bluuebunny/crossref_metadata_2025_split huggingface dataset:
Dickkopf1: An Immunomodulator in Tissue Injury, Inflammation, and Repair
Authors: Park Min Hee , Sung Eun-Ah , Sell Margot , Chae Wook-Jin 
Published: January 2023

Abstract
Upon injury, inflammation and repair processes are orchestrated to maintain tissue homeostasis. The Wnt ligands play essential roles in cell differentiation and proliferation for tissue repair and regeneration. It is increasingly clear that Wnt ligands play crucial immune-modulatory roles in inflammatory diseases. It is predicted that comprehensive research regarding the cross-talk between nonimmune and immune cells in tissue injury and repair will flourish. The Wnt system and immune system interaction will be critical to understanding tissue injury, inflammation, and repair. In this study, we will first introduce the Wnt system and review the role of the Wnt system in tissue regeneration and repair. We will review the previous literature regarding how the Wnt ligands regulate the immune system. Next, we will discuss the current and future perspectives of Wnt ligands to target cancer and other immunological diseases. Finally, we will discuss the quintessential Wnt antagonist Dickkopf1 as an immunomodulatory ligand.
B Cell Activation Results in IKK-Dependent, but Not c-Rel- or RelA-Dependent, Decreases in Transcription of the B Cell Tolerance-Inducing Gene Ets1
Authors: Kearly Alyssa , Ottens Kristina , Battaglia Michael C , Satterthwaite Anne B , Garrett-Sinha Lee Ann 
Published: January 2023

Abstract
Ets1 is a key transcription factor in B cells that is required to prevent premature differentiation into Ab-secreting cells. Previously, we showed that BCR and TLR signaling downregulate Ets1 levels and that the kinases PI3K, Btk, IKK, and JNK are required for this process. PI3K is important in activating Btk by generating the membrane lipid phosphatidylinositol (3,4,5)-trisphosphate, to which Btk binds via its PH domain. Btk in turn is important in activating the IKK kinase pathway, which it does by activating phospholipase Cγ2→protein kinase Cβ signaling. In this study, we have further investigated the pathways regulating Ets1 in mouse B cells. Although IKK is well known for its role in activating the canonical NF-κB pathway, IKK-mediated downregulation of Ets1 does not require either RelA or c-Rel. We also examined the potential roles of two other IKK targets that are not part of the NF-κB signaling pathway, Foxo3a and mTORC2, in regulating Ets1. We find that loss of Foxo3a or inhibition of mTORC2 does not block BCR-induced Ets1 downregulation. Therefore, these two pathways are not key IKK targets, implicating other as yet undefined IKK targets to play a role in this process.
IL-6/STAT3 Signaling Axis Enhances and Prolongs Pdcd1 Expression in Murine CD8 T Cells
Authors: Powell Michael D , Lu Peiyuan , Neeld Dennis K , Kania Anna K , George-Alexander Lou-Ella M M , Bally Alexander P R , Scharer Christopher D , Boss Jeremy M 
Published: January 2023

Abstract
CD8 cytotoxic T cells are a potent line of defense against invading pathogens. To aid in curtailing aberrant immune responses, the activation status of CD8 T cells is highly regulated. One mechanism in which CD8 T cell responses are dampened is via signaling through the immune-inhibitory receptor Programmed Cell Death Protein-1, encoded by Pdcd1. Pdcd1 expression is regulated through engagement of the TCR, as well as by signaling from extracellular cytokines. Understanding such pathways has influenced the development of numerous clinical treatments. In this study, we showed that signals from the cytokine IL-6 enhanced Pdcd1 expression when paired with TCR stimulation in murine CD8 T cells. Mechanistically, signals from IL-6 were propagated through activation of the transcription factor STAT3, resulting in IL-6–dependent binding of STAT3 to Pdcd1 cis-regulatory elements. Intriguingly, IL-6 stimulation overcame B Lymphocyte Maturation Protein 1–mediated epigenetic repression of Pdcd1, which resulted in a transcriptionally permissive landscape marked by heightened histone acetylation. Furthermore, in vivo–activated CD8 T cells derived from lymphocytic choriomeningitis virus infection required STAT3 for optimal Programmed Cell Death Protein-1 surface expression. Importantly, STAT3 was the only member of the STAT family present at Pdcd1 regulatory elements in lymphocytic choriomeningitis virus Ag-specific CD8 T cells. Collectively, these data define mechanisms by which the IL-6/STAT3 signaling axis can enhance and prolong Pdcd1 expression in murine CD8 T cells.
Variability in Severe Acute Respiratory Syndrome Coronavirus 2 IgG Antibody Affinity to Omicron and Delta Variants in Convalescent and Community mRNA-Vaccinated Individuals
Authors: Tu Michael K , Chiang Samantha H , Wong David T W , Strom Charles M 
Published: January 2023

