bluuebunny/crossref_metadata_2025_split huggingface dataset:
Corticotropin releasing factor receptor 2 exerts global suppression of mast cell degranulation and associated pathophysiology.
Authors: Mackey Emily , D’Costa Susan , Ayyadurai Saravannan , Gibson Amelia , Poopal Ashwini , Moeser Adam J 
Published: January 2023

Abstract
Psychological stress triggers mast cell (MC) activation and is a major risk factor in the onset and exacerbation of MC-associated disorders including allergy/anaphylaxis, irritable bowel syndrome, and autoimmune diseases. The mechanisms by which stress modulates MC function and disease susceptibility is poorly understood. Our previous studies showed that corticotropin releasing factor receptor 1 (CRF1) signaling potentiated stress-induced MC degranulation. Here we utilized CRF2 deficient (CRF2 −/−) mice and MCs to define the in vivo and in vitro biological importance of CRF receptor subtype 2, CRF2. Compared with WT mice, CRF2 −/− mice exhibited greater serum histamine levels following restraint stress (RS) (by 143%) and IgE-mediated passive systemic anaphylaxis (PSA) (by 415%). The heightened response was greater in CRF2 −/− females compared with males. CRF2 −/− mice exhibited greater RS-induced and PSA-induced elevations in intestinal permeability compared to WT mice. Bone marrow derived MCs (BMMCs) derived from CRF2 −/− mice exhibited greater release of β-hexosaminidase and histamine and heightened Ca2+ mobilization from intracellular stores in response to diverse MC stimuli including IgE/DNP, c48/80, and A23187. MC-deficient mice engrafted with CRF2 −/− BMMCs exhibited greater RS-induced intestinal permeability and PSA-induced hypothermia compared with WT BMMC-engrafted mice. Together, these results demonstrate that MC-CRF2 receptor signaling exerts a global suppression of MC degranulation and pathophysiology. Elucidation of the mechanisms by which CRF2 dampens MC degranulation could reveal novel therapeutic targets for hyperactive MC disorders.
The interaction of the RNA binding protein with microRNA regulates cytokine production in Th17 cells
Authors: Chen Jing , Yu Shiguang 
Published: January 2023

Abstract
GM-CSF produced by Th17 cells play an essential and non-redundant role in chronic inflammatory and autoimmune diseases, such as multiple sclerosis and rheumatoid arthritis. Although the transcriptional regulation of Th17 cells is well understood, the posttranscriptional regulation of GM-CSF gene expression remains unknown. The RNA-binding protein HuR positively regulates the stability of many target mRNAs via binding the AU-rich elements present in the 3′ untranslated region of many inflammatory cytokines including IL-4, IL-13, IL-17 and TNF-α. However, the regulation of GM-CSF expression by HuR in Th17 cells has not been fully characterized. CD4+ Th17 cells from HuR knockout mice had decreased GM-CSF steady-state mRNA compared with wild-type Th17 cells. Moreover, we demonstrated that HuR directly binds to GM-CSF mRNA 3′ untranslated region (3′UTR) by using RNA immunoprecipitation and biotin pulldown assays. In addition, knockout of HuR increases certain levels of microRNAs in Th17 cells, among them, miR-466i has multiple potential binding sites in the 3′ UTRs of GM-CSF and IL-17 mRNAs. In vitro luciferase assay showed that overexpression of miR-466i reduces activity of luciferase reporter vector containing GM-CSF or IL-17 mRNA 3 UTR, suggesting that miR-466i has the potential to mediate GM-CSF and IL-17 mRNA decay. Taken together, these findings indicate that interaction of HuR with miR-466i orchestrates GM-CSF expression by Th17 cells.
Alterations in p53 expression in PMBCs of PTSD patients leads to dysregulation in miRNA biogenesis which promotes an inflammatory Th17 immune cell phenotype.
Authors: Busbee Philip Brandon , Nagarkatti Mitzi , Nagarkatti Prakash 
Published: January 2023

