bluuebunny/crossref_metadata_2025_split huggingface dataset:
Development of Sialoglycan Recognizing Probes (SGRPs) With Defined Specificities: Towards Exploring the Dynamic Mammalian Sialoglycome
Authors: Srivastava Saurabh , Verhagen Andrea , Wasik Brian , Yu Hai , Sasmal Aniruddha , Bensing Barbara , Khan Naazneen , Khedri Zahra , Diaz Sandra , Sullam Paul , Varki Nissi , Chen Xi , Parrish Colin , Varki Ajit 
Published: January 2023

Abstract
Dense and complex glycans on vertebrate cell surfaces and secreted molecules often terminate with sialic acids (Sias), a diverse family of sugars involved in numerous biological processes, including cell-cell interactions, immune regulation, cellular homeostasis, host-pathogen interactions and microbial pathogeneses. Due to immense structural variations, a major fraction of sialoglycans remain poorly characterized by current inadequate conventional techniques. While traditional glycomic methods are useful, they can destroy or overlook crucial aspects of Sia diversity, or fail to elucidate native structures as they exist in biological systems. To date, in situdetection and analysis of sialoglycans have been largely based on plant lectins, sialidases or antibodies whose preferences are limited and/or uncertain.
We defined 9 classes of Sialoglycan Recognizing Probes (SGRPs: SGRP1- SGRP9) aiming to provide a simple and systematic approach to track mammalian sialome changes, using techniques common in most laboratories. Our approach utilizes molecules naturally evolved with maximized specificity towards sialoglycans such as bacterial adhesins, toxin subunits and viral hemagglutinin-esterases. We selected the experimentally proven best candidates for SGRPs and engineered each with a corresponding non-binding mutant as a negative control. Following sialoglycan microarray studies to confirm the binding specificity of our SGRPs, the optimized panel of SGRPs was subsequently applied in common detection methods such as ELISA, Western Blot and FACS analysis. While further work is needed to define a comprehensive suite of SGRPs, our efforts provide a reliable toolkit with specificity to track the mammalian sialoglycome.
Database of Immune Cell EQTLs, Expression, Epigenomics
Authors: Ha Brendan , Greenbaum Jason A , Shmiedel Benjamin J , Singh Divya , Madrigal Ariel , Valdovino-Gonzalez Alan G , White Brandie M , Zapardiel-Gonzalo Jose , Altay Gokmen , McVicker Graham , Seumois Gregory , Rao Anjana , Kronenberg Mitchell , Vijayanand Pandurangan , Peters Bjoern 
Published: January 2023

Abstract
Database of Immune Cell EQTLs, Expression, Epigenomics (DICE, dice-database.org) is a freely accessible web resource for diving deep into RNA-seq data across 13 human immune cell type (subsets of T cells, B cells, monocytes and NK cells), in a cohort of 91 healthy, genotyped donors1. The site is composed of four main modules that allow users to view the integrated data by gene, limit the scope to individual cell types, compare expression across cell types, and explore the effect of SNPs on gene expression. The site is optimized to be accessible on both desktop and mobile devices. DICE is an evolving resource with data for additional cell types being deposited on a continuous basis, with 3 additional B cell subsets being next in line. In addition to the core database website, an associated tools website (tools.dice-database.org) is actively being developed and currently hosts tools that operate on lists of genes to perform interactive GO enrichment analysis (GOnet), identify cell types most likely responsible for expression of a set of genes (CellTypeScorer), and examine GeneNetworks deduced from gene co-expression analysis.
Gene conversion identification and analysis in immunoglobulins
Authors: Bonissone Stefano R 
Published: January 2023

