2,493,233 results on '"IMMUNOLOGY"'
Search Results
2. MOG CNS Autoimmunity and MOGAD.
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Moseley, Carson E, Virupakshaiah, Akash, Forsthuber, Thomas G, Steinman, Lawrence, Waubant, Emmanuelle, and Zamvil, Scott S
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Biomedical and Clinical Sciences ,Immunology ,Brain Disorders ,Neurosciences ,Multiple Sclerosis ,Autoimmune Disease ,Eye Disease and Disorders of Vision ,Neurodegenerative ,2.1 Biological and endogenous factors ,Neurological ,Myelin-Oligodendrocyte Glycoprotein ,Humans ,Animals ,Autoantibodies ,Neuromyelitis Optica ,Autoimmunity ,Encephalomyelitis ,Autoimmune ,Experimental ,Demyelinating Autoimmune Diseases ,CNS - Abstract
At one time considered a possible form of neuromyelitis optica (NMO) spectrum disorder (NMOSD), it is now accepted that myelin oligodendrocyte glycoprotein (MOG) antibody (Ab)-associated disorder (MOGAD) is a distinct entity from either NMO or multiple sclerosis (MS) and represents a broad spectrum of clinical phenotypes. Whereas Abs targeting aquaporin-4 (AQP4) in NMO are pathogenic, the extent that anti-MOG Abs contribute to CNS damage in MOGAD is unclear. Both AQP4-specific Abs in NMO and MOG-specific Abs in MOGAD are predominantly IgG1, a T cell-dependent immunoglobulin (Ig) subclass. Key insights in neuroimmunology and MOGAD pathogenesis have been learned from MOG experimental autoimmune encephalomyelitis (EAE), described 2 decades before the term MOGAD was introduced. MOG-specific T cells are required in MOG EAE, and while anti-MOG Abs can exacerbate EAE and CNS demyelination, those Abs are neither necessary nor sufficient to cause EAE. Knowledge regarding the spectrum of MOGAD clinical and radiologic presentations is advancing rapidly, yet our grasp of MOGAD pathogenesis is incomplete. Understanding both the humoral and cellular immunology of MOGAD has implications for diagnosis, treatment, and prognosis.
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- 2024
3. Fam49b dampens TCR signal strength to regulate survival of positively selected thymocytes and peripheral T cells.
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Park, Chan-Su, Guan, Jian, Rhee, Peter, Gonzalez, Federico, Lee, Hee-Sung, Park, Ji-Hyun, Coscoy, Laurent, Robey, Ellen, Shastri, Nilabh, and Sadegh-Nasseri, Scheherazade
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Fam49b ,Rac ,T cell development ,cytoskeleton remodeling ,immunology ,inflammation ,intraepithelial T cells ,mouse ,negative selection ,Animals ,Mice ,Cell Survival ,Mice ,Knockout ,Receptors ,Antigen ,T-Cell ,Signal Transduction ,T-Lymphocytes ,Thymocytes - Abstract
The fate of developing T cells is determined by the strength of T cell receptor (TCR) signal they receive in the thymus. This process is finely regulated through the tuning of positive and negative regulators in thymocytes. The Family with sequence similarity 49 member B (Fam49b) protein is a newly discovered negative regulator of TCR signaling that has been shown to suppress Rac-1 activity in vitro in cultured T cell lines. However, the contribution of Fam49b to the thymic development of T cells is unknown. To investigate this important issue, we generated a novel mouse line deficient in Fam49b (Fam49b-KO). We observed that Fam49b-KO double positive (DP) thymocytes underwent excessive negative selection, whereas the positive selection stage was unaffected. Fam49b deficiency impaired the survival of single positive thymocytes and peripheral T cells. This altered development process resulted in significant reductions in CD4 and CD8 single-positive thymocytes as well as peripheral T cells. Interestingly, a large proportion of the TCRγδ+ and CD8αα+TCRαβ+ gut intraepithelial T lymphocytes were absent in Fam49b-KO mice. Our results demonstrate that Fam49b dampens thymocytes TCR signaling in order to escape negative selection during development, uncovering the function of Fam49b as a critical regulator of the selection process to ensure normal thymocyte development and peripheral T cells survival.
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- 2024
4. Role of LECT2 in exacerbating atopic dermatitis: insight from in vivo and in vitro models via NF-κB signaling pathway
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Liu, Zhifang, Jiang, Xinyu, Zhao, Keyu, Ruan, Hongyu, Ma, Yizhao, Ma, Yuhan, Zhou, Qiongyan, Zhang, Jing, Sun, Xiaoyan, Ma, Wenxue, and Xu, Suling
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Biochemistry and Cell Biology ,Biomedical and Clinical Sciences ,Biological Sciences ,Eczema / Atopic Dermatitis ,Brain Disorders ,2.1 Biological and endogenous factors ,1.1 Normal biological development and functioning ,Inflammatory and immune system ,Immunology ,Medical Microbiology ,Biochemistry and cell biology ,Genetics - Abstract
Leukocyte cell-derived chemotaxin 2 (LECT2) is linked to various immune diseases. Previously, we reported that serum LECT2 levels correlate with disease severity in atopic dermatitis (AD) patients. To investigate the role of LECT2 in AD and elucidate its potential mechanisms, we used LECT2 to treat an AD mouse model induced by 1-Chloro-2,4-dinitrobenzene (DNCB) in LECT2 knockout (KO) and wild-type (WT) mice, and an AD cell model using TNF-α/IFN-γ-induced HaCaT cells. Inflammatory factors and barrier proteins were analyzed by histology, immunohistochemistry, RT-qPCR, ELISA, and Western Blot. Activation of the NF-κB signaling pathway was evaluated by Western Blot and immunofluorescence. In the AD mouse model, LECT2 treatment increased epidermal and dermal thickness, mast cell infiltration, and downregulated barrier proteins. Inflammatory factors were increased in skin lesions and serum. In the AD cell model, LECT2 decreased barrier protein levels and increased inflammatory factor levels, enhancing NF-κB P65 nuclear translocation. These results indicate that LECT2 exacerbates AD-like responses by dysregulating the NF-κB signaling pathway, highlighting its potential as a therapeutic target for AD management.
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- 2024
5. Five decades of natural killer cell discovery
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Lanier, Lewis L
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Biomedical and Clinical Sciences ,Immunology ,Cancer ,Biodefense ,Infectious Diseases ,Emerging Infectious Diseases ,2.1 Biological and endogenous factors ,Aetiology ,Inflammatory and immune system ,Killer Cells ,Natural ,Animals ,Humans ,History ,20th Century ,Mice ,History ,21st Century ,Neoplasms ,Rats ,Medical and Health Sciences ,Biomedical and clinical sciences ,Health sciences - Abstract
The first descriptions of "non-specific" killing of tumor cells by lymphocytes were reported in 1973, and subsequently, the mediators of the activity were named "natural killer" (NK) cells by Rolf Kiessling and colleagues at the Karolinska Institute in 1975. The activity was detected in mice, rats, and humans that had no prior exposure to the tumors, major histocompatibility complex (MHC) antigen matching of the effectors and tumor cells was not required, and the cells responsible were distinct from MHC-restricted, antigen-specific T cells. In the ensuing five decades, research by many labs has extended knowledge of NK cells beyond an in vitro curiosity to demonstrate their in vivo relevance in host defense against tumors and microbial pathogens and their role in regulation of the immune system. This brief Perspective highlights a timeline of a few selected advancements in NK cell biology from a personal perspective of being involved in this quest.
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- 2024
6. Immediate myeloid depot for SARS-CoV-2 in the human lung
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Magnen, Mélia, You, Ran, Rao, Arjun A, Davis, Ryan T, Rodriguez, Lauren, Bernard, Olivier, Simoneau, Camille R, Hysenaj, Lisiena, Hu, Kenneth H, Maishan, Mazharul, Conrad, Catharina, Gbenedio, Oghenekevwe M, Samad, Bushra, Consortium, The Ucsf Comet, Love, Christina, Woodruff, Prescott G, Erle, David J, Hendrickson, Carolyn M, Calfee, Carolyn S, Matthay, Michael A, Roose, Jeroen P, Sil, Anita, Ott, Melanie, Langelier, Charles R, Krummel, Matthew F, and Looney, Mark R
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Medical Microbiology ,Biomedical and Clinical Sciences ,Immunology ,Lung ,Emerging Infectious Diseases ,Pneumonia & Influenza ,Biodefense ,Infectious Diseases ,Coronaviruses ,2.2 Factors relating to the physical environment ,Respiratory ,Infection ,Humans ,SARS-CoV-2 ,COVID-19 ,Angiotensin-Converting Enzyme 2 ,Macrophages ,Alveolar ,Myeloid Cells ,Virus Internalization ,Spike Glycoprotein ,Coronavirus ,Viral Tropism - Abstract
In the pathogenesis of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection, epithelial populations in the distal lung expressing Angiotensin-converting enzyme 2 (ACE2) are infrequent, and therefore, the model of viral expansion and immune cell engagement remains incompletely understood. Using human lungs to investigate early host-viral pathogenesis, we found that SARS-CoV-2 had a rapid and specific tropism for myeloid populations. Human alveolar macrophages (AMs) reliably expressed ACE2 allowing both spike-ACE2-dependent viral entry and infection. In contrast to Influenza A virus, SARS-CoV-2 infection of AMs was productive, amplifying viral titers. While AMs generated new viruses, the interferon responses to SARS-CoV-2 were muted, hiding the viral dissemination from specific antiviral immune responses. The reliable and veiled viral depot in myeloid cells in the very early phases of SARS-CoV-2 infection of human lungs enables viral expansion in the distal lung and potentially licenses subsequent immune pathologies.