Abstract
Post-traumatic stress disorder (PTSD) is a neurological disorder brought on by a traumatic or life-threatening event, causing symptoms such as reoccurring memories of trauma, mental numbing, and avoidance of cues that make them recall the trauma in question. In addition to insufficient treatment options, PTSD patients often express other comorbid health issues, particularly inflammatory disorders. Our lab has previously published a report showing peripheral blood mononuclear cells (PBMCs) from PTSD patients exhibit an increased inflammatory CD4+ T helper (Th) cell phenotype that correlated with PTSD severity. However, key regulators that promote this CD4+ inflammatory phenotype in PTSD patients have not yet been identified. In the current study we performed microRNA (miRNA) array analysis on PMBCs collected from healthy control and PTSD patients. Profiles from miRNA indicated that PTSD patients had a widespread downregulation of miRNA when compared to controls. Further analysis revealed that many of the miRNA were associated with transcription factor p53. Our examination of PBMCs from PTSD samples showed that p53 is in fact downregulated in these patients when compared to healthy controls. Downregulated miRNA associated with p53 were shown to negatively regulate the promotion and function of Th17 T cells, particularly miRNA let-7a, which targets IL-17 and Th-17 promoting IL-6. We therefore transfected PMBCs with let-7a and were able to show that let-7a modulation alone was able to greatly influence Th17 development. Collectively, these data reveal important mechanisms that promote an inflammatory phenotype in PTSD patients and bring attention to the novel involvement of p53 dysregulation in this patient population.
Bcl11b, a novel GATA3-interacting protein, regulates T-helper-2-cell differentiation and function
Authors: Fang Difeng , Gurram Rama Krishna , Cui Kairong , Zhong Chao , Hu Gangqing , Oler Andrew , Sharma Suveena , Liu Pentao , Sun Bing , Zhao Keji , Zhu Jinfang (Jeff) 
Published: January 2023

Abstract
GATA-binding protein 3 (GATA3) acts as the master transcription factor for type 2 T helper (Th2) cell differentiation and function. Fine-tuning GATA3 transcription activity is critical for effectively expelling extracellular parasites and preventing allergic disorders. However, it is still elusive how GATA3 function is regulated in Th2 cells. Here, we report that the transcription factor B-cell Lymphoma 11b (Bcl11b) is a novel component of the GATA3 transcriptional complex executing GATA3-mediated gene expression. Bcl11b binds to GATA3 through protein-protein interaction; ChIP-Seq analysis showed co-localization of Bcl11b and GATA3 at many important cis-regulatory elements in Th2 cells. The expression of type 2 cytokines, including IL-4, IL-5 and IL-13, is up-regulated in Bcl11b-deficient Th2 cells both in vitro and in vivo; such up-regulation is completely GATA3 dependent indicating that Bcl11b inhibits GATA3-mediated cytokines production. Genome-wide analysis of Bcl11b- and GATA3-mediated gene regulation (RNA-Seq) and co-binding pattern (ChIP-Seq) suggests that GATA3/Bcl11b complex are involved in limiting Th2 gene expression as well as inhibiting non-Th2 gene expression. Thus, Bcl11b, a previously unknown GATA3 binding protein, fine-tunes GATA3-mediated gene expression in Th2 cells.
MicroRNA-132, miR-146a, miR-155 as potential biomarkers of Methotrexate response in patients with Rheumatoid arthritis.
Authors: Singh Ankita , Patro Pradeepta Sekhar , Aggarwal Amita 
Published: January 2023

Abstract

Introduction
MiRNAs regulate signaling pathways of inflammation and thus can serve as biomarkers. Patients with Rheumatoid arthritis (RA) have high expression of miR-155, miR-146a and miR-132 in their peripheral blood cells. As one third of patients do not respond to methotrexate(MTX), the first line therapy in RA, we studied if levels of these miRNAs can predict response to MTX.