Abstract
The emergence of the omicron and delta variants of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has begun a number of discussions regarding breakthrough infection, waning immunity, need and timing for vaccine boosters, and whether existing mRNA vaccines for the original SARS-CoV-2 strain are adequate. Our work leverages a biosensor-based technique to evaluate the binding efficacy of SARS-CoV-2 S1-specific salivary Abs to the omicron and delta variants using a cohort of mRNA-vaccinated (n = 109) and convalescent (n = 19) subjects. We discovered a wide range of binding efficacies to the variant strains, with a mean reduction of 60.5, 26.7, and 14.7% in measurable signal to the omicron strain and 13.4, 2.4, and −6.4% mean reduction to the delta variant for convalescent, Pfizer-, and Moderna-vaccinated groups, respectively. This assay may be an important tool in determining susceptibility to infection or need for booster immunization as the pandemic evolves.
Dam–Infant Rhesus Macaque Pairs to Dissect Age-Dependent Responses to SARS-CoV-2 Infection
Authors: Langel Stephanie N , Garrido Carolina , Phan Caroline , Travieso Tatianna , Kirshner Helene , DeMarco Todd , Ma Zhong-Min , Reader J Rachel , Olstad Katherine J , Sammak Rebecca L , Shaan Lakshmanappa Yashavanth , Roh Jamin W , Watanabe Jennifer , Usachenko Jodie , Immareddy Ramya , Pollard Rachel , Iyer Smita S , Permar Sallie , Miller Lisa A , Van Rompay Koen K A , Blasi Maria 
Published: January 2023

Abstract
The global spread of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and its associated coronavirus disease (COVID-19) has led to a pandemic of unprecedented scale. An intriguing feature of the infection is the minimal disease in most children, a demographic at higher risk for other respiratory viral diseases. To investigate age-dependent effects of SARS-CoV-2 pathogenesis, we inoculated two rhesus macaque monkey dam–infant pairs with SARS-CoV-2 and conducted virological and transcriptomic analyses of the respiratory tract and evaluated systemic cytokine and Ab responses. Viral RNA levels in all sampled mucosal secretions were comparable across dam–infant pairs in the respiratory tract. Despite comparable viral loads, adult macaques showed higher IL-6 in serum at day 1 postinfection whereas CXCL10 was induced in all animals. Both groups mounted neutralizing Ab responses, with infants showing a more rapid induction at day 7. Transcriptome analysis of tracheal airway cells isolated at day 14 postinfection revealed significant upregulation of multiple IFN-stimulated genes in infants compared with adults. In contrast, a profibrotic transcriptomic signature with genes associated with cilia structure and function, extracellular matrix composition and metabolism, coagulation, angiogenesis, and hypoxia was induced in adults compared with infants. Our study in rhesus macaque monkey dam–infant pairs suggests age-dependent differential airway responses to SARS-CoV-2 infection and describes a model that can be used to investigate SARS-CoV-2 pathogenesis between infants and adults.
Characterization of Circulating Fibrocytes in People Living with HIV on Stable Antiretroviral Therapy
Authors: Dean Logan S , Chow Dominic C , Ndhlovu Lishomwa C , Boisvert William A , Chang Sandra P , Shikuma Cecilia M , Park Juwon 
Published: January 2023

