bluuebunny/crossref_metadata_2025_split huggingface dataset:
Using magnetic resonance imaging to elucidate the mechanism of experimental cerebral malaria rescue by 6-diazo-5-oxo-norleucine
Authors: Riggle Brittany Anne , Sinharay Sanhita , Hammoud Dima , Munasinghe Jeeva , Slusher Barbara , Powell Jonathan D , Seydel Karl , Taylor Terrie , Miller Louis H. , Pierce Susan K 
Published: January 2023

Abstract
We have previously demonstrated the efficacy of 6-diazo-5-oxo-L-norleucine (DON), a glutamine analog, as a possible adjunctive therapy to mitigate the clinical severity of human cerebral malaria (HCM) (Gordon et al. PNAS 2016). The pathology of HCM is heterogeneous, but generally includes the accumulation of infected red blood cells in the brain vascular endothelium, cerebral microhemorrhages, compromised blood-brain barrier and brain swelling. These changes manifest in severe neurologic symptoms including headache, fever, ataxia, seizures, retinopathy, and coma. The mouse model of CM, experimental cerebral malaria (ECM), approximates the main characteristics of HCM when susceptible C57BL/6 mice are infected with Plasmodium berghei ANKA (PbA) parasites. Studies in these mice found that treatment with DON, even in late stage ECM, rescued animals and increased survival while mitigating and reversing blood-brain barrier dysfunction and brain swelling. Recently, Seydel et al. (NEJM 2015) used magnetic resonance imaging (MRI) to characterize HCM pathology and correlate it to disease severity in children in Malawi. They observed increased brain volume in children that died from HCM that was uncommon in children that survived HCM. Herein, we perform MRI studies in the mouse model to determine if the disease course effectively recapitulates that of HCM, based on morphological changes in MRI. These studies may help elucidate the mechanisms underlying CM pathology, aiding the development of effective treatments. Furthermore, we utilize MRI to probe the mechanisms of action of recovery with DON treatment in order to evaluate the drug for possible clinical trials in HCM.
Constitutive Transcription of the ProIL-1β Gene in Human CCR5+ CD4 T Cells is Distinct from that of Monocytes
Authors: Pulugulla Sree H , Packard Thomas A , Galloway Nicole l.K. , Doitsh Gilad , Adamik Juraj , Galson Deborah L , Greene Warner C , Auron Philip E 
Published: January 2023

Abstract
Transcription of IL-1β activity has been extensively studied in stimulated myeloid cells, but not in lymphoid-derived CD4 T cells, the primary cellular target for infection by HIV. Most CCR5+ CD4 T cells in lymphoid tissues are non-permissive for productive HIV infection and die by Caspase-1-mediated pyroptosis, in which proInterleukin 1β (proIL-1β) precursor is converted to highly active mature IL-1β. It is unclear whether expression of proIL-1β protein in CCR5+ CD4 T cells is derived from active transcription of the IL1B gene, or from previously transcribed mRNA and/or stored protein. Our results reveal that despite very low amounts of IL1B mRNA, CCR5+ CD4 T cells accumulate intracellular proIL-1β protein at levels higher than that of both unstimulated myeloid THP-1 cells and CCR5− CD4 T cells. Further, we observe that the chromatin from CCR5+, but not CCR5− CD4 T cells, contain RNA polymerase II and bivalent H3K4me3 and H3K27me3 nucleosomes at the IL1B promoter, consistent with developmentally regulated constitutive gene expression. This observation contrasts with the rapidly activated and extremely robust H3K4me3 monovalent IL1B gene promoter in TLR4-activated monocytes. This unique phenomenon of CCR5+ CD4 T cells is important to understanding how non-myeloid lineage cells express and release significant levels of IL-1β in the apparent absence of transcription induction.
STAT1 activation represses IL-22 gene expression and psoriasis pathogenesis.
Authors: Bai Li , Xia Sisi , Ochando Jordi , Li Liwu , Xu Jiangnan , Ding Yaozhong 
Published: January 2023