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- 2024
7. Sex differences in the transcriptional response to acute inflammatory challenge: A randomized controlled trial of endotoxin
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Boyle, Chloe C, Cole, Steve W, Eisenberger, Naomi I, Olmstead, Richard, Breen, Elizabeth C, and Irwin, Michael R
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Biomedical and Clinical Sciences ,Clinical Sciences ,Genetics ,Women's Health ,Mental Health ,Neurosciences ,Clinical Research ,2.1 Biological and endogenous factors ,6.1 Pharmaceuticals ,Inflammatory and immune system ,Clinical sciences ,Immunology - Abstract
Background: Sex differences in immune-based disorders are well-established, with female sex associated with a markedly heightened risk of autoimmune disease. Female sex is also overrepresented in other conditions associated with elevated inflammation, including depression, chronic pain, and chronic fatigue. The mechanisms underlying these disparities are unclear. This study used an experimental model of inflammatory challenge to interrogate molecular mechanisms that may contribute to female vulnerability to disorders with an inflammatory basis. Method: In this analysis of a secondary outcome from a randomized controlled trial, 111 participants (67 female) received either a bolus injection of endotoxin (n = 59) or placebo (n = 52). Participants provided blood samples before and 0.5 h post-injection for assessment of differential activation of key pro-inflammatory (i.e., activator protein (AP)-1; nuclear factor (NF)-κB) and immunoregulatory (i.e., glucocorticoid receptor (GR); cAMP response element binding protein (CREB)) signaling pathways via genome-wide expression profiling and promoter-based bioinformatics analyses. Results: Relative to males, females exhibited greater endotoxin-induced increases in bioinformatic measures of CREB transcription factor activity (p's < 0.01). However, contrary to hypotheses, female vs. male sex was not associated with greater increases in activation of NF-κB, AP-1, or GR in response to endotoxin vs. placebo administration. Conclusions: This work suggests CREB signaling as a critical upstream biological pathway that should be further interrogated as a mechanism of female vulnerability to immune-related disorders. Future work should clarify whether increased CREB signaling indicates sex differences in activity of the sympathetic nervous system or other physiological pathways that signal through CREB, such as prostaglandin release.
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- 2024
8. Interferon-signaling pathways are upregulated in people with HIV with abnormal pulmonary diffusing capacity (DLCO)
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Zhang, Michelle, Dai, Guorui, Smith, Dana L, Zacco, Emanuela, Shimoda, Michiko, Kumar, Nitasha, Girling, Valerie, Gardner, Kendall, Hunt, Peter W, Huang, Laurence, and Lin, Jue
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Biomedical and Clinical Sciences ,Immunology ,Infectious Diseases ,Lung ,Sexually Transmitted Infections ,HIV/AIDS ,Genetics ,2.1 Biological and endogenous factors ,Good Health and Well Being ,Humans ,HIV Infections ,Cross-Sectional Studies ,Signal Transduction ,Male ,Pulmonary Diffusing Capacity ,Female ,Interferons ,Middle Aged ,Adult ,Pilot Projects ,Up-Regulation ,Gene Expression Profiling ,diffusing capacity ,HIV ,inflammation ,interferon ,lung ,Biological Sciences ,Medical and Health Sciences ,Psychology and Cognitive Sciences ,Virology ,Biomedical and clinical sciences ,Health sciences - Abstract
ObjectivePeople with HIV (PWH) are at greater risk of developing lung diseases even when they are antiretroviral therapy (ART)-adherent and virally suppressed. The most common pulmonary function abnormality in PWH is that of impaired diffusing capacity of the lungs for carbon monoxide (DL CO ), which is an independent risk factor for increased mortality in PWH. Earlier work has identified several plasma biomarkers of inflammation and immune activation to be associated with decreased DL CO . However, the underpinning molecular mechanisms of HIV-associated impaired DL CO are largely unknown.DesignCross-sectional pilot study with PWH with normal DL CO (values greater than or equal to the lower limit of normal, DL CO ≥ LLN, N = 9) or abnormal DL CO (DL CO
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- 2024
9. Transient PU.1 low fetal progenitors generate lymphoid progeny that contribute to adult immunity
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Montecino-Rodriguez, Encarnacion, Estrada, Oscar I, and Dorshkind, Kenneth
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Biomedical and Clinical Sciences ,Immunology ,Stem Cell Research - Nonembryonic - Non-Human ,Regenerative Medicine ,Stem Cell Research ,1.1 Normal biological development and functioning ,Underpinning research ,Generic health relevance ,Inflammatory and immune system ,Trans-Activators ,Animals ,Proto-Oncogene Proteins ,Mice ,B-Lymphocytes ,T-Lymphocytes ,Mice ,Inbred C57BL ,Hematopoietic Stem Cells ,Cell Differentiation ,Female ,Fetus ,Fetal Stem Cells ,Biological sciences ,Biomedical and clinical sciences - Abstract
Hematopoietic stem cells and multipotential progenitors emerge in multiple, overlapping waves of fetal development. Some of these populations seed the bone marrow and sustain adult B- and T-cell development long-term after birth. However, others are present transiently, but whether they are vestigial or generate B and T cells that contribute to the adult immune system is not well understood. We now report that transient fetal progenitors distinguished by expression of low levels of the PU.1 transcription factor generated activated and memory T and B cells that colonized and were maintained in secondary lymphoid tissues. These included the small and large intestines, where they may contribute to the maintenance of gut homeostasis through at least middle age. At least some of the activated/memory cells may have been the progeny of B-1 and marginal zone B cells, as transient PU.1low fetal progenitors efficiently generated those populations. Taken together, our data demonstrate the potential of B- and T-cell progeny of transient PU.1low fetal progenitors to make an early and long-term contribution to the adult immune system.
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- 2024
10. Hepatocellular carcinoma after direct‐acting antivirals for hepatitis C is associated with KIR‐HLA types predicting weak NK cell‐mediated immunity
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Ryan, James C, Haight, Christina, Niemi, Erene C, Grab, Joshua D, Dodge, Jennifer L, Lanier, Lewis L, and Monto, Alexander
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Biomedical and Clinical Sciences ,Oncology and Carcinogenesis ,Immunology ,Liver Disease ,Hepatitis - C ,Digestive Diseases ,Liver Cancer ,Emerging Infectious Diseases ,Cancer ,Rare Diseases ,Hepatitis ,Infectious Diseases ,Chronic Liver Disease and Cirrhosis ,6.1 Pharmaceuticals ,Good Health and Well Being ,Humans ,Carcinoma ,Hepatocellular ,Liver Neoplasms ,Killer Cells ,Natural ,Male ,Antiviral Agents ,Female ,Middle Aged ,Receptors ,KIR ,Aged ,Hepacivirus ,Hepatitis C ,HLA Antigens ,Adult ,Immunity ,Cellular ,Follow-Up Studies ,Hepatitis C ,Chronic ,Carcinoma ,Hepatocellular ,Immunity ,Innate ,Killer Cells ,Natural - Abstract
Background and aimsSecond-generation direct-acting antivirals (2G DAA) to cure HCV have led to dramatic clinical improvements. HCV-associated hepatocellular carcinoma (HCC), however, remains common. Impaired immune tumor surveillance may play a role in HCC development. Our cohort evaluated the effects of innate immune types and clinical variables on outcomes including HCC.MethodsParticipants underwent full HLA class I/KIR typing and long-term HCV follow-up.ResultsA total of 353 HCV+ participants were followed for a mean of 7 years. Cirrhosis: 25% at baseline, developed in 12% during follow-up. 158 participants received 2G DAA therapy. HCC developed without HCV therapy in 20 subjects, 24 HCC after HCV therapy, and 10 of these after 2G DAA. Two predictors of HCC among 2G DAA-treated patients: cirrhosis (OR, 10.0, p = 0.002) and HLA/KIR profiles predicting weak natural killer (NK) cell-mediated immunity (NK cell complementation groups 6, 9, 11, 12, OR of 5.1, p = 0.02). Without 2G DAA therapy: cirrhosis was the main clinical predictor of HCC (OR, 30.8, p < 0.0001), and weak NK-cell-mediated immunity did not predict HCC.ConclusionCirrhosis is the main risk state predisposing to HCC, but weak NK-cell-mediated immunity may predispose to post-2G DAA HCC more than intermediate or strong NK-cell-mediated immunity.