Abstract
Few, if any, somatic processes exhibit such sequence level diversity as the immunoglobulin rearrangement and somatic hypermutation (SHM) mechanisms. It is due to these processes that novel antibody receptors can be created against most pathogens.
Somatic hypermutation is attributable to the majority of non-junction diversity in studied repertoires, however, this has been largely due to the organisms most heavily studied in repertoire sequencing: human and mouse. Gene conversion is another mechanism that drives diversity in the immunoglobulin repertoire of other organisms, particularly in chicken and rabbit.
Confidently identifying gene conversion events has not been a focus for most repertoire sequencing studies, largely due to the organisms typically studied. However, their identification also poses an algorithmic and statistical problem: namely how to identify a tract of donor sequence from similar V genes, and subsequently assessing the significance of such an identification. The scant examples of analysis of immunoglobulin gene conversion in the literature have used two approaches: visual inspection and the use of GENECONV.
We propose two alternate approaches to identify the events: using a specialized pairwise alignment between the read, host, and donor references; and using a partial order alignment graph. These new approaches are validated on simulated antibody data, showing improved recall, and reduced false positive rates. The new approaches are more sensitive than GENECONV on smaller donor tract lengths (&lt; 100nt), and are not sensitive to higher mutation load. We then apply the new approach to identifying gene conversion events in high throughput repertoire sequencing of rabbit, and public human datasets.
Antibody epitope mapping at single residue resolution for unpurified antigens
Authors: Pan Jingxi , Zhang Sara 
Published: January 2023

Abstract
The vast majority of antigen-antibody interactions rely upon binding to conformational epitopes, which are composed of amino acids that are discontinuous in the protein sequence but are brought together upon three-dimensional protein folding. This character has made conformational epitopes particularly difficult to map because they are only formed in the native structure of the antigen protein. X-ray crystallography is a gold-standard method for mapping conformational epitopes at high-resolution, but it only works for highly purified antigens and is time consuming, and is not applicable when crystals of antigen-antibody complex are unavailable. Here we present a novel middle-down HDX-MS technology with subzero temperature separation that effectively tackles these limitations. It successfully mapped the conformational epitopes in a VPF growth factor targeted by a therapeutic antibody, in a complex protein mixture where the antigen content is as low as 10%. It provided single amino acid resolution by online gas-phase fragmentation on the LC-MS time scale. It also uses directly the whole antibody, pre-digestion of the antibody to Fab fragments is no longer needed.
In conclusion, the subzero temperature separation based HDX-MS technology represents an alternative high-resolution epitope mapping approach to X-ray crystallography, and is also a fast and cost-effective solution for new antibody and vaccine development. Its potential in paratope mapping, as well as epitope mapping for other difficult targets and bispecific antibodies will be discussed.
C15 is actionable drug target for anti-arthritis via activation Nrf2 signaling
Authors: Li Ting , Liao Kangsheng , Zhuang Yuxin , Wu Jianlin , Liu Juan 
Published: January 2023

Abstract
SNM is a purified compound isolated from Chinese Medicinal plant. In the current study, we found that SNM not only ameliorated the progression of collagen induced arthritis (CIA), but protected joints from destruction in mice, indicating that SNM probably restricted the local inflammation of arthritic joints. As synovium in the joints is the major target tissue of rheumatoid arthritis, the synovium fibroblasts derived from RA patients (RASFs) were employed to validate the anti-arthritic effect and explore underlying mechanism of SNM. The results demonstrated that SNM significantly inhibited IL-6 and IL-33 secretion, COX-2 expression and ROS production in RASFs. Mass spectrometry results demonstrated that cysteine 26 (C26) and lysine 873 (K873) of C15 are a direct target of SNM. Underlying mechanistic study showed that knockdown C15 resulted in the accumulation and phosphorylation of p62 and aggregation of Nrf2 and HO-1 in cytoplasma of RASFs. Consistently, SNM activated p62/Nrf2 signaling in RASFs via covalently binding at C26 and K873 of C15. Furthermore, the collagen antibody-induced arthritis (CAIA) model was established in Nrf2−/− mice to verify the role of Nrf2 in the anti-arthritic effect of SNM, and the results explored that Nrf2−/− mice are resistant to the anti-arthritic effect of SNM. Our findings explored that C15 is an actionable drug target for anti-arthritis via activation Nrf2 signaling.
Therapeutic vaccination by two DerG LEAPS conjugates incorporating different PG (aggrecan) epitopes protect by different immune mechanisms in the PG G1 domain induced mouse model of rheumatoid arthritis
Authors: Zimmerman Daniel H , Mikecz Katalin , Rosenthal Kenneth S , Markovics Adrienn , Carambula Roy , Ciemielewski Jason , Glant Tibor 
Published: January 2023

Abstract

Background
Development of a therapeutic vaccine for rheumatoid arthritis (RA) requires modulating antigen specific inflammatory T cell responses that drive disease. RA can be initiated and driven by responses to multiple antigens but peptide vaccines usually contain few epitopes. The challenge is to elicit the appropriate responses by these vaccines.