Abstract
IL-22 plays an important role in modulation of tissue repair and inflammatory responses and is implicated in psoriasis, ulcerative colitis, as well as liver and pancreas damage. The molecular mechanisms of its regulation have been actively studied. In our study, STAT1 but not T-bet deficiency resulted in higher levels of IL-22 expression and severer acanthosis in imiquimod-induced mouse psoriasiform skin inflammation, which indicates a critical role of STAT1 in repressing IL-22 gene expression and psoriasis pathogenesis. Quantitative RT-PCR data showed that high levels of IL-22 production were only observed in STAT1 but not T-bet deficient T cells stimulated with anti-CD3 and anti-CD28 in combination with or without IL-6 plus IL-23, further demonstrating that STAT1 but not T-bet is crucial to suppress IL-22 gene expression. There was no difference between STAT1 and T-bet deficiency in activation of transcription factors RORγt, c-Maf, ICOS or AhR, suggesting they do not play significant roles in STAT1 mediated IL-22 inhibition. A STAT binding motif was identified within IL-22 promoter, and CHIP assay showed direct interaction between STAT1 and IL-22 promoters, revealing a novel regulatory mechanism of IL-22 suppression by STAT1. Additional molecular mechanisms of STAT1 mediated IL-22 regulation are currently under investigation.
Transient FOXP3 upregulation protects human conventional T cells from restimulation-induced cell death during activation-induced proliferation
Authors: Voss Kelsey , Snow Andrew L 
Published: January 2023

Abstract
An efficient adaptive immune response relies on the rapid clonal expansion of effector T cells, followed by timely disposal of those cells in order to avoid damage to host tissues. Effector T cell proliferation is constrained by the action of forkhead box P3 (FOXP3)+ regulatory T cells (Tregs) and restimulation-induced cell death (RICD), an apoptotic pathway triggered by repeated stimulation through the T cell receptor (TCR) in the presence of interleukin-2 (IL-2). Constitutive FOXP3 expression renders Tregs resistant to RICD, in part through repression of the signaling adaptor molecule SLAM-associated protein (SAP) and FAS ligand (FASL). Interestingly, FOXP3 is also expressed transiently in human conventional T cells (Tcons) during initial rounds of activation-induced proliferation, but its function in this context remains unclear. Here we uncover a new role for FOXP3 induction in protecting both CD4+ and CD8+ human Tcons from premature RICD during the expansion phase. SiRNA-mediated silencing of FOXP3 sensitized early effector Tcons to RICD. This increase in RICD was completely dependent on de novo transcription, but FOXP3 knockdown did not alter SAP or FASL expression in these cells. Instead, FOXP3 silencing increased glycolysis and reduced autophagy in Tcons, which we and others have linked to changes in apoptosis sensitivity. Surprisingly, FOXP3-dependent autophagy specifically protected CD4+ but not CD8+ Tcons from RICD. Our results suggest a fundamentally different mechanism connecting transient FOXP3 expression to metabolic activity and RICD resistance in CD4+ versus CD8+ T cells.
Influence of age on mycobacterial myocarditis and heart failure
Authors: Rajaram Murugesan , Headley Colwyn , Murphy Nathaniel , Schlesinger Larry S , Mohler Peter J , Turner Joanne 
Published: January 2023

Abstract
Mycobacterium avium complex (MAC) consists of M. avium and M. intracellulare and enters the host primarily through the gastrointestinal track and pulmonary route. MAC is a common cause of mycobacterial infection in immune compromised individuals including, the elderly and those with COPD, HIV/AIDS or cystic fibrosis. The disease symptoms are reminiscent of tuberculosis (TB). Mycobacterium can infect every organ in the body including the heart causing carditis (pericarditis, myocarditis and endocarditis). Myocardial TB is difficult to diagnose and treat and can cause heart failure and ventricular tachyarrhythmia which can ultimately lead to sudden cardiac arrest. Very little is known regarding cardiac dysfunction during mycobacterial infection in the elderly. In this study we examined cardiac electrical activity, cardiac inflammation and fibrosis in young and old mice after 32 days of M. avium infection. The electrocardiogram of old mice shows abnormalities that include sinus node pause and first degree heart block. Thus, we hypothesize that mycobacterial infection leads to increased cardiac inflammation, fibrosis and necrosis which lead to significant electrical disturbances in old mice. The proposed work will identify new molecular mechanisms and key factors that cause sudden cardiac arrest during mycobacterial infection and will thereby provide us with additional strategies to protect the heart from cardiac damage during infection.
Immunologic non-response during HIV infection is characterized by systemic immune activation
Authors: Rousseau Rodney , Choi Yoojin , Lau Elizabeth , Kim Connie J , Benko Erika , Huibner Sanja , Kovacs Colin , Kaul Rupert 
Published: January 2023

Abstract

Introduction
Despite effective treatment HIV infection is characterized by non-AIDS health burdens, linked to immune activation, gut damage and microbial translocation. Some HIV+ individuals achieve viral suppression but do not recover blood CD4 T cells; these immunologic non-responders (INRs) are at elevated disease risk. We hypothesized that INRs have higher immune activation and markers related to gut damage, as compared to HIV+ treatment responders (TRs).

