bluuebunny/crossref_metadata_2025_split huggingface dataset:
Bromodomain inhibition instructs macrophages to promote beta cell proliferation and suppress autoimmune diabetes
Authors: Yang Meixiang , Wang Ke , Fu Wenxian 
Published: January 2023

Abstract
A hallmark of autoimmune type 1 diabetes (T1D) is the decline of beta cell mass. Any regimen to promote beta cell expansion will have a great therapeutic promise. We have previously demonstrated that an epigenetic inhibitor targeting BET proteins (I-BET) promotes beta cell proliferation in an animal model of T1D. However, the underlying mechanisms remains unknown. Using both gain-of and loss-of function assays, we demonstrate that macrophages play an indispensable role in I-BET-elicited beta cell proliferation. In vivo ablation of macrophages significantly abolishes, while the supplementation of I-BET preconditioned macrophages enhances, I-BET induced beta cell proliferation. On a molecular level, elevated production of platelet-derived growth factor (PDGF) in I-BET treated macrophages mobilizes PDGFR signaling in beta cells. In summary, these findings reveal a novel strategy to expand beta cells by harnessing macrophages.
The GRB2-associated binding protein 3 is required for IL-2 and IL-15 induced NK cell expansion and limits trophoblast invasion during pregnancy
Authors: Sliz Anna , Locker Kathryn C.S. , Lampe Kristin , Godarova Alzbeta , Plas David R , Janssen Edith , Jones Helen , Herr Andrew B , Hoebe Kasper 
Published: January 2023

Abstract
The Grb2-associated binding protein 3 (Gab3) is a scaffolding protein that belongs to the Grb2-assocated binding family of proteins along with Gab1 and Gab2. Gab3 is expressed exclusively in immune cells including NK cells, CD8+T cells, mast cells and macrophages, however the function of Gab3 has remained elusive. Based on two independent mouse models; a hypomorph germline mouse model carrying a missense mutation in the PH domain of Gab3 and complete Gab3-KO mice, we uncovered a key role for Gab3 in peripheral NK cell function. Specifically, loss of Gab3 results in impaired IL-2/IL-15-induced NK cell priming and expansion, due to a selective impairment in MAPK- but not STAT5-signaling. In vivo, we show that Gab3 is required for recognition and elimination of “missing-self” and tumor targets. Gab3-deficient mice exhibit impaired uterine NK cell expansion that is associated with abnormal spiral artery remodeling and increased trophoblast invasion in the decidua basalis. This coincides with stillbirth, retained placenta, maternal hemorrhage and undelivered fetoplacental units at term. Thus, our studies identify Gab3 as a novel component required for IL-2/IL-15-mediated NK cell priming and expansion that is essential for anti-tumor responses and for controlling fetal trophoblast invasion during pregnancy.
The role of Th17 lymphocytes in drug-resistant epilepsy
Authors: Ouédraogo Oumarou , Jamann Hélène , Daigneault Audrey , Clenet Marie-Laure , Lahav Boaz , Bérubé A. , Cossette Patrick , Keezer Mark , Nguyen Dang Khoa , Larochelle Catherine 
Published: January 2023

Abstract
Epilepsy is a chronic neuronal disorder affecting ~65 millions people throughout the world. 1/3 of patients suffer from drug-resistant epilepsy (DRE).

Objective
to assess the relationship between different Th17 markers and the clinical course of epilepsy to uncover new potential immune biomarkers and therapeutic targets of interest for DRE.

Approach
Subjects between 19–55 years old with a focal diagnosed epilepsy were recruited at the CHUM epilepsy clinic. The profile of peripheral blood T lymphocytes from DRE patients (n=48) is compared to well-controlled epilepsy (WCE; n=30) and healthy controls (n=35). Peripheral blood mononuclear cells (PBMCs) were isolated by gradient density centrifugation before ex vivo analysis of surface markers (flow cytometry). Total CD4 T lymphocytes were magnetically isolated from PBMCs and stimulated overnight before analysis of cytokine expression or processed for RNA extraction before analysis of transcription factors expression by qRT-PCR.

Results
Our data suggest that antiepileptic drugs are associated with a relative ‘immunosuppression’, more pronounced in WCE. Epilepsy is associated with an altered distribution of immune cell populations with a higher CD4:CD8 ratio. A higher proportion of CD4 T lymphocytes from DRE subjects express CCR6 and CD161 compared to WCE. The proportion of CD4 T cells expressing pro-inflammatory cytokines from Th17/1 lineage (IL-17A, IL-22, IFN-γ, GM-CSF, TNFα) is higher in DRE than WCE, while anti-inflammatory cytokines (IL-4, IL-10) tend to be lower.