Methods
Patients with RA (ACR 2010 criteria), DMARD naïve with active disease (DAS 28 &gt;3.2) were enrolled. Blood sample was collected. All patients were treated with MTX by gradually increasing dose to a maximum of 25mg/week or the maximal tolerated dose. No corticosteroids were given. At 4 months disease activity was measured by DAS 28 and EULAR response was assessed. miR-132, miR-146a and miR-155 were measured using real time qPCR in the whole blood RNA. Let7a was used as a housekeeping gene.

Results
80 patients (83.8% females; mean age 41.05+12.19 years); mean duration of disease 2.23+1.95years; mean DAS28 4.56+ 0.71) were enrolled. Among 80 patients 59 were classified as good responders while 14 were moderate- responders and 7 were non-responders at 4 months. The baseline miRNA levels did not correlate with the baseline DAS28 score or any other clinical parameters of RA patients. All the three miRNA’s were lower in responders as compared to non-responders but it was significant only for miR-155 (p=0.016) with mean value −7.531±0.833 for responders (n=73) and −6.476±1.069 for non-responders (n=7). ROC curve analysis showed that miR-155 with cutoff value of −7.3(dtCt) is predictor of non-response to MTX treatment with a sensitivity of 67.1% and a specificity of 71.4% (AUC:0.777, p=0.016).

Conclusion
MicroRNA-155 may serve as a good biomarker of response to MTX.
Oral idebenone attenuates murine lupus
Authors: Blanco Luz P , Lightfoot Yaima , Seto Nickie , Carmona-Rivera Carmelo , Liu Yudong , Hoffmann Victoria , Kaplan Mariana J 
Published: January 2023

Abstract
A role for mitochondrial dysfunction has been proposed in the immune dysregulation and organ damage characteristic of systemic lupus erythematous (SLE) disease pathogenesis. We have now examined the role of drugs that may improve mitochondrial function in SLE symptomatology in murine models of lupus. Idebenone is a synthetic quinone analog compound of coenzyme Q10 that has been safely used in humans to treat diverse diseases where mitochondria function is deficient. Idebenone is considered a strong antioxidant able to protect cells against enhanced reactive oxygen species’ toxicity. Idebenone also improves electron transfer chain function in overloaded and/or damaged mitochondria. Idebenone was administered 250 mg/day/kg orally to two different mouse models of SLE starting in preclinical stages (10 weeks of age) for 6 weeks (MRL/lpr mice) or 4 months (NZM2328 mice). Disease attenuation was observed in both models at euthanasia. Specifically, proteinuria, intestinal inflammation and splenomegaly were decreased in both models upon exposure to idebenone, while levels of autoantibodies were not affected. In the MRL/lpr mouse model, skin lesions characteristic of this model were significantly decreased. In addition, levels of proinflammatory cytokines, type I IFNs and inflammasome-related genes were significantly decreased. No obvious toxicity was observed following exposure to idebenone. In conclusion, idebenone modulates lupus disease activity and organ damage severity and future studies should further address mechanism of action and potential role in human disease.
Farnesylthiosalicylic acid reduces disease severity in the collagen type-II induced arthritis mouse model by inhibiting Ras Signaling in pathogenic T cells
Authors: Zayoud Morad , Vax Einva , Sfadia Galit Elad , Kloog Yoel , Goldstein Itamar 
Published: January 2023

Abstract

Background
Ras proteins are vital for normal T cell activation, and downstream effectors of Ras include the MEK/ERK, PI3-kinase/AKT, and NF-kB pathways. T cells from Rheumatoid Arthritis patients exhibit abnormal activation of the Ras/MEK/ERK pathway. The small molecule Farnesylthiosalicylic acid (FTS) blocks the interaction between Ras proteins and their prenyl binding chaperones, attenuating plasma membrane localization and signaling.