Method
We used the proteoglycan (PG, aggrecan) G1 domain-induced arthritis model of RA. Mice were immunized with either one or two different DerG LEAPS vaccines containing PG epitopes (PG70 or PG275Cit) in Seppic ISA51vg adjuvant subcutaneously after signs of arthritis were noted. Mice were examined trice weekly for arthritis progression. At study end serum antibodies to the vaccine epitopes and splenic T-cell responses to PG G1 domain were determined.

Results
Immunization with DerGPG70 or DerGPG275Cit conjugate, alone or in combination, stopped the progression of disease. DerGPG275Cit was effective in protection but did not induce significant serum antibodies whereas DerGPG70 (alone or with DerGPG275Cit) induced both protection and antibodies. Spleen cells from DerGPG70-immunized mice had an anti-inflammatory response to PG G1 in vitro.

Conclusions
Immunization with DerG LEAPS conjugates of different epitopes of PG alone or together were effective at modulating the inflammatory response and stopping disease progression. As observed previously, the DerGPG70 conjugate modulated disease through up-regulation of Th2, and down-regulation of Th1 and Th17 responses. Results suggest mechanistically different immune responses to the two vaccines. Combination of them provided not only broader epitope coverage, but also a greater therapeutic effect than either vaccine alone.
An Accidental Discovery of a New Potential Mouse Model of the Axial Spondyloarthritis
Authors: Banda Nirmal K 
Published: January 2023

Abstract
Many preclinical mouse models of arthritis exists but none of the axial spondyloarthritides (axSpA) mouse model to examine the pathogenic mechanism(s) and the effect of drugs. Collagen antibody induced arthritis (CAIA) is one of the most widely used mouse model of arthritis and it is complement-dependent. We found in 100s of mice developing CAIA also developed axSpA. To induce CAIA in mice, at day 0, mice were injected intraperitoneally with anti-collagen antibodies, followed by lipopolysaccharide injection at day 3. On day 10, mice were sacrificed and assessed according to gross spinal morphology and paw synovitis scores. CAIA mice demonstrated an exaggerated kyphosis through the spine, as well as hypertrophic cartilage and osseous damage of the intravertebral joints. ImmunoHistoChemical staining of the kyphotic area revealed increased complement C3 staining and macrophage staining, with localization to the intravertebral joint margins. In vivo imaging showed that anti-collagen antibodies-conjugated with IRDye® 800CW not only localized to cartilage surface in the joints but also in the spine in arthritic mice. Thus CAIA exhibited salient features of axSpA therefore it could be a by-product of autoimmune arthritis. This new mouse model of axSpA may allow investigators to shed light on the basic aspects of axSpA development and treatment.
Reconstitution of iNKT cells enhances antitumor immunity through liver education of iNKT cells and modulation of tumor microenvironment
Authors: Zhang Hui , Zhu Zhaohui , Zhang Faya , Modrak Samantha 
Published: January 2023

Abstract
Invariant natural killer (iNKT) cells are a specific population of T cells that functionally are more like innateimmune regulatory cells and play important roles in antitumor immunity. It is reported that reconstitution of iNKT cells enhances antitumor immunity in human and mice, however, the underlying mechanism is not known. Using thymocytes and splenocytes to reconstitute iNKT cells in iNKT KO mice, we found that reconstitution of iNKT cells dramatically inhibits tumor development, progression and metastasis, and increases the survival of tumor-bearing mice. Most of the transferred cells accumulated in the liver. After two weeks of transfer around 70% of the transferred thymocytes in the liver differentiated into iNKT cells. Transferring CXCR6− thymocytes enhanced antitumor immunity, transferring CXCR6− splenocytes inhibited antitumor immunity. The enhanced antitumor immunity was abolished in IFN-γ and iNKT double KO mice, which suggests that this antitumor immunity is IFN-γ-dependent. Depletion of NK cells, but not CD8+ T cells or CD4+ T cells, diminishes iNKT cell reconstitution-induced antitumor immunity. Reconstitution of iNKT cells increased tumor-infiltrated lymphocytes (TIL), specifically IFN-γ-producing CD8+ T cells and NK cells, but decreased MDSC and M2 macrophages and down regulated the expression of TGFβ, Arginase and iNOS in the tumor. Taken together, liver education of iNKT cells plays a key role in iNKT cell reconstitution-induced antitumor immunity. This enhanced antitumor immunity depends on IFN-γ and NK cells of the host through modulating tumor microenvironment.
Targeted ablation of FoxP3+ T cells activates peripheral and tumor-infiltrating cytotoxic CD8+ T cells in multiple syngeneic mouse tumor models
Authors: Delfino Teresita , Wang Yingyun , Schartner Jill , Rutz Sascha 
Published: January 2023