Conclusion
Our preliminary results suggest an increased frequency of pro-inflammatory Th17/1 lymphocytes and their related cytokines in DRE. Pro-inflammatory CD4 T cells could play a role in DRE.
Stress Induced Immune Dysregulation: A Continuum Spanning Antarctica Winterover, Spaceflight, and Terrestrial Patients
Authors: Krieger Stephanie S , Makedonas George , Mehta Satish , Nelman Mayra , Pierson Duane , Tyring Stephen , Choukèr Alexander , Feuerecker Matthias , Strewe Claudia , Sams Clarence , Crucian Brian 
Published: January 2023

Abstract
Spaceflight, a unique environment characterized by stress, microgravity, isolation, circadian misalignment, and radiation exposure, impacts immune health. This analysis compares various aspects of immune dysregulation in astronauts during long-duration orbital spaceflight to ground-analog populations, including hypoxic and normoxic Antarctic winterover. Astronaut data were also compared to a clinical immunodeficiency population, shingles patients, to help interpret clinical risks during deep space missions.
A comprehensive evaluation was performed across all platforms which included plasma and mitogen stimulated cytokine profiles, T cell function, and peripheral leukocyte distribution. A cross platform analysis was then performed to define in-flight immune alterations, determine analog appropriateness, and interpret clinical risk.
Astronauts manifest a distinct pattern of immune alterations, including unaltered leukocyte distribution, reduced T/NK cell function, and increases in plasma cytokines leading to the reactivation of latent herpesviruses. The pattern is similar to that observed in shingles patients, but reduced in magnitude. Immune alterations during interior Antarctic winterover were dissimilar from spaceflight, likely due to hypobaric hypoxia. Normoxic winterover, to date only cytokine data exist, appears more homologous to spaceflight.
Stress induced reductions in immunity can lead to clinical disease. This phenomenon may represent a continuum, where alterations in astronauts may represent more subtle variations which precede the development of disease. Antarctica data, at a magnitude between flight and disease, suggest that stress and circadian issues may be a primary contributor.
Elevated expression levels of the voltage-gated sodium channel 1.7 and BAFF receptor in peripheral monocytes contribute to activation of monocytes of patients with primary Sjögren’s syndrome
Authors: Yoshimoto Keiko , Ikeda Yumi , Suzuki Katsuya , Takeuchi Tsutomu 
Published: January 2023

Abstract

Background & Purpose
We reported that elevated expression of BAFF-receptor (BR3) in peripheral monocytes of patients with primary Sjögren’s syndrome (pSS) resulted in robust increased in IL-6 production by the cells. It has been reported that the pathways via voltage-gated sodium channels, such as Nav1.7, in monocytic lineage are involved in production of inflammatory cytokines, such as IL-6, in inflammatory pain diseases. In this study, we investigated the expression levels of Nav1.7 and BR3 in peripheral monocytes in patients with pSS in an attempt to discriminate the disease from other autoimmune diseases, such as active RA and active SLE.

Methods
The expression levels of Nav1.7 and BR3 in peripheral monocytes were analyzed by FACS using whole blood samples from patients with pSS (n = 28), active RA (n = 15), active SLE (n = 37) and healthy controls (HC; n = 15). Peripheral monocytes were stimulated with BAFF in the presence or absence of an inhibitor against Nav1.7. The amount of IL-6 in the culture supernatants was measured by ELISA.

Results
FACS analysis revealed that the expression levels of Nav1.7 and BR3 in pSS monocytes was significantly higher than those of active RA (p = 0.005, 0.003), active SLE (p &lt;0.001, 0.004) and HC (p &lt; 0.001, 0.002). Interestingly, the expression level of Nav 1.7 in pSS monocytes was significantly and positively correlated with that of BR3 in the cells (p = 0.01). Moreover, a specific inhibitor against Nav 1.7 suppressed IL-6 production by sBAFF-stimulated peripheral monocytes in a dose dependent manner.