Objectives
To investigate the immunomodulatory effect of FTS alone or combined with methotrexate (MTX) in the DBA/1 mouse collagen type-II induced arthritis (CIA) model.

Methods
Arthritis was induced in 8–10 week old male DBA/1 mice by immunization with collagen type-II (CII) and complete Freund’s adjuvant (CFA). Animals were treated semi-prophylactically with once daily oral FTS (100 mg/kg); weekly i.p injection of MTX (0.5 mg/kg), FTS combined with MTX, or daily oral vehicle solution (control). Arthritis severity was scored daily from disease onset until study termination and multiple immunological biomarkers of inflammation were analyzed.

Results
Our data from the mouse CIA model show that the therapeutic efficacy of FTS was similar to MTX, and both drugs significantly reduced arthritis severity compared to CMC controls. Importantly, FTS significantly inhibited the production of pathogenic anti-CII autoantibodies and upregulation of serum IL-6 and IL-17A compared to control arthritic mice. The in depth, multiplex, analysis of the effect of FTS on the T cell cytokine response to CII, revealed strong suppression of IL-22, IL-17, IL-9, GM-CSF and TNF production. Importantly, FTS therapy positively correlated with reduced p-ERK1/2 and p-AKT levels in splenic lymphocytes.
A comparison of the immunogenicity of a live attenuated herpes zoster vaccine (ZV) and the recombinant gE/AS01B candidate vaccine in older adults
Authors: Weinberg Adriana , Johnson Michael J , Kroehl Miranda , Lang Nancy , Reinhold Dominik , Levin Myron J 
Published: January 2023

Abstract
Herpes zoster (HZ) has high morbidity in older adults. ZV, which is recommended for individuals ≥60 y, is 51% effective against HZ in the 1st 3 y after vaccination; efficacy decreases with the age of the vaccinee; and wanes to ~40% at 5 y. gE/ASO1B is a recombinant adjuvanted vaccine with 97% efficacy against HZ that does not vary with age of the vaccinee and wanes to 87% at 4y. We compared the cell-mediated immunity (CMI) of ZV and gE/ASO1B at 30 d after the last dose of vaccine and at 1 y.
Subjects were 50–70+ yoa who never received ZV (1ary) and adults ≥70 yoa who received ZV ≥5 y previously (boosted). Participants received ZV at entry or gE/ASO1B at 0 and 60 d. Blood from days 0, 30 (ZV peak response), 90 (peak gE/ASO1B) and 365 was used to measure CMI to varicella zoster virus (VZV) and to gE by IFNg and IL2 fluorospot [spot forming cells/106 PBMC (SFC)] and by flow cytometry assessing VZV- and gE-specific proliferation and effector (Teff), effector memory (Tem), and central memory (Tcm) outcomes.
The higher CMI responses that best distinguished gE/ASO1B from ZV recipients after adjusting for age, gender, prior ZV administration and baseline CMI were: 1) VZV-specific IL2 and gE-specific IL2 and IFNg SFC at peak response (p≤0.004); 2) higher VZV-specific CD8+ and gE-specific CD4+ and CD8+ responses measured by proliferation at peak (p&lt;0.05); 3) higher CD4+ Tcm% and Tem% and lower Teff% at peak response (p≤0.005); 4) higher VZV-specific and gE-specific IL2 and IFNg SFC at 1 y in all gE/ASO1B groups, but only in the boosted ZV group. CMI did not differ among gE/ASO1B recipients by age or prior ZV administration.
The higher memory CD4+ and CD8+ responses detected in gE/AS01B recipients might contribute to its superior efficacy and persistence of protection against HZ.
Modulation of DNA/ALVAC/gp120 vaccine immune-response by vaccination with Insulin-Like Growth Factor 1 (IGF-1)
Authors: Bissa Massimiliano , Galli Veronica , Schifanella Luca , Gorini Giacomo , De Castro Isabela Silva , Brown Dallas , Doster Melvin N , Liyanage Namal , Rosati Margherita , Felber Barbara K. , Pavlakis George N , Phogat Sanjay , Franchini Genoveffa 
Published: January 2023