Abstract
FoxP3+ regulatory T cells (Treg) are essential to prevent autoimmunity, but have also been implicated in suppressing anti-tumor immune responses. We assessed the impact of Treg depletion in 8 different syngeneic tumor models, including cancer immunotherapy-sensitive and -resistant models. Robust, rapid tumor control or regression was observed in all models tested. Analysis of both peripheral and tumor-infiltrating T cells revealed that Treg depletion resulted in robust proliferation and cytokine production by CD8+ T cells in lymph nodes, spleen, and tumor tissue. Tumor regression was CD8+ T cell-dependent, as antibody mediated-depletion of these cells abrogated tumor regression in a representative model. Interestingly, studies using FTY720 to pharmacologically block T cell egress from the lymph nodes suggest that following Treg depletion, cancer immunotherapy-sensitive models may not require new T cell infiltration into the tumor for tumor regression. This is in contrast to an immunotherapy-resistant model, which failed to regress following Treg depletion when lymph node egress was concurrently blocked. These data suggest that Tregs play a critical role in suppressing both priming of novel anti-tumor CD8+ T cells responses as well as limiting effector functionality of tumor-infiltrating CD8+ T cells within the tumor microenvironment.
Intratumoral Localization of Pattern Recognition Receptor Signaling Informs CAR T Cell Design
Authors: Johnson Lexus , June Carl H , Minn Andy J 
Published: January 2023

Abstract
Immune therapies have significantly improved outcomes for cancer patients with poor prognosis, but mechanisms that underlie response or resistance to therapy remain elusive. Type I and Type II interferon signaling is required for immune activation but is also known to drive programs of tumor-intrinsic resistance. We propose that activation of pattern recognition receptor (PRR) signaling in specific cellular compartments underlies this seemingly contradictory observation. We have recently identified the highly structured RNA RN7SL1 (7SL) as a novel intratumoral PAMP (pathogen associated molecular pattern) capable of activating PRR signaling. When over-expressed in tumor cells, the resulting tumors are resistant to immune checkpoint blockade (ICB) therapy. However, 7SL is stimulatory to primary human DCs, and improves T cell priming in vitro. Furthermore, direct intratumoral injection of 7SL improves immune activation and response to ICB in vivo. Thus, we propose the localization of PAMP recognition and PRR signaling may represent an important determinant of response to ICB therapy. Based on this finding, we have developed a CAR T cell capable of producing 7SL in the tumor microenvironment, as well as a fully syngeneic B16 solid tumor model for CAR T cell therapy. Murine 7SL-CAR T cells control tumors more robustly than controls and synergize with ICB. Importantly, this effect is dependent on endogenous T cells, indicating that 7SL-CAR T cells are jump-starting an endogenous polyclonal anti-tumor immune response. In total, this represents a novel insight into the role of PRR signaling in tumors and leverages the findings to create a therapy with potential to serve patients that are currently refractory to CAR-T or ICB therapies alone.
Robust antitumor effects of SNA-based T cell therapy
Authors: Dominguez Donye , Chernyak Natalia , guan Monica , Chou Yushang , Long Alan , Qin Lei , Cole Lisa , Ann Jihae , Chen Siqi , Fan Jie , Lee Andrew , Mirkin Chad , Zhang Bin 
Published: January 2023