Conclusion
Our results strongly suggest that the crosstalk between BAFF signaling and sodium channel is involved in activation of pSS monocytes and can be a therapeutic target for pSS.
Anti-inflammatory effects of xanthohumol in RAW 264.7 macrophages are mediated through the activation of AMP kinase
Authors: Mills Devin M , Samuels Janaiya , Hawkins Meridith , Gavre Adrian , Shashidharamurthy Rangaiah , Rayalam Srujana 
Published: January 2023

Abstract
Xanthohumol (XN), a prenylated chalcone extracted from common hop plants, has been studied for its anti-inflammatory properties. In this study, we hypothesize that XN induces M2 polarization of macrophages and the resulting anti-inflammatory effects are mediated through the activation of adenosine monophosphate-activated protein kinase (AMPK) signaling pathway. RAW 264.7 cells were treated with either 0.1% DMSO or XN and the culture supernatant was collected for ELISA and whole cell lysates were collected for western blotting. Our results demonstrate that XN upregulated the secretion of IL10, a signature cytokine for M2 polarization, in RAW264.7 cells. We further demonstrated that XN increased arginase expression, a marker for M2 polarization, and suppressed IFNγ-mediated upregulation of inducible nitric oxide synthase (iNOS) expression, a marker for M1 polarization. Additionally, XN decreased IFNγ – induced elevation of nitrite release, indicating the inhibitory effects of XN against M1 polarization. Furthermore, XN at 25μM increased the secretion of catecholamines from macrophages comparable to IL4, an inducer of M2 phenotype and these effects were accompanied by an increased expression of tyrosine hydroxylase, a rate-limiting enzyme of catecholamine biosynthesis. Finally, XN and AICAR, an AMPK stimulator, upregulated the expression of phospho-AMPK and arginase while dorsomorphin, an established inhibitor of the AMPK pathway failed to do so in RAW264.7 cells. These results provide evidence for the anti-inflammatory effects of XN mediated through the induction of M2 polarization and activation of AMPK signaling pathway.
Characterisation of immune complexes in Kawasaki Disease and other infectious diseases by protein sequencing
Authors: Menikou Stephanie , McArdle Andrew , Kaforou Myrsini , Shimizu Chisato , Wright Victoria J , Herberg Jethro A , Kanegaye John T , Tremoulet Adriana , Burns Jane C , Levin Michael 
Published: January 2023

Abstract

Background
Kawasaki Disease is a paediatric inflammatory disease associated with self-limiting vasculitis. It has a world-wide distribution with an ethnic bias towards East Asian populations and is the most common cause of acquired heart disease in children in developed countries. The immunopathogenesis of KD remains poorly understood. The presence of antibody-antigens (pathogen) known as immune complexes in the blood of children with KD was established in numerous studies leading to the hypothesis that immune complexes contribute to the damages of the coronary artery.

Methodology
Using proteomic technologies we characterised the composition of immune complexes in KD and compare the immune complexes in KD with those in children with other febrile illnesses, TB and healthy children. Immune complexes were precipitated from the blood of 80 children with KD, 80 children with other febrile conditions, 30 with TB and 30 healthy children. We used Lumos Orbitrap mass spectrometry to identify the recovered proteins. Using the bioinformatics program PEAKS, we performed database searches and compared the protein abundances between the different comparator groups.

Conclusions
Immune complexes isolated from children with KD are different from those recovered from other febrile illnesses in terms of the nature of proteins within the complex. The pattern of proteins in the immune complexes containing immunoglobulins, complement proteins as well as other serum proteins, provides insight into the nature of the unique inflammatory response in KD versus the other inflammatory diseases.
Early treatment of a CD137L neutralizing antibody decreases mechanical hypersensitivity and functional recovery time following a sciatic nerve crush
Authors: Wakley Alexa A , Cao Ling 
Published: January 2023

Abstract
To investigate the role of CD137L in pain development and nerve regeneration following peripheral nerve injury, we examined pain-like and functional recovery-related behavioral responses following intrathecal injection (IT) of a CD137L neutralizing antibody (αCD137L; daily day 0–7) after sciatic nerve crush (SNC) in male and female B6 mice. Mice were randomly assigned to 1 of 4 groups: no IT, PBS, 0.1 or 0.5μg of αCD137L, and then were evaluated for sensitivity (von Frey, Hargreaves, & cold plantar test), sensory (pin prick assay) and motor (hind limb grip strength, toe spread reflex and toe spacing score) functional recovery before surgery and on post-surgery days 1–77. On post-SNC day 1, all groups showed changes in sensitivity and decreased sensory and functional responses. By day 7, αCD137L treated mice showed reduced mechanical hypersensitivity compared to no IT and PBS-treated controls and were at baseline levels by day 42, about 1–2 weeks earlier than both control groups. All groups showed hyposensitivity to heat stimulus on day 1, but quickly returned to baseline with no group differences. On days 1–35 hyposensitivity to a cold stimulus was also found in all groups, but αCD137Ltreated mice were slightly more sensitive on days 49–77. Grip strength improved in all groups on day 14 without significant group differences. On days 3–14, αCD137L-treated groups had higher toe space scores compared to controls. Finally, sensory recovery (pin prick) in αCD137L-treated groups emerged on day 3, a week earlier than the control groups. Together, our results suggest that CD137L likely contributes to sensory hypersensitivity and functional changes early on following peripheral nervy injury.
A Toll-like Receptor 5 agonist entolimod mitigates radiation damage through a neutrophil-dependent mechanism
Authors: Brackett Craig M , Greene Kellee , Kandar Bojidar , Trageser Nicholas , Kandefer Rachel , Pal Srabani , Burdelya Lyudmila , Gudkov Andrei 
Published: January 2023