Abstract
ALVAC-SIV/gp120 vaccine reduced the risk of infection in SIVmac251 model. Protection was associated with antibodies (Abs) to V2 region of gp120 protein, mucosal NKp44+ cells, and the expression of 11 genes in the Ras pathway. IGF-1 hormone is a Ras activator and its plasma level diminishes with aging. We hypothesized that IGF-1 might affect the efficacy of the ALVAC-SIV/gp120 platform by modulating the immune responses, particularly when administered in old macaques. In this study we enrolled 25 young (Group 1, av. 3 years) and 34 old macaques (Group 2, av. 9 years) having significantly different plasma levels of IGF-1, and we immunized them with a DNA-SIV/ALVAC-SIV/gp120 vaccine. During immunizations, half of the animals of each group were also administered IGF-1, as recombinant protein (Increlex, Ipsen) and as DNA vaccine. All the animals, including controls, were challenged intra-vaginally with repeated low-doses of SIVmac251. The estimated vaccine efficacy in young macaques of Group 1 was 69%. IGF-1 administration did not increase the efficacy; although, it determined a significant increase of serum Abs titers against V2 and frequency of mucosal NKp44+ cells. Furthermore, IGF-1 treated macaques showed higher frequencies of circulating classical (CCR2+CD14+CD16−) and intermediate (CCR2+CD14+CD16+) monocytes and lower frequencies of mucosal CD4+ T cells expressing α4β7 or CCR5 compared to the untreated animals. These data suggest that IGF-1 administration might improve protective immune responses and decrease possible SIV target cells in the mucosa. Therefore, IGF-1 administration during vaccination might particularly benefit older animals. Challenge exposure of older animals in Group 2 is ongoing.
Sustained delivery of a HIV subunit vaccine using silk microneedle skin patches
Authors: Boopathy Archana Vidya , Mandal Anasuya , Kulp Dan W , Kumari Sudha , Wang Wade , He Yanpu , Tokatlian Talar , Schief William R , Hammond Paula T , Irvine Darrell J 
Published: January 2023

Abstract
Many broadly neutralizing antibodies (bNAbs) against HIV exhibit high degrees of somatic hypermutation, suggesting that immunization approaches promoting germinal center (GC) stimulation and affinity maturation may be critical for an HIV vaccine. To this end, we recently demonstrated that sustained exposure of draining lymph nodes (LNs) to env immunogens through repeated injections over 2 weeks enhanced env capture on follicular dendritic cell networks in LNs, with Tfh expansion and GC induction. To obtain similar sustained vaccine kinetics for mass immunization, we developed a submicron-scale dissolving silk microneedle array (MN) for dermal vaccine delivery. We utilized silk protein to encapsulate an HIV envelope trimer (BG505 SOSIP variants) with adjuvants supported by a poly acrylic acid (PAA) base. Upon dermal application, rapid PAA dissolution is followed by silk beta sheet-dependent sustained release of encapsulated vaccine with minimal local inflammation. Antigenicity of SOSIP was maintained in silk as determined by binding to structure-sensitive bNAbs- PGT151, PGT145, PGT121 and VRCO1 without binding to non-bNAb 14e. Following immunization in mice, skin and draining LNs were subjected to lipid clearance using organic solvents and imaged by confocal microscopy. We observed SOSIP and silk co-retention at the skin site of microneedle application after one week. MN delivery resulted in higher SOSIP retention and increased SOSIP-specific T follicular helper cells in the GCs of vaccine draining LNs on day 14 post prime, and increased anti-SOSIP IgG titers on day 28 post prime compared to intradermal injections. Taken together, these results suggest the potential of silk MNs in modulating release of HIV subunit vaccine.
Protection and durable humoral and cellular immune responses in cynomolgus macaques following administration of a Zaire Ebola virus (EBOV) GP DNA vaccine delivered by intramuscular or intradermal electroporation
Authors: Patel Ami , Reuschel Emma L. , Kraynyak Kimberly Ann , Park Daniel H , Racine Trina , Yan Jian , Khan Amir , Morrow Matthew P , Muthumani Kar , Shedlock Devon J , Broderick Kate E. , Audet Jonathan , Jones Shane , Bello Alexander , Soule Geoff , Tran Kaylie N , Tierney Kevin , Qiu Xiangguo , Kobinger Gary P , Humeau Laurent , Sardesai Niranjan , Weiner David 
Published: January 2023