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- 2024
11. γδ T cells as critical anti-tumor immune effectors
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Arias-Badia, Marcel, Chang, Ryan, and Fong, Lawrence
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Biomedical and Clinical Sciences ,Oncology and Carcinogenesis ,Immunology ,Immunotherapy ,Cancer ,1.1 Normal biological development and functioning ,2.1 Biological and endogenous factors ,Infection ,Inflammatory and immune system ,Oncology and carcinogenesis - Abstract
While the effector cells that mediate anti-tumor immunity have historically been attributed to αβ T cells and natural killer cells, γδ T cells are now being recognized as a complementary mechanism mediating tumor rejection. γδ T cells possess a host of functions ranging from antigen presentation to regulatory function and, importantly, have critical roles in eliciting anti-tumor responses where other immune effectors may be rendered ineffective. Recent discoveries have elucidated how these differing functions are mediated by γδ T cells with specific T cell receptors and spatial distribution. Their relative resistance to mechanisms of dysfunction like T cell exhaustion has spurred the development of therapeutic approaches exploiting γδ T cells, and an improved understanding of these cells should enable more effective immunotherapies.
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- 2024
12. The CCL2-CCR4 axis promotes Regulatory T cell trafficking to canine glioma tissues
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Panek, WK, Toedebusch, RG, Mclaughlin, BE, Dickinson, PJ, Van Dyke, JE, Woolard, KD, Berens, ME, Lesniak, MS, Sturges, BK, Vernau, KM, Li, C, Miska, J, and Toedebusch, Christine M
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Biomedical and Clinical Sciences ,Oncology and Carcinogenesis ,Immunology ,Brain Cancer ,Rare Diseases ,Immunotherapy ,Neurosciences ,Cancer ,Brain Disorders ,2.1 Biological and endogenous factors ,Dog ,Glioblastoma ,Tumor-infiltrating lymphocyte ,CCL2 ,CCR4 ,Cell Line ,Tumor ,Animals ,Dogs ,Humans ,Glioma ,Brain Neoplasms ,Cell Movement ,T-Lymphocytes ,Regulatory ,Chemokine CCL2 ,Receptors ,CCR4 ,Oncology & Carcinogenesis ,Oncology and carcinogenesis - Abstract
PurposeSpontaneously occurring glioma in pet dogs is increasingly recognized as a valuable translational model for human glioblastoma. Canine high-grade glioma and human glioblastomas share many molecular similarities, including the accumulation of immunosuppressive regulatory T cells (Tregs) that inhibit anti-tumor immune responses. Identifying in dog mechanisms responsible for Treg recruitment may afford to target the cellular population driving immunosuppression, the results providing a rationale for translational clinical studies in human patients. Our group has previously identified C-C motif chemokine 2 (CCL2) as a glioma-derived T-reg chemoattractant acting on chemokine receptor 4 (CCR4) in a murine orthotopic glioma model. Recently, we demonstrated a robust increase of CCL2 in the brain tissue of canine patients bearing high-grade glioma.MethodsWe performed a series of in vitro experiments using canine Tregs and patient-derived canine glioma cell lines (GSC 1110, GSC 0514, J3T-Bg, G06A) to interrogate the CCL2-CCR4 signaling axis in the canine.ResultsWe established a flow cytometry gating strategy for identifying and isolating FOXP3+ Tregs in dogs. The canine CD4 + CD25high T-cell population was highly enriched in FOXP3 and CCR4 expression, indicating they are bona fide Tregs. Canine Treg migration was enhanced by CCL2 or by glioma cell line-derived supernatant. Blockade of the CCL2-CCR4 axis significantly reduced migration of canine Tregs. CCL2 mRNA was expressed in all glioma cell lines, and expression increased when exposed to Tregs but not CD4 + helper T-cells.ConclusionOur study validates CCL2-CCR4 as a bi-directional Treg-glioma immunosuppressive and tumor-promoting axis in canine high-grade glioma.
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- 2024
13. Differential susceptibility of cells infected with defective and intact HIV proviruses to killing by obatoclax and other small molecules
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Kadiyala, Gayatri Nikhila, Telwatte, Sushama, Wedrychowski, Adam, Janssens, Julie, Kim, Sun Jin, Kim, Peggy, Deeks, Steven, Wong, Joseph K, and Yukl, Steven A
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Medical Microbiology ,Biomedical and Clinical Sciences ,Immunology ,HIV/AIDS ,Infectious Diseases ,Sexually Transmitted Infections ,Genetics ,5.1 Pharmaceuticals ,6.1 Pharmaceuticals ,Infection ,Humans ,Indoles ,HIV Infections ,Pyrroles ,Leukocytes ,Mononuclear ,Proviruses ,apoptosis ,Bcl-2 ,DNA ,HIV ,IAP ,interferon ,mTOR ,PD-1 ,proteasome ,RIG-I ,TLR7 ,Biological Sciences ,Medical and Health Sciences ,Psychology and Cognitive Sciences ,Virology ,Biomedical and clinical sciences ,Health sciences - Abstract
ObjectivesSome drugs that augment cell-intrinsic defenses or modulate cell death/survival pathways have been reported to selectively kill cells infected with HIV or Simian Immunodeficiency Virus (SIV), but comparative studies are lacking. We hypothesized that these drugs may differ in their ability to kill cells infected with intact and defective proviruses.DesignTo investigate this hypothesis, drugs were tested ex vivo on peripheral blood mononuclear cells (PBMC) from nine antiretroviral therapy (ART)-suppressed individuals.MethodsWe tested drugs currently in clinical use or human trials, including auranofin (p53 modulator), interferon alpha2A, interferon gamma, acitretin (RIG-I inducer), GS-9620/vesatolimod (TLR7 agonist), nivolumab (PD-1 blocker), obatoclax (Bcl-2 inhibitor), birinapant [inhibitor of apoptosis proteins (IAP) inhibitor], bortezomib (proteasome inhibitor), and INK128/sapanisertib [mammalian target of rapamycin mTOR] [c]1/2 inhibitor). After 6 days of treatment, we measured cell counts/viabilities and quantified levels of total, intact, and defective HIV DNA by droplet digital PCR (Intact Proviral DNA Assay).ResultsObatoclax reduced intact HIV DNA [median = 27-30% of dimethyl sulfoxide control (DMSO)] but not defective or total HIV DNA. Other drugs showed no statistically significant effects.ConclusionObatoclax and other Bcl-2 inhibitors deserve further study in combination therapies aimed at reducing the intact HIV reservoir in order to achieve a functional cure and/or reduce HIV-associated immune activation.
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- 2024
14. Curating Genetic Associations with Rheumatologic Autoimmune Diseases to Improve Patient Outcomes
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Bridges, S Louis, Shapira, Rachel, Aksentijevich, Ivona, Mack, Steven J, Merriman, Tony R, Klein, Clarissa J, Bowen, B Monica, Klein, Teri E, and ., the ClinGen Rheumatologic Autoimmune Disease Clinical Domain Working Group
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Biomedical and Clinical Sciences ,Clinical Sciences ,Immunology ,ClinGen Rheumatologic Autoimmune Disease Clinical Domain Working Group (see Appendix). - Published
- 2024
15. The identification of intact HIV proviral DNA from human cerebrospinal fluid
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Zhang, Zhan, Reece, Monica D, Roa, Sebastian, Tyor, William, Franklin, Donald R, Letendre, Scott L, Marconi, Vincent C, Anderson, Albert M, and Gavegnano, Christina
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Medical Microbiology ,Biomedical and Clinical Sciences ,Immunology ,Mental Health ,HIV/AIDS ,Neurosciences ,Infectious Diseases ,Clinical Research ,Sexually Transmitted Infections ,Infection ,Central nervous system ,Cerebrospinal fluid ,HIV ,Inflammation ,Reservoir ,Pharmacology and Pharmaceutical Sciences ,Public Health and Health Services ,Neurology & Neurosurgery ,Pharmacology and pharmaceutical sciences ,Biological psychology - Abstract
We evaluated the HIV-1 DNA reservoir in peripheral blood mononuclear cells (PBMC) and cerebrospinal fluid (CSF) in people with HIV (PWH) and associations to cognitive dysfunction. Using the intact proviral DNA assay (IPDA), an emerging technique to identify provirus that may be the source of viral rebound, we assessed HIV DNA in CSF and PBMC in PWH regardless of antiretroviral therapy (ART). CSF was used as a sampling surrogate for the central nervous system (CNS) as opposed to tissue. IDPA results (3' defective, 5' defective, and intact HIV DNA) were analyzed by compartment (Wilcoxon signed rank; matched and unmatched pairs). Cognitive performance, measured via a battery of nine neuropsychological (NP) tests, were analyzed for correlation to HIV DNA (Spearman's rho). 11 CSF and 8 PBMC samples from PWH were evaluated both unmatched and matched. Total CSF HIV DNA was detectable in all participants and was significantly higher than in matched PBMCs (p = 0.0039). Intact CSF HIV DNA was detected in 7/11 participants and correlated closely with those in PBMCs but tended to be higher in CSF than in PBMC. CSF HIV DNA did not correlate with global NP performance, but higher values did correlate with worse executive function (p = 0.0440). Intact HIV DNA is frequently present in the CSF of PWH regardless of ART. This further supports the presence of an HIV CNS reservoir and provides a method to study CNS reservoirs during HIV cure studies. Larger studies are needed to evaluate relationships with CNS clinical outcomes.