Abstract
The increased risk of exposure to life-threating nuclear and radiation emergencies warrants the development of FDA-approved medical radiation countermeasures (MRC) as radio mitigators, which can be used after exposure to total body irradiation. Currently, Neupogen and Neulasta are the only FDA-approved radio mitigators but are unfortunately limited by adverse side effects and the need for additional medical supportive care. Bacterial flagellin, the natural agonist of Toll-like receptor (TLR) 5, and apharmacologically optimized derivative entolimod developed by us have powerful activity as a single agent MRC in rodents and non-human primates. Currently entolimod is being developed as a MRC under the FDA’s Animal Efficacy Rule, which guides development of drugs for which efficacy testing in humans would be unethical. The lack of induction of cytokine storm post systemically administered entolimod was demonstrated in rodents, non-human primates, and Phase I clinical trials involving nearly 200 subjects. Entolimod stimulates TLR5 on hepatocytes followed by activation of immunoregulatory signaling pathways, production of pro-inflammatory cytokines, and rapid recruitment of immune cells to the liver. Neutrophils are among the first immune cells that are rapidly recruited to both non-lymphoid and lymphoid tissues post-entolimod. We found that this entolimod-elicited neutrophil response was essential to mitigating radiation damage by promoting the recovery of hematopoietic stem cells in the bone marrow. This work underscores the underappreciated importance of TLR5-elicited neutrophils in promoting there generation of hematopoiesis following total body irradiation.
Functional studies to understand immune modifiers in cystic fibrosis
Authors: Lu Shiping , Song Kejing , Bomberger Jennifer , Kolls Jay K 
Published: January 2023

Abstract
Cystic fibrosis (CF) is an inherited lethal disease caused by mutated cystic fibrosis transmembrane conductance regulator (CFTR), around 60% with homozygous F508del mutation. Pseudomonas aeruginosa (P. aeruginosa) is the most predominant lung pathogen in CF patients, causing decreased lung function and increased mortality as compromised integrity and function of pulmonary epithelium. Genome-wide association (GWA) studies revealed several single nucleotide polymorphisms (SNPs) in class II major histocompatibility complex (MHCII) of the F508del population are associated with delayed age of colonization, as well as lung function. Up to 7% of lung B-cells in the CF lung are specific for P. aeruginosa but these cells show very little somatic hypermutation. Thus, we hypothesized there may exist differences in antibody isotypes, titer, specificity or affinity, specific to P. aeruginosa, which influence/determine lung function. To test this, we assessed a homozygous F508del mutated cohort of non-progressive CF patients with confirmed P. aeruginosa colonization. In this cohort, we found that the sera of CF patients had significantly higher IgG and IgG1 compared to non-CF controls. We also observed higher surface binding of antibodies from CF sera to P. aeruginosa. And CF sera inhibited bacterial biofilm formation time-dependently. In addition, we are querying T-cell immunity at the single cell level. Taken together these studies should shed light on the role of class II MHC as a gene modifier in CF.
Development of an outbred disease model of Hermansky-Pudlak Syndrome in Threespine Stickleback
Authors: Beck Emily A , Currey Mark C , Niebergall Emily , Bassham Susan , Cresko William A. 
Published: January 2023