Methods
Thirty-six men who have sex with men (MSM) were recruited through the Maple Leaf Medical Clinic in Toronto. INRs (n=15) were defined as having a CD4 T cell count &lt;350/μl, despite &gt;2 years of HIV suppression. TRs (n=15) had a nadir CD4 T cell count &lt;350/μl, but restored blood CD4 T cell count &gt;350/μl. HIV-negative MSM (n=6) were also recruited. T cell activation (%HLA-DR+CD38+) and other cellular markers were assessed by flow cytometry. Plasma markers of coagulation (D-Dimer), and microbial translocation-associated immune activation (sCD14) were quantified by immunosorbent assay.

Results
INRs had elevated levels of CD8 and CD4 T cell activation compared to TRs (p&lt;0.05). INRs had a reduced CD4/CD8 ratio compared to TRs (p&lt;0.001), and lower CD4 T cell count was associated with elevated CD8 T cell activation (p&lt;0.05). There was a trend towards higher plasma D-dimer levels in INRs compared to TRs (p=0.12).

Conclusion
INR men had a reduced CD4/CD8 ratio, higher levels of systemic immune activation, and a trending elevation in markers of coagulation. These data highlight a need for characterization of tissue-specific gut immune function in the INR context. Ultimately gut-targeted clinical interventions may be useful to mitigate adverse health outcomes in INR individuals.
miR-155 and let-7a potentiate auto-inflammatory and tumor-like proliferative dysregulation in post-infectious Lyme arthritis synovial tissue
Authors: Lochhead Robert B , Strle Klemen , Steere Allen 
Published: January 2023

Abstract
Post-infectious Lyme arthritis (LA) is a model for testing the causal relationship between infection and autoimmunity. The initial trigger for LA, Borrelia burgdorferi infection, is known with certainty, but it is unclear why some patients have persistent synovitis after completion of antibiotic therapy. To elucidate the inflammatory nature of post-infectious LA, whole transcriptome sequencing was performed on synovial tissue from 14 patients with post-infectious LA and compared with that from patients with other forms of inflammatory arthritis or degenerative arthritis. LA patient synovial tissue had a highly inflammatory expression signature, similar to patients with other immune disorders including Type IV hypersensitivity and autoimmune diseases. This profile included upregulation of IFN-responsive genes and genes associated with MHC Class II antigen processing and presentation, T cell activation, and cell-mediated cytotoxicity; and down-regulation of genes involved in tissue repair and cell metabolism. Fibroblasts isolated from synovial tissue and primary fibroblasts in vitro expressed markers of inflammation and active proliferation, consistent with the tumor-like proliferative nature of the synovial lesion. miR-155, a proinflammatory and oncogenic microRNA, was highly expressed and positively correlated with markers of inflammation and Class II antigen presentation. Expression of tumor suppressor let-7a was downregulated, negatively correlated with markers of inflammation, and positively correlated with markers of appropriate wound repair. We postulate that these two microRNAs potentiate epigenetic transformation of synovial fibroblasts into an auto-inflammatory and proliferative phenotype.
Trauma, stress, and HIV-associated immune cell levels in women
Authors: Kohlmeier Alison , Haddad Lisa B , Haaland Richard E , Brown Nakita L , Lupo L. Davis , Mehta Christina B , Sheth Anandi N , Titanji Kehmia , Hart Clyde E , Ofotokun Igho 
Published: January 2023

Abstract
Lifetime trauma, stress exposure, and current perceived stress are believed to lower immune responsiveness to infections but their effect on immune cell targets of HIV infection and pathogenesis are not known. We examined lifetime trauma and current perceived stress for associations with HIV target cells in genital mucosa and PBMC from 50 STI negative women of reproductive age. Validated scores for the number of traumatic exposures on the lifetime trauma and victimization history (LTVH) instrument, the 51-item Chronic Stress Scale (CSS) and the 10-item current perceived stress scale (PSS) were compiled. Paired cervicovaginal lavage (CVL) and blood samples were analyzed for T cell expression of CCR5 and activation markers (CD38, HLA-DR). Spearman correlations were used to evaluate associations between T cell subsets and LTVH, CSS, and PSS scores. LTVH number correlated with PBMC CD4/CD8 ratios and CCR5+ expression on CCR7+ CD4 T cells, but were inversely correlated with effector memory T cell frequency; CSS score was correlated CCR5+ expression on CCR7+ CD4 T cells. PSS scores were not correlated with T cell phenotypes. Genital tract T cell subsets were highly variable and not correlated with LTVH, CSS, or PSS scores. These findings suggest that increased lifetime trauma and chronic stress exposure is associated with shifts in circulating T cell populations that influence HIV susceptibility and its long-term pathogenesis. A better understanding of how lifetime trauma/stress exposure may affect immunologic mediators of HIV susceptibility, biomedical prevention efficacy, and HIV disease progression is warranted.
CD47-SIRPα axis restricts the therapeutic antitumor immunity through controlling tumor mitochondrial DNA-mediated innate sensing selectively in dendritic cells
Authors: Xu Meng , Fu Yang-Xin 
Published: January 2023