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- 2024
16. Epigenetic Induction of Cancer-Testis Antigens and Endogenous Retroviruses at Single-Cell Level Enhances Immune Recognition and Response in Glioma
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Lai, Thomas J, Sun, Lu, Li, Kevin, Prins, Terry J, Treger, Janet, Li, Tie, Sun, Matthew Z, Nathanson, David A, Liau, Linda M, Lai, Albert, Prins, Robert M, and Everson, Richard G
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Biomedical and Clinical Sciences ,Oncology and Carcinogenesis ,Immunology ,Human Genome ,Rare Diseases ,Clinical Research ,Brain Cancer ,Neurosciences ,Brain Disorders ,Cancer ,Orphan Drug ,Genetics ,Cancer Genomics ,2.1 Biological and endogenous factors ,Humans ,Antigens ,Neoplasm ,Epigenesis ,Genetic ,Decitabine ,Glioma ,Endogenous Retroviruses ,Brain Neoplasms ,DNA Methylation ,Cell Line ,Tumor ,Single-Cell Analysis ,Gene Expression Regulation ,Neoplastic ,Membrane Proteins ,Promoter Regions ,Genetic ,Glioblastoma - Abstract
Glioblastoma (GBM) is the most common malignant primary brain tumor and remains incurable. Previous work has shown that systemic administration of Decitabine (DAC) induces sufficient expression of cancer-testis antigens (CTA) in GBM for targeting by adoptive T-cell therapy in vivo. However, the mechanisms by which DAC enhances immunogenicity in GBM remain to be elucidated. Using New York esophageal squamous cell carcinoma 1 (NY-ESO-1) as a representative inducible CTA, we demonstrate in patient tissue, immortalized glioma cells, and primary patient-derived gliomaspheres that basal CTA expression is restricted by promoter hypermethylation in gliomas. DAC treatment of glioma cells specifically inhibits DNA methylation silencing to render NY-ESO-1 and other CTA into inducible tumor antigens at single-cell resolution. Functionally, NY-ESO-1 T-cell receptor-engineered effector cell targeting of DAC-induced antigen in primary glioma cells promotes specific and polyfunctional T-cell cytokine profiles. In addition to induction of CTA, DAC concomitantly reactivates tumor-intrinsic human endogenous retroviruses, interferon response signatures, and MHC-I. Overall, we demonstrate that DAC induces targetable tumor antigen and enhances T-cell functionality against GBM, ultimately contributing to the improvement of targeted immune therapies in glioma.SignificanceThis study dissects the tumor-intrinsic epigenetic and transcriptional mechanisms underlying enhanced T-cell functionality targeting decitabine-induced cancer-testis antigens in glioma. Our findings demonstrate concomitant induction of tumor antigens, reactivation of human endogenous retroviruses, and stimulation of interferon signaling as a mechanistic rationale to epigenetically prime human gliomas to immunotherapeutic targeting.
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- 2024
17. Risk Prediction for Clonal Cytopenia: Multicenter Real-World Evidence.
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Xie, Zhuoer, Komrokji, Rami S, Al-Ali, Najla, Regelson, Alexandra, Geyer, Susan, Patel, Anand A, Saygin, Caner, Zeidan, Amer M, Bewersdorf, Jan Philipp, Mendez, Lourdes M, Kishtagari, Ashwin, Zeidner, Joshua F, Coombs, Catherine C, Madanat, Yazan F, Chung, Stephen S, Badar, Talha, Foran, James M, Desai, Pinkal, Tsai, Charlton, Griffiths, Elizabeth A, Al Malki, Monzr M, Amanam, Idoroenyi, Lai, Catherine, Deeg, H Joachim, Ades, Lionel, Arana-Yi, Cecilia, Osman, Afaf Eg, Dinner, Shira Naomi, Abaza, Yasmin, Taylor, Justin, Chandhok, Namrata S, Soong, Deborah, Brunner, Andrew M, Carraway, Hetty E, Singh, Abhay, Elena, Chiara, Ferrari, Jacqueline, Galli, Anna, Pozzi, Sara, Padron, Eric, Patnaik, Mrinal M, Malcovati, Luca, Savona, Michael R, and Al-Kali, Aref
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Cardiorespiratory Medicine and Haematology ,Clinical Sciences ,Paediatrics and Reproductive Medicine ,Immunology ,Biochemistry and cell biology ,Cardiovascular medicine and haematology ,Paediatrics - Abstract
Clonal cytopenia of undetermined significance (CCUS) represents a distinct disease entity characterized by myeloid-related somatic mutations with a variant allele fraction of ≥2% in individuals with unexplained cytopenia(s) but without a myeloid neoplasm (MN). Notably, CCUS carries a risk of progressing to MN, particularly in cases featuring high-risk mutations. Understanding CCUS requires dedicated studies to elucidate its risk factors and natural history. Our analysis of 357 CCUS patients investigated the interplay between clonality, cytopenia, and prognosis. Multivariate analysis identified 3 key adverse prognostic factors: the presence of splicing mutation(s) (score = 2 points), platelet count
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- 2024
18. Expansion of highly interferon‐responsive T cells in early‐onset Alzheimer's disease
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Sirkis, Daniel W, Solsberg, Caroline Warly, Johnson, Taylor P, Bonham, Luke W, Oddi, Alexis P, Geier, Ethan G, Miller, Bruce L, Rabinovici, Gil D, and Yokoyama, Jennifer S
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Biomedical and Clinical Sciences ,Immunology ,Alzheimer's Disease including Alzheimer's Disease Related Dementias (AD/ADRD) ,Dementia ,Acquired Cognitive Impairment ,Aging ,Brain Disorders ,Genetics ,Neurodegenerative ,Alzheimer's Disease ,Human Genome ,Neurosciences ,2.1 Biological and endogenous factors ,Neurological ,Good Health and Well Being ,Humans ,Alzheimer Disease ,Female ,Male ,Interferons ,Middle Aged ,CD4-Positive T-Lymphocytes ,Leukocytes ,Mononuclear ,Aged ,Alzheimer's disease ,CD4 T cells ,cerebrospinal fluid ,droplet digital PCR ,early-onset Alzheimer's disease ,interferon ,interferon signaling-associated gene ,peripheral blood mononuclear cells ,single-cell RNA-sequencing ,T cells ,tauopathy ,early‐onset Alzheimer's disease ,interferon signaling‐associated gene ,single‐cell RNA‐sequencing ,Clinical Sciences ,Geriatrics ,Clinical sciences ,Biological psychology - Abstract
IntroductionAltered immune signatures are emerging as a central theme in neurodegenerative disease, yet little is known about immune responses in early-onset Alzheimer's disease (EOAD).MethodsWe examined single-cell RNA-sequencing (scRNA-seq) data from peripheral blood mononuclear cells (PBMCs) and droplet digital polymerase chain reaction (ddPCR) data from CD4 T cells from participants with EOAD and clinically normal controls.ResultsWe analyzed PBMCs from 16 individuals by scRNA-seq and discovered increased interferon signaling-associated gene (ISAG) expression and striking expansion of antiviral-like ISAGhi T cells in EOAD. Isolating CD4 T cells from 19 individuals, including four cases analyzed by scRNA-seq, we confirmed increased expression of ISAGhi marker genes. Publicly available cerebrospinal fluid leukocyte scRNA-seq data from late-onset mild cognitive impairment and AD also revealed increased expression of interferon-response genes.DiscussionAntiviral-like ISAGhi T cells are expanded in EOAD. Additional research into these cells and the role of heightened peripheral IFN signaling in neurodegeneration is warranted.HighlightsInterferon-responsive T cells expanded in early-onset Alzheimer's disease (AD). Increased interferon-associated gene expression present in early- and late-onset AD. Peripheral immune changes in T and NK cells driven by females with early-onset AD.