Abstract
Highly effective combination antiretroviral therapy has reduced HIV infection to a manageable chronic disease, shifting the clinical landscape toward management of noninfectious comorbidities in people living with HIV (PLWH). These comorbidities are diverse, generally associated with accelerated aging, and present within multiple organ systems. Mechanistically, immune dysregulation and chronic inflammation, both of which persist in PLWH with well-controlled virally suppressive HIV infection, are suggested to create and exacerbate noninfectious comorbidity development. Persistent inflammation often leads to fibrosis, which is the common end point pathologic feature associated with most comorbidities. Fibrocytes are bone marrow–derived fibroblast-like cells, which emerged as key effector cells in tissue repair and pathologic fibrotic diseases. Despite their relevance to fibrosis, the circulating fibrocyte concentration in PLWH remains poorly characterized, and an understanding of their functional role in chronic HIV is limited. In this study, utilizing PBMCs from a cross-sectional adult HIV cohort study with matched uninfected controls (HIV−), we aimed to identify and compare circulating fibrocytes in blood. Both the percentage and number of fibrocytes and α-smooth muscle actin+ fibrocytes in circulation did not differ between the HIV+ and HIV− groups. However, circulating fibrocyte levels were significantly associated with increasing age in both the HIV+ and HIV− groups (the percentage and number; r = 0.575, p ≤ 0.0001 and r = 0.558, p ≤ 0.0001, respectively). Our study demonstrates that circulating fibrocyte levels and their fibroblast-like phenotype defined as collagen I and α-smooth muscle actin+ expression are comparable between, and strongly associated with, age irrespective of HIV status.
Acly Deficiency Enhances Myelopoiesis through Acetyl Coenzyme A and Metabolic–Epigenetic Cross-Talk
Authors: Greenwood Dalton L , Ramsey Haley E , Nguyen Phuong T T , Patterson Andrew R , Voss Kelsey , Bader Jackie E , Sugiura Ayaka , Bacigalupa Zachary A , Schaefer Samuel , Ye Xiang , Dahunsi Debolanle O , Madden Matthew Z , Wellen Kathryn E , Savona Michael R , Ferrell P Brent , Rathmell Jeffrey C 
Published: January 2023

Abstract
Hematopoiesis integrates cytokine signaling, metabolism, and epigenetic modifications to regulate blood cell generation. These processes are linked, as metabolites provide essential substrates for epigenetic marks. In this study, we demonstrate that ATP citrate lyase (Acly), which metabolizes citrate to generate cytosolic acetyl-CoA and is of clinical interest, can regulate chromatin accessibility to limit myeloid differentiation. Acly was tested for a role in murine hematopoiesis by small-molecule inhibition or genetic deletion in lineage-depleted, c-Kit–enriched hematopoietic stem and progenitor cells from Mus musculus. Treatments increased the abundance of cell populations that expressed the myeloid integrin CD11b and other markers of myeloid differentiation. When single-cell RNA sequencing was performed, we found that Acly inhibitor–treated hematopoietic stem and progenitor cells exhibited greater gene expression signatures for macrophages and enrichment of these populations. Similarly, the single-cell assay for transposase-accessible chromatin sequencing showed increased chromatin accessibility at genes associated with myeloid differentiation, including CD11b, CD11c, and IRF8. Mechanistically, Acly deficiency altered chromatin accessibility and expression of multiple C/EBP family transcription factors known to regulate myeloid differentiation and cell metabolism, with increased Cebpe and decreased Cebpa and Cebpb. This effect of Acly deficiency was accompanied by altered mitochondrial metabolism with decreased mitochondrial polarization but increased mitochondrial content and production of reactive oxygen species. The bias to myeloid differentiation appeared due to insufficient generation of acetyl-CoA, as exogenous acetate to support alternate compensatory pathways to produce acetyl-CoA reversed this phenotype. Acly inhibition thus can promote myelopoiesis through deprivation of acetyl-CoA and altered histone acetylome to regulate C/EBP transcription factor family activity for myeloid differentiation.
Cytotoxic T lymphocytes in asymptomatic long-term nonprogressing HIV-1 infection. Breadth and specificity of the response and relation to in vivo viral quasispecies in a person with prolonged infection and low viral load.
Authors: Harrer T , Harrer E , Kalams S A , Barbosa P , Trocha A , Johnson R P , Elbeik T , Feinberg M B , Buchbinder S P , Walker B D 
Published: January 2023

Abstract
Although vigorous activated and memory CTL have been associated with HIV-1 infection, data are lacking regarding the breadth of epitopes recognized in a given individual and the relationship to the viral quasispecies present in vivo. In this study we performed a detailed analysis of the HIV-1-specific CTL response in a seropositive person with documented HIV-1 infection of 15 yr duration, stable CD4 counts above 500 cells/ml, and viral load persistently below 500 molecules of RNA/ml of plasma. Epitope mapping studies revealed the presence of HLA class I-restricted CTL responses to six different epitopes in p17, p24, RT, Env, and Nef, which conferred broadly cross-reactive recognition of reported HIV-1 variants. Sequence analysis of autologous viruses revealed the absence of immune escape variants within five of the six epitopes. Despite consistently low viral RNA levels in plasma and viral DNA levels in PBMC, in vivo-activated circulating CTL were detected against three of the epitopes. Five of the six epitopes, including the three dominant epitopes, have been detected in persons with progressive disease, suggesting that nonprogressors may not target unique epitopes. This study demonstrates that HIV-1-specific CTL can be highly activated and broadly directed in the setting of an extremely low viral load, and that neither high viral load nor antigenic diversity is required for the generation of a multispecific CTL response. Although the detection of strong CTL responses, low viral load, and lack of immune escape are consistent with the hypothesis that CTL may contribute to lack of disease progression in this individual, the contribution of these responses to maintenance of the asymptomatic state remains to be determined.
Impaired learning resulting from respiratory syncytial virus (VIR2P.1028)
Authors: Espinoza Janyra , Bohmwald Karen , Céspedes Pablo , Gomez Roberto , Riquelme Sebastían , Cortes Claudia , Valenzuela Javier , Sandoval Rodrigo , Pancetti Floria , Bueno Susan , Riedel Claudia , Kalergis Alexis 
Published: January 2023