Abstract
The use of toll like receptor (TLR) agonists for immunotherapy remains under intense investigation. Activation of TLRs unleash the power of dendritic cells (DCs) to induce a robust antitumor CD8+ T cell response. However, the role of TLRs in CD8+ T cells has been largely overlooked. T cells do express endosomal TLR9, but it is not readily targetable in these non-phagocytic cells. Using the novel delivery platform of spherical nucleic acids (SNAs), we have devised a way to efficiently activate endosomal TLR9 by CpG, while simultaneously delivering tumor antigens to intracellular compartments in T cells. Activation of TLR9 in CD8+ T cells endows them with special properties. First, T cells themselves express appreciable levels of co-stimulatory molecules after activation of CpG derived from SNAs, thereby functioning as antigen presenting cells to cross-prime antigen-specific CD8+ T cells. Second, SNA activated T cells act as chaperones (T chaperones) of SNA material. Through exosomal transfer, T chaperones shuttle CpG and antigen, mouse or human, to bystander DCs for further cross-presentation of antigen. Third, antigen specific T chaperones are highly cytotoxic and resist tumor induced immune suppression. These combined effects of adoptive therapy using tumor antigen specific T chaperones achieve tumor regression in aggressive melanoma models without irradiation or cytokine supplementation, which complicate T cell-based therapies. T chaperones represent a novel cell-based therapy that co-delivers adjuvant and antigen to efficiently boost antitumor CD8+ T cell activity, eliminating the need for viral manipulation and shortens the long, and costly, production time associated with other T cell therapies.
A lipid mediated paracrine signaling network stimulates tumor associated macrophage development in cancer and metastasis
Authors: Rai Vivek , Ray Rashmi 
Published: January 2023

Abstract
Tumor microenvironment consist of dynamic interactions between tumor cells and the surrounding non-transformed cells. Inflammatory cells constitute a major population of the non-transformed cells. Tumor associated macrophages (TAMs), the predominant population of inflammatory cells have major roles in cancer progression and metastasis but the exact stimulus and triggers for the tumor cells-macrophage interaction remains unclear. Autotaxin or lysophospholipaseD (LysoPLD) catalyses the synthesis of lyophosphatidic acid - the smallest phospholipid from lysophosphatidylcholine by its enzymatic action. Autotaxin is implicated in breast cancer, ovarian cancer and many other cancers. Lysophosphatidic acid (LPA) is involved in numerous biological processes encompassing cell growth, cell proliferation, cell migration, cancer and metastasis. LPA effects are mediated on different cell types via its cognate G-protein coupled receptors (GPCRs) or non-receptor pathways. Our recent study has shown that LPA converts monocytes into macrophages both in mice and humans and has an important role to play with immune cells. Here, we show that cancer cells in tumor growth are associated with tumor associated macrophages via a signature paracrine link. Our studies identify previously unknown signaling link between tumor cells and macrophages. Furthermore, we identify that suppression of this paracrine network can suppress tumor growth. This study suggests that inhibition of this paracrine network may act as a new therapeutic approach to control cancer and metastasis
Immune microenvironment landscape and the role of neutrophils in glioblastoma
Authors: Friedmann-Morvinski Dinorah , Magod Prerna , Agemy Lilach , Rousso-Noori Liat 
Published: January 2023

Abstract
Glioblastoma (GBM) is an aggressive, highly invasive primary brain tumor with near total fatality. Using a Cre-inducible lentiviral GBM mouse model we previously showed that gliomas can originate from terminally differentiated neurons and astrocytes, which can dedifferentiate to a stem cell-like state upon transformation. We believe that the tumor microenvironment (TME) may contribute to the process of tumor reprogramming. Although the majority of infiltrating cells in the tumor are peripheral macrophages and microglia, recent appreciation of the effects of neutrophils in cancer directed our efforts in understanding their role in GBM.
Flow cytometry analysis revealed differences in the brain TME of both the innate and adaptive immune populations compared to healthy brain tissue, changes were also seen in spleen and bone marrow even at early stages of GBM development. The neutrophils population varies not only at different time-points but also between tumor subtypes. We believe neutrophils switch from anti-tumor to pro-tumor phenotype. Depletion of neutrophils right before tumor initiation accelerated the onset of the disease while co-transplantation of equal ratio of glioma cells and naïve neutrophils delayed the initiation of tumors lesions. In-vitro assays showed higher migration and formation of neutrophils extracellular traps (NETs) on exposure to glioma cells condition media or glioma derived exosomes. Our findings suggest neutrophils play a role in tumor initiation and progression, and further understanding the transition of neutrophils from anti-tumor to pro-tumor phenotype will shed light into new strategies to treat GBM.