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- 2024
19. Circadian control of tumor immunosuppression affects efficacy of immune checkpoint blockade
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Fortin, Bridget M, Pfeiffer, Shannon M, Insua-Rodríguez, Jacob, Alshetaiwi, Hamad, Moshensky, Alexander, Song, Wei A, Mahieu, Alisa L, Chun, Sung Kook, Lewis, Amber N, Hsu, Alex, Adam, Isam, Eng, Oliver S, Pannunzio, Nicholas R, Seldin, Marcus M, Marazzi, Ivan, Marangoni, Francesco, Lawson, Devon A, Kessenbrock, Kai, and Masri, Selma
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Biomedical and Clinical Sciences ,Oncology and Carcinogenesis ,Immunology ,Genetics ,Cancer ,Immunotherapy ,Colo-Rectal Cancer ,Sleep Research ,Digestive Diseases ,Aetiology ,2.1 Biological and endogenous factors ,Inflammatory and immune system ,Animals ,Mice ,Immune Checkpoint Inhibitors ,Myeloid-Derived Suppressor Cells ,Circadian Clocks ,B7-H1 Antigen ,Mice ,Inbred C57BL ,Circadian Rhythm ,CD8-Positive T-Lymphocytes ,Colorectal Neoplasms ,Tumor Microenvironment ,Immune Tolerance ,Humans ,Female ,Cell Line ,Tumor ,Single-Cell Analysis ,Immunosuppression Therapy ,Cytokines ,Male ,Biochemistry and cell biology - Abstract
The circadian clock is a critical regulator of immunity, and this circadian control of immune modulation has an essential function in host defense and tumor immunosurveillance. Here we use a single-cell RNA sequencing approach and a genetic model of colorectal cancer to identify clock-dependent changes to the immune landscape that control the abundance of immunosuppressive cells and consequent suppression of cytotoxic CD8+ T cells. Of these immunosuppressive cell types, PD-L1-expressing myeloid-derived suppressor cells (MDSCs) peak in abundance in a rhythmic manner. Disruption of the epithelial cell clock regulates the secretion of cytokines that promote heightened inflammation, recruitment of neutrophils and the subsequent development of MDSCs. We also show that time-of-day anti-PD-L1 delivery is most effective when synchronized with the abundance of immunosuppressive MDSCs. Collectively, these data indicate that circadian gating of tumor immunosuppression informs the timing and efficacy of immune checkpoint inhibitors.
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- 2024
20. Gene expression and chromatin conformation of microglia in virally suppressed people with HIV
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Schlachetzki, Johannes CM, Gianella, Sara, Ouyang, Zhengyu, Lana, Addison J, Yang, Xiaoxu, O’Brien, Sydney, Challacombe, Jean F, Gaskill, Peter J, Jordan-Sciutto, Kelly L, Chaillon, Antoine, Moore, David, Achim, Cristian L, Ellis, Ronald J, Smith, Davey M, and Glass, Christopher K
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Medical Microbiology ,Biomedical and Clinical Sciences ,Immunology ,Sexually Transmitted Infections ,HIV/AIDS ,Neurosciences ,Genetics ,Infectious Diseases ,2.1 Biological and endogenous factors ,Infection ,Microglia ,Humans ,HIV Infections ,Chromatin ,Male ,HIV-1 ,Virus Latency ,RNA ,Viral ,Brain ,Female ,Adult ,Middle Aged ,Gene Expression ,Viral Load ,Biological sciences ,Biomedical and clinical sciences - Abstract
The presence of HIV in sequestered reservoirs is a central impediment to a functional cure, allowing HIV to persist despite life-long antiretroviral therapy (ART), and driving a variety of comorbid conditions. Our understanding of the latent HIV reservoir in the central nervous system is incomplete, because of difficulties in accessing human central nervous system tissues. Microglia contribute to HIV reservoirs, but the molecular phenotype of HIV-infected microglia is poorly understood. We leveraged the unique "Last Gift" rapid autopsy program, in which people with HIV are closely followed until days or even hours before death. Microglial populations were heterogeneous regarding their gene expression profiles but showed similar chromatin accessibility landscapes. Despite ART, we detected occasional microglia containing cell-associated HIV RNA and HIV DNA integrated into open regions of the host's genome (∼0.005%). Microglia with detectable HIV RNA showed an inflammatory phenotype. These results demonstrate a distinct myeloid cell reservoir in the brains of people with HIV despite suppressive ART. Strategies for curing HIV and neurocognitive impairment will need to consider the myeloid compartment to be successful.
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- 2024
21. Fusobacterium nucleatum subsp. nucleatum RadD binds Siglec-7 and inhibits NK cell-mediated cancer cell killing.
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Galaski, Johanna, Rishiq, Ahmed, Liu, Mingdong, Bsoul, Reem, Bergson, Almog, Lux, Renate, Bachrach, Gilad, and Mandelboim, Ofer
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cancer ,immunology ,microbiology ,molecular biology - Abstract
Fusobacterium nucleatum is an oral commensal bacterium that can colonize extraoral tumor entities, such as colorectal cancer and breast cancer. Recent studies revealed its ability to modulate the immune response in the tumor microenvironment (TME), promoting cancer progression and metastasis. Importantly, F. nucleatum subsp. animalis was shown to bind to Siglec-7 via lipopolysaccharides, leading to a pro-inflammatory profile in human monocyte-derived dendritic cells. In this study, we show that F. nucleatum subsp. nucleatum RadD binds to Siglec-7 on NK cells, thereby inhibiting NK cell-mediated cancer cell killing. We demonstrate that this binding is dependent on arginine residue R124 in Siglec-7. Finally, we determine that this binding is independent of the known interaction of RadD with IgA. Taken together, our findings elucidate the targeting of Siglec-7 by F. nucleatum subsp. nucleatum RadD as a means to modulate the NK cell response and potentially promoting immune evasion and tumor progression.
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- 2024
22. Protocol to study the immune profile of syngeneic mouse tumor models.
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Miyauchi, Sayuri, Arimoto, Kei-Ichiro, Liu, Mengdan, Zhang, Yue, and Zhang, Dong-Er
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cancer ,flow cytometry ,immunology ,single cell - Abstract
Flow cytometry, single-cell RNA sequencing, and other analyses enable us to capture immune profiles of the tumor microenvironment. Here, we present a protocol to characterize the immune profile of tumor-bearing mice. We describe steps for establishing mouse models and preparing single-cell suspensions from tumor tissue and other immune-related organs, which can be further analyzed by flow cytometry and other omics assays. We then detail procedures for staining, flow cytometry analysis, and phenotyping of the immune cell populations. For complete details on the use and execution of this protocol, please refer to Miyauchi et al.1.
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- 2024
23. A pathologically expanded, clonal lineage of IL-21-producing CD4+ T cells drives inflammatory neuropathy.
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Seyedsadr, Maryamsadat, Bang, Madison, McCarthy, Ethan, Zhang, Shirley, Chen, Ho-Chung, Mohebbi, Mahnia, Hugo, Willy, Whitmire, Jason, Lechner, Melissa, and Su, Maureen
- Subjects
Autoimmune diseases ,Autoimmunity ,Cytokines ,Immunology ,T cells ,Animals ,Mice ,Interleukins ,CD4-Positive T-Lymphocytes ,Cell Lineage ,Mice ,Knockout - Abstract
Inflammatory neuropathies, which include chronic inflammatory demyelinating polyneuropathy (CIDP) and Guillain Barré syndrome (GBS), result from autoimmune destruction of the PNS and are characterized by progressive weakness and sensory loss. CD4+ T cells play a key role in the autoimmune destruction of the PNS. Yet, key properties of pathogenic CD4+ T cells remain incompletely understood. Here, we used paired single-cell RNA-Seq (scRNA-Seq) and single-cell T cell receptor-sequencing (scTCR-Seq) of peripheral nerves from an inflammatory neuropathy mouse model to identify IL-21-expressing CD4+ T cells that were clonally expanded and multifunctional. These IL-21-expressing CD4+ T cells consisted of 2 transcriptionally distinct expanded cell populations, which expressed genes associated with T follicular helper (Tfh) and T peripheral helper (Tph) cell subsets. Remarkably, TCR clonotypes were shared between these 2 IL-21-expressing cell populations, suggesting a common lineage differentiation pathway. Finally, we demonstrated that IL-21 receptor-KO (IL-21R-KO) mice were protected from neuropathy development and had decreased immune infiltration into peripheral nerves. IL-21 signaling upregulated CXCR6, a chemokine receptor that promotes CD4+ T cell localization in peripheral nerves. Together, these findings point to IL-21 signaling, Tfh/Tph differentiation, and CXCR6-mediated cellular localization as potential therapeutic targets in inflammatory neuropathies.
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- 2024
24. Genomic insights into redox-driven microbial processes for carbon decomposition in thawing Arctic soils and permafrost.