Abstract
Respiratory syncytial virus (RSV) is the leading cause of respiratory distress in infants worldwide. Neurologic alterations, such as seizures and ataxia, have been associated with RSV infection. We demonstrate the presence of RSV proteins and RNA in zones of the brain—such as the hippocampus, ventromedial hypothalamic nucleus, and brainstem—of infected mice. One month after disease resolution, rodents showed behavioral and cognitive impairment in marble burying (MB) and Morris water maze (MWM) tests. Our data indicate that the learning impairment caused by RSV is a result of a deficient induction of long-term potentiation in the hippocampus of infected animals. In addition, immunization with recombinant bacillus Calmette-Guérin (BCG) expressing RSV nucleoprotein prevented behavioral disorders, corroborating the specific effect of RSV infection over the central nervous system. Our findings provide evidence that RSV can spread from the airways to the central nervous system and cause functional alterations to the brain, both of which can be prevented by proper immunization against RSV.
The RAG1 Ubiquitin Ligase Domain Stimulates Recombination of TCRβ and TCRα Genes and Influences Development of αβ T Cell Lineages
Authors: Burn Thomas N , Miot Charline , Gordon Scott M , Culberson Erica J , Diamond Tamir , Kreiger Portia A , Hayer Katharina E , Bhattacharyya Anamika , Jones Jessica M , Bassing Craig H , Behrens Edward M 
Published: January 2023

Abstract
RAG1/RAG2 (RAG) endonuclease-mediated assembly of diverse lymphocyte Ag receptor genes by V(D)J recombination is critical for the development and immune function of T and B cells. The RAG1 protein contains a ubiquitin ligase domain that stabilizes RAG1 and stimulates RAG endonuclease activity in vitro. We report in this study that mice with a mutation that inactivates the Rag1 ubiquitin ligase in vitro exhibit decreased rearrangements and altered repertoires of TCRβ and TCRα genes in thymocytes and impaired thymocyte developmental transitions that require the assembly and selection of functional TCRβ and/or TCRα genes. These Rag1 mutant mice present diminished positive selection and superantigen-mediated negative selection of conventional αβ T cells, decreased genesis of invariant NK T lineage αβ T cells, and mature CD4+ αβ T cells with elevated autoimmune potential. Our findings reveal that the Rag1 ubiquitin ligase domain functions in vivo to stimulate TCRβ and TCRα gene recombination and influence differentiation of αβ T lineage cells, thereby establishing replete diversity of αβ TCRs and populations of αβ T cells while restraining generation of potentially autoreactive conventional αβ T cells.
Co-administration of recombinant chicken IL-7 or chicken NK-lysin peptide 2 increases efficacy of Eimeria tenella elongation factor-1α in Eimeria maxima infected chicken
Authors: Lee Youngsub , Park In-kyung , Wickramasuriya Samiru S , Lillehoj Hyun S 
Published: January 2023

