currently experiencing a decline. One of the causes that affect the decline in the market share of Honda motorcycles is the decline in buying interest of consumers who have been customers of Honda motorcycles to make repeat purchases. In addition, consumers of new motorcycles are also less interested in buying Honda motorcycles.This study aims to determine the effect of product quality, price and promotion on purchasing decisions for Honda motorcycles in Batu sub-district. The sampling in this study was non-probability sampling using a purposive sampling technique, totaling 40 people in Batu District who had purchased a Honda motorcycle. The data analysis technique in this study used multiple linear regression with the SPSS Version 25.0 program, after going through the instrument test and classical assumption test. The results of the study prove that two independent variables, namely product quality and promotion, have a significant and significant influence on the purchase decision variable for Honda motorcycles, while the price variable does not have a significant influence on respondents in determining the decision to buy a Honda motorcycle. Tests carried out together showed that all independent variables (product quality, price and promotion) had an effect on purchasing decisions. Keywords: Purchase Decision, Product Quality, Price, Promotion
Pengaruh Customer Satisfaction dan Trust In Brand terhadap Customer Retention pada Konsumen Minimarket Indomaret di Pasuruan
Authors: Widyaratna Lianita , Astutik Mitha Widya 
Published: August 2023

ABSTRACTIn this study, the authors use customer satisfaction and trust in brand as independent variables to test how they affect customer retention. The population used in this study were consumers of the Indomaret Minimarket in Pasuruan. Where this population is a population whose numbers are not known with certainty. In this study, the sample was taken using non-probability sampling, using purposive sampling technique, the number of samples taken using the Lameshow formula and obtained 100 respondents. The analytical tool used is multiple linear regression using the SPSS program. The research results obtained from the t test results that customer satisfaction and trust in brand each have a positive effect on customer retention. Meanwhile, the results of the F test are obtained simultaneously that customer satisfaction and trust in brand have an effect on customer retention. The coefficient of determination seen in the adjusted R-squared value is 0.284 or 28.4%. Customer satisfaction is the dominant influence that affects customer retention compared to trust in brandKeywords : customer satisfaction, trust in brand, customer retentionABSTRAKDalam penelitian ini, penulis menggunakan customer satisfaction dan trust in brand sebagai variabel independen akan menguji bagaimana pengaruhnya terhadap retensi pelanggan. Populasi yang digunakan dalam penelitian ini adalah konsumen Minimarket Indomaret di Pasuruan. Dimana populasi ini merupakan populasi yang jumlahnya tidak diketahui secara pasti. Dalam penelitian ini pengambilan sampel menggunakan non-probability sampling, dengan menggunakan teknik purposive sampling, jumlah sampel yang diambil menggunakan rumus Lameshow dan didapatkan 100 responden. Alat analisis yang digunakan adalah regresi linier berganda dengan menggunakan program SPSS. Hasil penelitan didapatkan dari hasil uji t bahwa customer satisfaction maupun trust in brand masing-masing berpengaruh positif terhadap customer retention. Sedangkan hasil uji F didapatkan secara bersama-sama customer satisfaction dan trust in brand berpengaruh terhadap customer retention. Koefisien determinasi yang terlihat pada nilai adjusted R-squared adalah 0,284 atau 28.4%. Customer satisfaction merupakan pengaruh dominan yang mempengaruhi customer retention dibandingkan dengan trust in brand.Kata Kunci : customer satisfaction, trust in brand, customer retention