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Li, Yaoming, Xue, Yaxin, Roy Chowdhury, Taniya, Graham, David E, Tringe, Susannah G, Jansson, Janet K, and Taş, Neslihan
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Microbiology ,Biological Sciences ,Climate Action ,soil microbiome ,soil metagenome ,permafrost microbiology ,metagenome-assembled genomes ,permafrost virus ,permafrost thaw ,anaerobic carbon mineralization ,iron reduction ,sulfate reduction ,methanogenesis ,Immunology - Abstract
Climate change is rapidly transforming Arctic landscapes where increasing soil temperatures speed up permafrost thaw. This exposes large carbon stocks to microbial decomposition, possibly worsening climate change by releasing more greenhouse gases. Understanding how microbes break down soil carbon, especially under the anaerobic conditions of thawing permafrost, is important to determine future changes. Here, we studied the microbial community dynamics and soil carbon decomposition potential in permafrost and active layer soils under anaerobic laboratory conditions that simulated an Arctic summer thaw. The microbial and viral compositions in the samples were analyzed based on metagenomes, metagenome-assembled genomes, and metagenomic viral contigs (mVCs). Following the thawing of permafrost, there was a notable shift in microbial community structure, with fermentative Firmicutes and Bacteroidota taking over from Actinobacteria and Proteobacteria over the 60-day incubation period. The increase in iron and sulfate-reducing microbes had a significant role in limiting methane production from thawed permafrost, underscoring the competition within microbial communities. We explored the growth strategies of microbial communities and found that slow growth was the major strategy in both the active layer and permafrost. Our findings challenge the assumption that fast-growing microbes mainly respond to environmental changes like permafrost thaw. Instead, they indicate a common strategy of slow growth among microbial communities, likely due to the thermodynamic constraints of soil substrates and electron acceptors, and the need for microbes to adjust to post-thaw conditions. The mVCs harbored a wide range of auxiliary metabolic genes that may support cell protection from ice formation in virus-infected cells.ImportanceAs the Arctic warms, thawing permafrost unlocks carbon, potentially accelerating climate change by releasing greenhouse gases. Our research delves into the underlying biogeochemical processes likely mediated by the soil microbial community in response to the wet and anaerobic conditions, akin to an Arctic summer thaw. We observed a significant shift in the microbial community post-thaw, with fermentative bacteria like Firmicutes and Bacteroidota taking over and switching to different fermentation pathways. The dominance of iron and sulfate-reducing bacteria likely constrained methane production in the thawing permafrost. Slow-growing microbes outweighed fast-growing ones, even after thaw, upending the expectation that rapid microbial responses to dominate after permafrost thaws. This research highlights the nuanced and complex interactions within Arctic soil microbial communities and underscores the challenges in predicting microbial response to environmental change.
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- 2024
25. Plasma membrane abundance dictates phagocytic capacity and functional cross-talk in myeloid cells
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Winer, Benjamin Y, Settle, Alexander H, Yakimov, Alexandrina M, Jeronimo, Carlos, Lazarov, Tomi, Tipping, Murray, Saoi, Michelle, Sawh, Anjelique, Sepp, Anna-Liisa L, Galiano, Michael, Perry, Justin SA, Wong, Yung Yu, Geissmann, Frederic, Cross, Justin, Zhou, Ting, Kam, Lance C, Pasolli, H Amalia, Hohl, Tobias, Cyster, Jason G, Weiner, Orion D, and Huse, Morgan
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Biomedical and Clinical Sciences ,Clinical Sciences ,Immunology ,Cancer ,2.1 Biological and endogenous factors ,Animals ,Phagocytosis ,Cell Membrane ,Mice ,Mice ,Knockout ,Myeloid Cells ,Mice ,Inbred C57BL ,Neutrophils ,Macrophages ,Clinical sciences - Abstract
Professional phagocytes like neutrophils and macrophages tightly control what they consume, how much they consume, and when they move after cargo uptake. We show that plasma membrane abundance is a key arbiter of these cellular behaviors. Neutrophils and macrophages lacking the G protein subunit Gβ4 exhibited profound plasma membrane expansion, accompanied by marked reduction in plasma membrane tension. These biophysical changes promoted the phagocytosis of bacteria, fungus, apoptotic corpses, and cancer cells. We also found that Gβ4-deficient neutrophils are defective in the normal inhibition of migration following cargo uptake. Sphingolipid synthesis played a central role in these phenotypes by driving plasma membrane accumulation in cells lacking Gβ4. In Gβ4 knockout mice, neutrophils not only exhibited enhanced phagocytosis of inhaled fungal conidia in the lung but also increased trafficking of engulfed pathogens to other organs. Together, these results reveal an unexpected, biophysical control mechanism central to myeloid functional decision-making.
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- 2024
26. Safety of Extended Pirtobrutinib Exposure in Relapsed and/or Refractory B-Cell Malignancies.
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Roeker, Lindsey E, Coombs, Catherine C, Shah, Nirav N, Jurczak, Wojciech, Woyach, Jennifer A, Cheah, Chan Y, Patel, Krish, Maddocks, Kami, Wang, Yucai, Zinzani, Pier Luigi, Munir, Talha, Koh, Youngil, Thompson, Meghan C, Muehlenbein, Catherine E, Wang, Chunxiao, Sizelove, Richard, Abhyankar, Sarang, Hasanabba, Safarulla, Tsai, Donald E, Eyre, Toby A, and Wang, Michael
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Biomedical and Clinical Sciences ,Clinical Sciences ,Oncology and Carcinogenesis ,Patient Safety ,Infectious Diseases ,Cancer ,Clinical Trials and Supportive Activities ,Rare Diseases ,Hematology ,Clinical Research ,Development of treatments and therapeutic interventions ,5.1 Pharmaceuticals ,Evaluation of treatments and therapeutic interventions ,6.1 Pharmaceuticals ,B-cell malignancies ,Bruton tyrosine kinase inhibitor ,Long-term safety ,Toxicity ,Cardiorespiratory Medicine and Haematology ,Immunology ,Cardiovascular medicine and haematology - Abstract
IntroductionPirtobrutinib, a highly selective, noncovalent (reversible) Bruton tyrosine kinase inhibitor, has demonstrated promising efficacy in B-cell malignancies and is associated with low rates of discontinuation and dose reduction. Pirtobrutinib is administered until disease progression or toxicity, necessitating an understanding of the safety profile in patients with extended treatment.MethodsHere we report the safety of pirtobrutinib in patients with relapsed/refractory B-cell malignancies with extended (≥12 months) drug exposure from the BRUIN trial. Assessments included median time-to-first-occurrence of adverse events (AEs), dose reductions, and discontinuations due to treatment-emergent AEs (TEAEs) and select AEs of interest (AESIs).ResultsOf 773 patients enrolled, 326 (42%) received treatment for ≥12 months. In the extended exposure cohort, the median time-on-treatment was 19 months. The most common all-cause TEAEs were fatigue (32%) and diarrhea (31%). TEAEs leading to dose reduction occurred in 23 (7%) and discontinuations in 11 (3%) extended exposure patients. One patient had a fatal treatment-related AE (COVID-19 pneumonia). Infections (73.0%) were the most common AESI with a median time-to-first-occurrence of 7.4 months. Majority of TEAEs and AESIs occurred during the first year of therapy.ConclusionsPirtobrutinib therapy continues to demonstrate an excellent safety profile amenable to long-term administration without evidence of new or worsening toxicity signals.
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- 2024
27. Autologous neutralizing antibody responses after antiretroviral therapy in acute and early HIV-1
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Whitehill, Gregory D, Joy, Jaimy, Marino, Francesco E, Krause, Ryan J, Mallick, Suvadip, Courtney, Hunter M, Park, Kyewon, Carey, John W, Hoh, Rebecca, Hartig, Heather, Pae, Vivian, Sarvadhavabhatla, Sannidhi, Donaire, Maria Sophia B, Deeks, Steven G, Lynch, Rebecca M, Lee, Sulggi A, and Bar, Katharine J
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Medical Microbiology ,Biomedical and Clinical Sciences ,Immunology ,Prevention ,Infectious Diseases ,Sexually Transmitted Infections ,Clinical Trials and Supportive Activities ,HIV/AIDS ,Biotechnology ,Clinical Research ,Aetiology ,2.2 Factors relating to the physical environment ,Infection ,Good Health and Well Being ,Humans ,HIV-1 ,HIV Infections ,Antibodies ,Neutralizing ,Male ,HIV Antibodies ,Female ,Adult ,Middle Aged ,AIDS vaccine ,AIDS/HIV ,Adaptive immunity ,Medical and Health Sciences ,Biological sciences ,Biomedical and clinical sciences ,Health sciences - Abstract
BACKGROUNDEarly antiretroviral therapy initiation (ARTi) in HIV-1 restricts reservoir size and diversity while preserving immune function, potentially improving opportunities for immunotherapeutic cure strategies. For antibody-based cure approaches, the development of autologous neutralizing antibodies (anAbs) after acute/early ARTi is relevant but is poorly understood.METHODSWe characterized antibody responses in a cohort of 23 participants following ARTi in acute HIV (
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- 2024
28. Interstitial macrophages are a focus of viral takeover and inflammation in COVID-19 initiation in human lung
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Wu, Timothy Ting-Hsuan, Travaglini, Kyle J, Rustagi, Arjun, Xu, Duo, Zhang, Yue, Andronov, Leonid, Jang, SoRi, Gillich, Astrid, Dehghannasiri, Roozbeh, Martínez-Colón, Giovanny J, Beck, Aimee, Liu, Daniel Dan, Wilk, Aaron J, Morri, Maurizio, Trope, Winston L, Bierman, Rob, Weissman, Irving L, Shrager, Joseph B, Quake, Stephen R, Kuo, Christin S, Salzman, Julia, Moerner, WE, Kim, Peter S, Blish, Catherine A, and Krasnow, Mark A
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Medical Microbiology ,Biomedical and Clinical Sciences ,Lung ,Vaccine Related ,Emerging Infectious Diseases ,Infectious Diseases ,Pneumonia ,Prevention ,Pneumonia & Influenza ,2.2 Factors relating to the physical environment ,2.1 Biological and endogenous factors ,Aetiology ,Infection ,Respiratory ,Good Health and Well Being ,Humans ,COVID-19 ,SARS-CoV-2 ,Macrophages ,Inflammation ,RNA ,Viral ,Medical and Health Sciences ,Immunology ,Biomedical and clinical sciences ,Health sciences - Abstract
Early stages of deadly respiratory diseases including COVID-19 are challenging to elucidate in humans. Here, we define cellular tropism and transcriptomic effects of SARS-CoV-2 virus by productively infecting healthy human lung tissue and using scRNA-seq to reconstruct the transcriptional program in "infection pseudotime" for individual lung cell types. SARS-CoV-2 predominantly infected activated interstitial macrophages (IMs), which can accumulate thousands of viral RNA molecules, taking over 60% of the cell transcriptome and forming dense viral RNA bodies while inducing host profibrotic (TGFB1, SPP1) and inflammatory (early interferon response, CCL2/7/8/13, CXCL10, and IL6/10) programs and destroying host cell architecture. Infected alveolar macrophages (AMs) showed none of these extreme responses. Spike-dependent viral entry into AMs used ACE2 and Sialoadhesin/CD169, whereas IM entry used DC-SIGN/CD209. These results identify activated IMs as a prominent site of viral takeover, the focus of inflammation and fibrosis, and suggest targeting CD209 to prevent early pathology in COVID-19 pneumonia. This approach can be generalized to any human lung infection and to evaluate therapeutics.