Abstract
Mounting evidence shows that humans respond heterogeneously to diseases and treatments due to their genetic variation, leading to the growth of the field of personalized medicine. Research on model organisms is vital to seek scientific understandings of disease in this broader context, but current research in nonhuman disease models struggles to demonstrate the genetic variability of humans. One disease that exemplifies this issue is Hermansky-Pudlak Syndrome (HPS). HPS is a genetic syndrome resulting from mutations in one of ten HPS genes involved in endosome trafficking, which can result in oculocutaneous albinism, blood diathesis, pulmonary fibrosis, vision impairment, and granulomatous enterocolitis phenotypically indistinguishable from Crohn’s Disease. Currently no disease models for HPS exist that accurately demonstrate the variability of the human disease. Here we present an outbred mutant model of threespine stickleback (Gasterosteus aculeatus) fish exhibiting symptoms consistent with HPS. Using genetic mapping approaches we narrowed this mutation to a region of the genome containing hps4the causative disease gene of Hermansky-Pudlak Syndrome Type 4. Using histological staining and imaging we are confirming the presence of each symptom comprising the syndrome and hope to develop the first outbred system to tackle this disease. Ultimately, the application of outbred medical models in diverse organisms will be important for the advancement of personalized medicine, greatly enhancing our understanding of how genetic variation affects disease states.
Epitope profiling of plasma antibody in Alzheimer’s disease dementia patients
Authors: Park Sung-Gyoo , Sim Kyu Young , Byeon Yeongseon , Lee Kun Ho 
Published: January 2023

Abstract
Antibodies show excellent stability in blood; therefore, they can be utilized for screening of convenient blood-based markers of Alzheimer’s disease dementia (AD). This study used unbiased microarrays comprising 29,240 random peptides to screen for AD-specific antibodies. The results showed that 1) antibodies are specifically regulated in AD and certain combinations show high area under the receiver operating characteristic curve values (0.862–0.961); 2) AD-specific IgG antibodies arise from established IgM antibody-secreting cells; and 3) analysis of proteins targeted by differentially regulated antibodies identified AD-related signaling pathways. Thus, plasma antibodies targeting specific epitopes are regulated in AD; these epitopes may facilitate biomarker development.
Unraveling the role of fibrosis in the TB Granuloma
Authors: Evans Stephanie , Wong Eileen A , Flynn JoAnne L , Mattila Joshua T , Kirschner Denise 
Published: January 2023

Abstract
Tuberculosis (TB), a deadly infectious disease caused by the bacterium Mycobacterium tuberculosis (Mtb). The disease is characterized by the development of granulomas consisting of immune cells that form a cluster around the bacteria to limit bacterial growth and disease outcomes. Control of the TB epidemic is limited by a complicated drug regimen, development of antibiotic resistance, and the lack of an effective vaccine against infection and disease. Fibrosis is common in older granulomas, and has been associated with both positive and negative disease outcomes. Little is known about fibrosis in TB, partly due to the fact that fibroblasts are difficult to identify using traditional antibody-based techniques.
To provide insight into the role that fibrosis plays at a single granuloma scale, we have developed a computational, agent-based model of granuloma formation in the lung following infection with Mtb. In previously published work we have identified the mechanisms driving fibrosis within a granuloma i.e. how the granuloma environment effects fibrosis. Using immunohistochemistry, we have characterized fibroblasts and early collagen deposition in TB granulomas. Here we have extended this work to look at how fibrosis affects the ability of a granuloma to control bacteria, focusing on the role of both fibroblasts. Predictions show that early fibrosis alters the structure of the granuloma with few long-term effects on bacterial control, however late fibrosis decreases the promotability of bacterial dissemination. This work has implications on treatment options for TB that typically cause early fibrosis to occur.
BET bromodomain targeting suppresses the PD-1/PD-L1 pathway in triple-negative breast cancer and elicits anti-tumor immune response
Authors: Andrieu Guillaume , Shafran Jordan S , Denis Gerald V 
Published: January 2023

Abstract
Therapeutic strategies aiming to leverage anti-tumor immunity are being intensively investigated because they show promising results in several cancer therapies. In tumors able to evade immune clearance, the PD-1/PD-L1 pathway constitutes an important target to restore a functional anti-tumor immune response. Here, we report that BET protein inhibition suppresses the PD-1/PD-L1 axis in triple-negative breast cancer. BET proteins control PD-1 expression in effector T cells, and PD-L1 in breast cancer cells. BET protein targeting reduces T cell-derived interferon-gamma production and signaling, thereby suppressing PD-L1 sustained induction in breast cancer cells. Moreover, BET protein inhibition improves tumor cell-specific T cell cytotoxic function. Overall, we demonstrate that BET protein targeting represents a promising strategy to overcome tumor-reactive T cell exhaustion and improve anti-tumor immune responses, by reducing the PD-1/PD-L1 axis in triple-negative breast cancer.