Abstract
STING (Stimulator of interferon genes)-dependent cytosolic DNA sensing is critical for the activation of antitumor immunity. However, the molecular determinants driving the differential DNA sensing of tumor cells in diverse professional phagocytes remain largely unexplored. Here we show that preventing the engagement of SIRPα (signal regulatory protein α) by CD47 promoted DNA sensing selectively in DCs, but not in macrophage, although both macrophages and DCs phagocytosed tumor cells efficiently. DCs were specialized to preserve mitochondrial DNA (mtDNA) from the engulfed tumor cells that served to initiate type I interferon-dependent antitumor immunity. Mechanically, interruption of CD47-SIRPα interactions prevented the translocation of SIRPα to NOX2 on DC phagosomes, which inhibited phago-lysosome fusion and mtDNA degradation. MtDNA is thus recognized by cyclic-GMP-AMP synthase (cGAS) in DC cytosol, which contributes to type I IFN production and antitumor adaptive immunity. Our findings identify CD47-SIRPα as a major innate checkpoint that dictates the unique capacity of DCs in immune recognition and therapeutic intervention of CD47-SIRPα axis could unleash DC-driven T-cell-mediated cancer immunity.
Inflammatory disease severity is ameliorated by inhibition of neutrophil-derived MPO that supports endothelial/epithelial integrity
Authors: Strzepa Anna , Dittel Bonnie N 
Published: January 2023

Abstract
Neutrophils are the most abundant leukocytes and provide a first line of defense against pathogens. Neutrophil granules store enzymes with anti-bacterial activities that can also damage tissues when released in an uncontrolled manner. Neutrophil infiltrates are prevalent in damaged tissues from mice with experimental autoimmune encephalomyelitis (EAE), dextran sodium sulfate (DSS)-colitis and contact hypersensitivity (CHS). The most cytotoxic and abundant enzyme expressed by neutrophils is myeloperoxidase (MPO). MPO utilizes hydrogen peroxide to generate highly reactive molecular moieties, that modify proteins, lipids and DNA, resulting in tissue damage. A pathogenic role for MPO was observed in EAE, DSS-colitis and CHS. MPO-deficiency, is associated with improved functioning of the vasculature, indicating that vasculature is a important target of MPO-activity. However, the precise molecular targets, associated with neutrophil-derived MPO are not known. To establish the importance of MPO as a candidate for therapeutic inhibition, we used animal models of colitis and CHS. Our strategy to modulate MPO activity was the use of MPO-deficient animals and the MPO-specific inhibitor KYC (N-acetyl lysyltyrosylcysteine amide). Our data indicated that MPO-deficient animals, exhibited significantly reduced disease severity in both DSS-colitis and CHS, which correlated with reduced intestinal and vascular permeability, respectively. In addition, MPO inhibition with KYC was also an effective strategy to reduce colitis and CHS severity. KYC mediated MPO inhibition enhanced endothelial integrity in vitro. Our data indicate that MPO could be potential therapeutic target in the treatment of inflammatory diseases.
Treatment with CD122 antibody durably reverses autoimmune skin disease in a mouse model of vitiligo
Authors: Richmond Jillian M , Zapata Lucio , Garg Madhuri , Strassner James , Rashighi Mehdi , Riding Rebecca , Ahmed Maggi , Essien Kingsley , Pell Lila , Agarwal Priti , Tsurushita Naoya , Tso J Yun , Harris John 
Published: January 2023