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- 2024
29. A Pipeline for Evaluation of Machine Learning/Artificial Intelligence Models to Quantify Programmed Death Ligand 1 Immunohistochemistry
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Knudsen, Beatrice S, Jadhav, Alok, Perry, Lindsey J, Thagaard, Jeppe, Deftereos, Georgios, Ying, Jian, Brintz, Ben J, and Zhang, Wei
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Biomedical and Clinical Sciences ,Oncology and Carcinogenesis ,Immunology ,Cancer ,Machine Learning and Artificial Intelligence ,Lung Cancer ,Bioengineering ,Immunotherapy ,Lung ,Networking and Information Technology R&D (NITRD) ,Humans ,Lung Neoplasms ,Immunohistochemistry ,Artificial Intelligence ,Machine Learning ,Biomarkers ,Tumor ,B7-H1 Antigen ,cancer segmentation ,digital pathology ,programmed death ligand 1 ,tumor proportion scores ,Clinical Sciences ,Pathology ,Clinical sciences - Abstract
Immunohistochemistry (IHC) is used to guide treatment decisions in multiple cancer types. For treatment with checkpoint inhibitors, programmed death ligand 1 (PD-L1) IHC is used as a companion diagnostic. However, the scoring of PD-L1 is complicated by its expression in cancer and immune cells. Separation of cancer and noncancer regions is needed to calculate tumor proportion scores (TPS) of PD-L1, which is based on the percentage of PD-L1-positive cancer cells. Evaluation of PD-L1 expression requires highly experienced pathologists and is often challenging and time-consuming. Here, we used a multi-institutional cohort of 77 lung cancer cases stained centrally with the PD-L1 22C3 clone. We developed a 4-step pipeline for measuring TPS that includes the coregistration of hematoxylin and eosin, PD-L1, and negative control (NC) digital slides for exclusion of necrosis, segmentation of cancer regions, and quantification of PD-L1+ cells. As cancer segmentation is a challenging step for TPS generation, we trained DeepLab V3 in the Visiopharm software package to outline cancer regions in PD-L1 and NC images and evaluated the model performance by mean intersection over union (mIoU) against manual outlines. Only 14 cases were required to accomplish a mIoU of 0.82 for cancer segmentation in hematoxylin-stained NC cases. For PD-L1-stained slides, a model trained on PD-L1 tiles augmented by registered NC tiles achieved a mIoU of 0.79. In segmented cancer regions from whole slide images, the digital TPS achieved an accuracy of 75% against the manual TPS scores from the pathology report. Major reasons for algorithmic inaccuracies include the inclusion of immune cells in cancer outlines and poor nuclear segmentation of cancer cells. Our transparent and stepwise approach and performance metrics can be applied to any IHC assay to provide pathologists with important insights on when to apply and how to evaluate commercial automated IHC scoring systems.
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- 2024
30. Mechanotransduction-induced interplay between phospholamban and yes-activated protein induces smooth muscle cell hypertrophy
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Rawson, Renee, Duong, Loan, Tkachenko, Eugene, Chiang, Austin WT, Okamoto, Kevin, Dohil, Ranjan, Lewis, Nathan E, Kurten, Richard, Abud, Edsel M, and Aceves, Seema S
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Medical Physiology ,Biomedical and Clinical Sciences ,Digestive Diseases ,Food Allergies ,2.1 Biological and endogenous factors ,Aetiology ,Life on Land ,Mechanotransduction ,Cellular ,Humans ,Myocytes ,Smooth Muscle ,Hypertrophy ,Calcium-Binding Proteins ,YAP-Signaling Proteins ,Animals ,Adaptor Proteins ,Signal Transducing ,Transcription Factors ,Mice ,Biological Sciences ,Medical and Health Sciences ,Immunology - Abstract
The gastrointestinal system is a hollow organ affected by fibrostenotic diseases that cause volumetric compromise of the lumen via smooth muscle hypertrophy and fibrosis. Many of the driving mechanisms remain unclear. Yes-associated protein-1 (YAP) is a critical mechanosensory transcriptional regulator that mediates cell hypertrophy in response to elevated extracellular rigidity. In the type 2 inflammatory disorder, eosinophilic esophagitis (EoE), phospholamban (PLN) can induce smooth muscle cell hypertrophy. We used EoE as a disease model for understanding a mechanistic pathway in which PLN and YAP interact in response to rigid extracellular substrate to induce smooth muscle cell hypertrophy. PLN-induced YAP nuclear sequestration in a feed-forward loop caused increased cell size in response to a rigid substrate. This mechanism of rigidity sensing may have previously unappreciated clinical implications for PLN-expressing hollow systems such as the esophagus and heart.
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- 2024
31. The Impact of Cannabis Use on Cognition in People with HIV: Evidence of Function-Dependent Effects and Mechanisms from Clinical and Preclinical Studies
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Ayoub, Samantha M, Holloway, Breanna M, Miranda, Alannah H, Roberts, Benjamin Z, Young, Jared W, Minassian, Arpi, and Ellis, Ronald J
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Pharmacology and Pharmaceutical Sciences ,Biomedical and Clinical Sciences ,HIV/AIDS ,Behavioral and Social Science ,Substance Misuse ,Neurosciences ,Clinical Research ,Cannabinoid Research ,Infectious Diseases ,Drug Abuse (NIDA only) ,Clinical Trials and Supportive Activities ,Prevention ,Sexually Transmitted Infections ,5.1 Pharmaceuticals ,2.2 Factors relating to the physical environment ,Mental health ,Humans ,HIV Infections ,Cognition ,Cannabis ,Cannabinoids ,Animals ,Cognitive Dysfunction ,Marijuana Use ,NeuroHIV ,HIV-associated neurocognitive disorders ,Immunology ,Medical Microbiology ,Virology ,Clinical sciences - Abstract
Purpose of reviewCannabis may have beneficial anti-inflammatory effects in people with HIV (PWH); however, given this population's high burden of persisting neurocognitive impairment (NCI), clinicians are concerned they may be particularly vulnerable to the deleterious effects of cannabis on cognition. Here, we present a systematic scoping review of clinical and preclinical studies evaluating the effects of cannabinoid exposure on cognition in HIV.Recent findingsResults revealed little evidence to support a harmful impact of cannabis use on cognition in HIV, with few eligible preclinical data existing. Furthermore, the beneficial/harmful effects of cannabis use observed on cognition were function-dependent and confounded by several factors (e.g., age, frequency of use). Results are discussed alongside potential mechanisms of cannabis effects on cognition in HIV (e.g., anti-inflammatory), and considerations are outlined for screening PWH that may benefit from cannabis interventions. We further highlight the value of accelerating research discoveries in this area by utilizing translatable cross-species tasks to facilitate comparisons across human and animal work.