Abstract
The 2013–2016 Ebola virus disease (EVD) was the first time that the spread of the virus reached epidemic status. There are no licensed vaccines; however the most advanced candidate rVSV-ZEBOV vaccine, is a live-attenuated vesicular stomatitis virus encoding the Ebola virus glycoprotein (GP), and has demonstrated efficacy in a ring-vaccination trial. However, several EVD viral vector vaccine trials have reported adverse events that could limit administration to certain populations. The establishment of robust anamnestic responses has yet to be fully understood with these candidates and may be limited by potential anti-vector immunity. We designed EVD DNA vaccines as an alternative platform with a remarkable safety profile that is serology independent, allowing for possible repeat vector administration. We designed 3 novel synthetic Zaire Ebola virus (EBOV) GP DNA sequences which were tested alone or as multivalent formulations delivered by in vivo intramuscular (IM) or intradermal (ID) electroporation (EP). The EBOV-GP DNA vaccines were highly protective against lethal EBOV-Makona challenge in cynomolgus macaques, with 100% protection in NHPs receiving vaccine by ID-EP delivery and 75% protection in NHPs receiving 2 doses IM-EP. Vaccinated NHPs had no detectable viremia following challenge. Animals (n=4–5/group) injected with different IM-EP or ID-EP DNA regimens were followed to monitor long-term immunogenicity. NHPs have durable total IgG antibody titers and T cells responses to EBOV GP antigen, including polyfunctional CD4 and CD8 T cells and responses in memory subset populations. Together, the data strong support EBOV-GP DNA vaccine delivery for protection and the generation of robust memory immune responses.
The genetics and expression of canine antigen receptors analysed with a novel RNA-seq strategy.
Authors: Martin Jolyon N E , Ponstingl Hannes , Sargan David , Bradley Allan 
Published: January 2023

Abstract

INTRODUCTION
Dogs are an excellent model for human disease, e.g. the treatment of canine lymphoma is often predictive of the human response to that treatment. However, an incomplete picture of their antigen-receptor (AR) gene loci and a limited set of available experimental tools has restricted their use. This work advances the annotation of the canine AR loci, develops methods to interrogate their expression patterns, and looks into breed-specific features of the loci.

METHODS
A bioinformatic approach alongside unbiased RNA-seq was used to complete the annotation of the canine AR genes, and these sequences were used to query 107 whole genome sequences from 19 breeds. A 5’RACE strategy was developed to selectively amplify ARs for next generation sequencing, and this was applied to RNA isolated from canine peripheral blood samples.

RESULTS
&gt;5,500 novel alleles were identified across the ~550 gene segments (of which 326 were newly annotated) of the AR loci, yielding insight into AR evolution as well as confirming the greater conservation between dog and human than mouse with either. The 5’RACE strategy was validated with a pilot study that cast light onto the baseline expression and mutation patterns of healthy dogs, finding they closely mirrored their human counterparts.

CONCLUSION
This work brings our understanding of the genetics and expression of ARs in dogs to the same high standard as mice and men. The large number of genome sequences serves as a reference for future studies, and has allowed statistically powerful conclusions to be drawn on the pressures that have shaped these loci. Finally, it confirms the dog as a superior immunological model, particularly in the context of the high conservation seen in both sequence and expression features.