Abstract
Vitiligo is a disfiguring autoimmune skin disease characterized by patchy depigmentation. Vitiligo affects approximately 1% of the population worldwide, and it is mediated by CD8+ T cells that kill melanocytes, the pigment producing cells in the skin. Like many autoimmune diseases, treatment options for vitiligo are limited, and depigmentation rapidly recurs after therapy is stopped. We hypothesized that tissue resident memory T cells (Trm) persisted in the skin to reactivate disease. We first confirmed the presence of melanocyte-specific cells with Trm phenotypes in biopsies from human patients and in a mouse model of vitiligo. Functional analysis of Trm cells in mice with vitiligo revealed that they can sense antigen in the skin as determined by Nur77-GFP reporting, as well as secrete cytokines and chemokines as determined by IFNγ, CXCL9 and CXCL10 reporting. Treatment with the S1P1 inhibitor FTY720 resulted in rapid repigmentation, yet preserved Trm. Treatment with a CD122 blocking antibody effectively depleted autoreactive Trm. Importantly, CD122 antibody was also able to durably reverse disease mice. We propose that depleting Trm by targeting the IL-15 axis may prove to be a highly effective and durable treatment for vitiligo and other autoimmune diseases.
Implementation of just-in-time teaching strategy as an active learning instructional pedagogy for PharmD integrated microbiology and virology course
Authors: Madiraju Charitha , Tellez-Corrales Eglis , Hua Henry , Brown Deborah M 
Published: January 2023

Abstract
Just-In-Time Teaching (JiTT) is an active learning pedagogy that has been successfully adopted by various disciplines. However, it is unclear if JiTT presents value to a pharmacy curriculum. The current study implemented JiTT as an active-learning tool for an Integrated Microbiology and Virology course offered during the first year of a PharmD program. At the end of the course, students were provided with a survey that included items about JiTT. Several items were aggregated into a single rating about the degree that students agreed with various statements purporting JiTT as helpful, with score choices ranging from 1 (I strongly disagree) to 4 (I strongly agree). Overall, students strongly endorsed JiTT as helpful (M = 3.61, SD = 0.50), and even the lowest score, 2.50, was neutral in tone. Students were asked to endorse rationales for why JiTT questions were used in this course; 93.02% felt that JiTT helped them keep track with the material, and only 34.88% felt that JiTT gave them “extra work.” These results—and other findings stated in the poster —suggest that students in a pharmacy program find value in JiTT.
Tyrosine kinase Syk interacts with Hrs after TLR3 stimulation in murine microglial cells.
Authors: Mielcarska Matylda Barbara , Bossowska-Nowicka Magdalena , Gregorczyk Karolina Paulina , Wyzewski Zbigniew , Toka Felix Ngosa 
Published: January 2023

Abstract
TLR3 (Toll-like receptor 3) belongs to the family of receptors involved in innate immune response. Present in endosomal compartment in cells, TLR3 recognizes the dsRNA (double-stranded RNA), viral nucleic acid or intermediate during viral replication and initiates signal transduction leading to inflammatory response. However, the first steps of signaling cascade occurring in cells immediately after TLR3 stimulation are still not well understood and require careful attention. In this paper we demonstrate that after poly(I:C) (dsRNA mimetic) stimulation of murine microglial cells (C8D1A cell line) tyrosine kinase Syk interacts with Hrs (hepatocyte growth factor regulated tyrosine kinase substrate), one of the ESCRT-0 (endosomal sorting complex required for transportation-0) components. This protein complex was recently implicated in trafficking of other endosomal TLRs, TLR7 and TLR9, and plays a possible role in the TLR3 signaling. Phosphorylation of Hrs, which is a very likely result of Hrs-Syk interaction, also takes place after poly(I:C) stimulation, strongly suggesting that an association between activated TLR3 and ESCRT-0 exists. Therefore, Hrs may influence TLR3 signaling pathways, but this requires further investigation.
Utilization of protein-peptide conjugates for NK cell activation as a strategy for cancer immunotherapy.
Authors: Bitsaktsis Constantine , Phillips Mariana , Sabatino David 
Published: January 2023

Abstract
Cancer-based immunotherapy aims to develop biologics that can stimulate immune responses towards tumor eradication, as is the case of monoclonal antibodies (mAb) and their related analogs. Although the latter have been the most prevalently used biologics in cancer immunotherapy strategies, novel therapeutics may overcome their production, administration, and pharmacological limitations. The synthesis of intermediate size molecules, particularly chemically synthesized protein-peptide bioconjugates (PPB), possessing the targeting and effector functions of antibodies, represent a novel class of immunotherapeutics that may circumvent these limitations. In this study we proposed and executed the rational design of a novel class of cancer-targeting immunostimulatory protein-peptide conjugates (CTIPPC) that may potentially work as a synthetic antibody mimic. In this proof-of-concept, the CTIPPC aimed to target the tumor expressed GRP78, while recruiting and activating NK cells for tumor targeted immunotherapy. The sustained capabilities of the CTIPP conjugates to elicit NK-dependent immunostimmulatory activities were assessed via measuring cytokine secretion, NK cell migration, and the overall anti-tumor cytotoxic activity of NK cells. These studies shed important insights into the effective design, preparation and biological evaluation of a new class of semi-synthetic protein-peptide conjugates.