Abstract
This study was conducted to improve the efficacy of recombinant Eimeria tenella elongation factor-1α (EF-1α) antigen by co-administrating recombinant chicken IL-7 or chicken NK-lysin peptide 2 in Eimeria maxima-challenged chickens. On day 4, birds were administered with following five groups: (CON) control birds without Eimeria infection, (NC) sterile PBS solution plus adjuvant (ISA 78 VG), (COM 1) 100 μg of recombinant EF-1α plus ISA 78 VG, (COM 2) COM 1 component plus 1 μg of recombinant chIL-7, and (COM 3) COM 2 component plus 5 μg of cNK2 peptide. One week after, the boosting immunization were administrated with same concentration of components as the primary immunization. All birds except CON were orally inoculated with E. maxima (1.0 × 104 oocysts/bird) on day 19. Animal experiment demonstrated that the birds immunized with recombinant EF-1α showed greater serum anti EF-1α level, and co-administration of recombinant chIL-7 increased the level of IL-7 in serum. Vaccination of COM 2 mitigated intestinal lesion formation at 6 days post-infection (dpi) and increased body weight at 6 dpi and 9 dpi. Vaccination of COM 3 reduced fecal oocyst shedding compared with NC. E. maxima infection up-regulated expression level of jejunal proinflammatory cytokines (IL-β, IL-17F) and type I cytokines (IFN-γ and IL-10), and those expression levels were decreased by administration of COM 1, COM 2 or COM 3. Down-regulated expression of tight junction (TJ) protein (Jam2 and Occludin) by E. maxima challenge were increased by COM 2or COM 3, respectively. Overall animal experiment results demonstrated a potential effect that co-administration of recombinant IL-7 or cNK-2 peptide can increase the efficacy of recombinant EF-1α in E. maxima-infected chicken.
Funding was partly supported by ARS CRIS 8042-32000-107-00D, NIFA SBIR 2015-33610-23499, and NIFA SBIR 2016-33610-25686.
Direct MHC Class I Antigen Presentation Regulation by Ribosomal Biogenesis Inhibitor CX-5461
Authors: Kazemi Soheila , Dolan Brian P 
Published: January 2023

Abstract
Direct MHC class I antigen presentation relies on on-going protein synthesis by the antigen presenting cell. This is especially true for the presentation of peptides derived from Defective Ribosomal Products (DRiPs) which are inherently defective proteins rapidly degraded following their synthesis. Recently an inhibitor of RNA polymerase I, known as CX-5461, has been described which can inhibit ribosome biogenesis. Here we queried if interruption of ribosome biogenesis could impact direct antigen presentation using a reporter protein whose stability can be controlled post-translationally. We first determined a dose and time of treatment with CX-5461 which was not toxic to cells, but greatly decreased the levels of RNA within EL4 cells. Once an acceptable dose was determined, we examined presentation of a model peptide derived from the Shield-controlled recombinant antigenic protein (SCRAP) which is a fusion protein consisting of a destabilization domain, the SIINFEKL peptide, and a fluorescent reporter protein. SCRAP levels can be controlled through the addition of the small molecule Shield-1, which stabilizes SCRAP and prevents its degradation. After treatment with CX-5461, we found the levels of SCRAP protein partially decreased within the cell, indicating a loss in protein synthesis. Concurrently, presentation of the reporter peptide was diminished from both the DRiP and non-DRiP form of SCRAP. These data indicate that interruption of ribosome biogenesis has a minor impact on direct antigen presentation and protein synthesis.
Profiling MHC-I and MHC-II canonical and out-of-frame epitopes from SARS-CoV-2 and seasonal human coronavirus infected human cells
Authors: Nanaware Padma Pandurang , Becerra-Artiles Aniuska , Cruz John , Calvo-Calle J Mauricio , Khaja Muneeruddin , Shaffer Scott A , Stern Lawrence J 
Published: January 2023

Abstract
Understanding the targets of adaptive immunity to SARS-CoV-2 is essential for vaccine development and interpretation of coronavirus disease 2019 (COVID-19) pathogenesis. SARS-CoV-2 and other human coronaviruses share substantial sequence homology raising the possibility that the previous exposure to seasonal “common cold” human coronaviruses could impact the T cell response upon SARS-CoV-2 infection. Detailed investigation of the antigenic peptides presented in SARS-CoV-2 and other common coronavirus infections would be beneficial to understand the impact of preexisting T cell mediated immunity on SARS-CoV-2 infection. The repertoire of naturally processed and presented viral peptides by MHC II upon SARS-CoV-2 and seasonal human coronaviruses infections remains largely uncharacterized. Here, we report the MHC I and II immunopeptidome of cells infected with SARS-CoV-2 or hCoV-OC43, one of the seasonal coronaviruses. We identified 11 MHC I peptides and 13 MHC II peptides of SARS-CoV-2 infected cells including both canonical and out-of-frame spike epitopes, 27 MHC I and 91 MHC II peptides from membrane, nucleocapsid, spike and hemagglutinin-esterase from OC43 infected cells using mass spectrometry. We validated some peptides using HLA peptide binding assays, and these peptides were shown to recall T cell responses in donors with presumed history of common cold viral infection. Some of these peptides share substantial homology with common cold coronaviruses, indicating possibility of conserved T cell epitopes eliciting the protective immunity in COVID-19. The identification of naturally presented peptides and their striking homology with other coronavirus could aid in the peptide selection for the vaccine development.