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- 2024
32. Optimizing Identification of Allergic Sensitization to Seasonal Inhalant Allergens in the USA: Implications for Constructing Optimal Panels to Evaluate Patients with Allergy
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Kwong, Kenny Y, Chen, Zhen, Scott, Lyne, and Hilborne, Lee H
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Biomedical and Clinical Sciences ,Clinical Sciences ,Health Effects of Indoor Air Pollution ,Social Determinants of Health ,Inflammatory and immune system ,Allergen ,Seasonal allergens ,Sensitization ,Optimal inhalant ,Immunology ,Allergy - Abstract
IntroductionWhile a specific number and type of antigens are recognized to detect perennial inhalant allergies, the optimal number and combination of allergens to reliably identify seasonal allergic sensitization is unclear due to limited national data. This study analyzed aeroallergen testing data from a large US clinical reference laboratory to provide guidance for optimizing seasonal allergen test selection.MethodsThe 2019 serum IgE tests for seasonal inhalant allergens were identified from the Quest Diagnostics database. Patients with results for at least 1 of 31 seasonal allergens across 4 allergen classes (11 trees, 7 weeds, 5 grasses, and 8 molds) were analyzed. A step-by-step conditional approach was employed to determine the minimum number and species of allergens needed to identify at least 98% of sensitized patients for each class.ResultsOf 88,042 patients tested for ≥1 seasonal allergen, 1.5%, 1.8%, 1.3%, and 1.6% were tested for all trees, weeds, grasses, and molds, respectively. Of those tested for all allergens within a class, 40.4%, 38.6%, 29.5%, and 21.2% were sensitized to at least one tree, weed, grass, or mold allergen, respectively. Identification of ≥98% of sensitized patients within a class required 8 allergens for trees (mountain cedar, maple box elder, walnut, white ash, elm, birch, cottonwood, and hickory/pecan), 5 for weeds (common ragweed short, rough pigweed, English plantain, lamb's quarters/goosefoot, and Russian thistle), 3 for grasses (June/Kentucky blue grass, Johnson grass, and Bermuda grass), and 7 for molds (Alternaria alternata, Aspergillus fumigatus, Mucor racemosus, Epicoccum purpurascens, Penicillium notatum, Helminthosporium halodes, and Fusarium moniliforme).ConclusionA minimum of 23 antigens is required to optimally detect sensitization to four classes of seasonal allergens (i.e., ≥98% identification). The addition of these allergens to unique perennial allergens (cat, dog, mouse, cockroach, and 2 dust mite species) results in a comprehensive elucidation of inhalant allergen sensitization. This knowledge provides a pivotal guide for clinical laboratories as they construct allergen panels to optimize diagnostic yield.
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- 2024
33. LXR signaling pathways link cholesterol metabolism with risk for prediabetes and diabetes
- Author
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Ding, Jingzhong, Nguyen, Anh Tram, Lohman, Kurt, Hensley, Michael T, Parker, Daniel, Hou, Li, Taylor, Jackson, Voora, Deepak, Sawyer, Janet K, Boudyguina, Elena, Bancks, Michael P, Bertoni, Alain, Pankow, James S, Rotter, Jerome I, Goodarzi, Mark O, Tracy, Russell P, Murdoch, David M, Duprez, Daniel, Rich, Stephen S, Psaty, Bruce M, Siscovick, David, Newgard, Christopher B, Herrington, David, Hoeschele, Ina, Shea, Steven, Stein, James H, Patel, Manesh, Post, Wendy, Jacobs, David, Parks, John S, and Liu, Yongmei
- Subjects
Biochemistry and Cell Biology ,Biomedical and Clinical Sciences ,Biological Sciences ,Atherosclerosis ,Clinical Research ,Health Disparities ,Obesity ,Diabetes ,Genetics ,Nutrition ,Prevention ,Cardiovascular ,2.1 Biological and endogenous factors ,Metabolic and endocrine ,Humans ,Prediabetic State ,Male ,Female ,Diabetes Mellitus ,Type 2 ,Middle Aged ,Liver X Receptors ,Cholesterol ,Aged ,Signal Transduction ,ATP Binding Cassette Transporter ,Subfamily G ,Member 1 ,Monocytes ,Risk Factors ,ATP Binding Cassette Transporter 1 ,Aged ,80 and over ,Expression profiling ,Metabolism ,Medical and Health Sciences ,Immunology ,Biological sciences ,Biomedical and clinical sciences ,Health sciences - Abstract
BACKGROUNDPreclinical studies suggest that cholesterol accumulation leads to insulin resistance. We previously reported that alterations in a monocyte cholesterol metabolism transcriptional network (CMTN) - suggestive of cellular cholesterol accumulation - were cross-sectionally associated with obesity and type 2 diabetes (T2D). Here, we sought to determine whether the CMTN alterations independently predict incident prediabetes/T2D risk, and correlate with cellular cholesterol accumulation.METHODSMonocyte mRNA expression of 11 CMTN genes was quantified among 934 Multi-Ethnic Study of Atherosclerosis (MESA) participants free of prediabetes/T2D; cellular cholesterol was measured in a subset of 24 monocyte samples.RESULTSDuring a median 6-year follow-up, lower expression of 3 highly correlated LXR target genes - ABCG1 and ABCA1 (cholesterol efflux) and MYLIP (cholesterol uptake suppression) - and not other CMTN genes, was significantly associated with higher risk of incident prediabetes/T2D. Lower expression of the LXR target genes correlated with higher cellular cholesterol levels (e.g., 47% of variance in cellular total cholesterol explained by ABCG1 expression). Further, adding the LXR target genes to overweight/obesity and other known predictors significantly improved prediction of incident prediabetes/T2D.CONCLUSIONThese data suggest that the aberrant LXR/ABCG1-ABCA1-MYLIP pathway (LAAMP) is a major T2D risk factor and support a potential role for aberrant LAAMP and cellular cholesterol accumulation in diabetogenesis.FUNDINGThe MESA Epigenomics and Transcriptomics Studies were funded by NIH grants 1R01HL101250, 1RF1AG054474, R01HL126477, R01DK101921, and R01HL135009. This work was supported by funding from NIDDK R01DK103531 and NHLBI R01HL119962.
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- 2024
34. Mediator kinase inhibition reverses castration resistance of advanced prostate cancer
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Li, Jing, Hilimire, Thomas A, Yueying, Liu, Wang, Lili, Liang, Jiaxin, Győrffy, Balázs, Sikirzhytski, Vitali, Ji, Hao, Zhang, Li, Cheng, Chen, Ding, Xiaokai, Kerr, Kendall R, Dowling, Charles E, Chumanevich, Alexander A, Mack, Zachary T, Schools, Gary P, Lim, Chang-uk, Ellis, Leigh, Zi, Xiaolin, Porter, Donald C, Broude, Eugenia V, McInnes, Campbell, Wilding, George, Lilly, Michael B, Roninson, Igor B, and Chen, Mengqian
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Biomedical and Clinical Sciences ,Clinical Sciences ,Oncology and Carcinogenesis ,Urologic Diseases ,Genetics ,Prostate Cancer ,Cancer ,Development of treatments and therapeutic interventions ,5.1 Pharmaceuticals ,Male ,Humans ,Animals ,Prostatic Neoplasms ,Castration-Resistant ,Mice ,Cyclin-Dependent Kinases ,Cyclin-Dependent Kinase 8 ,Cell Line ,Tumor ,Xenograft Model Antitumor Assays ,Protein Kinase Inhibitors ,Gene Expression Regulation ,Neoplastic ,Tumor Microenvironment ,Oncology ,Therapeutics ,Transcription ,Medical and Health Sciences ,Immunology ,Biological sciences ,Biomedical and clinical sciences ,Health sciences - Abstract
Mediator kinases CDK19 and CDK8, pleiotropic regulators of transcriptional reprogramming, are differentially regulated by androgen signaling, but both kinases are upregulated in castration-resistant prostate cancer (CRPC). Genetic or pharmacological inhibition of CDK8 and CDK19 reverses the castration-resistant phenotype and restores the sensitivity of CRPC xenografts to androgen deprivation in vivo. Prolonged CDK8/19 inhibitor treatment combined with castration not only suppressed the growth of CRPC xenografts but also induced tumor regression and cures. Transcriptomic analysis revealed that Mediator kinase inhibition amplified and modulated the effects of castration on gene expression, disrupting CRPC adaptation to androgen deprivation. Mediator kinase inactivation in tumor cells also affected stromal gene expression, indicating that Mediator kinase activity in CRPC molded the tumor microenvironment. The combination of castration and Mediator kinase inhibition downregulated the MYC pathway, and Mediator kinase inhibition suppressed a MYC-driven CRPC tumor model even without castration. CDK8/19 inhibitors showed efficacy in patient-derived xenograft models of CRPC, and a gene signature of Mediator kinase activity correlated with tumor progression and overall survival in clinical samples of metastatic CRPC. These results indicate that Mediator kinases mediated androgen-independent in vivo growth of CRPC, supporting the development of CDK8/19 inhibitors for the treatment of this presently incurable disease.
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- 2024
35. Coordinated immune dysregulation in Juvenile Dermatomyositis revealed by single-cell genomics
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Rabadam, Gabrielle, Wibrand, Camilla, Flynn, Emily, Hartoularos, George C, Sun, Yang, Madubata, Chioma, Fragiadakis, Gabriela K, Ye, Jimmie, Kim, Susan, Gartner, Zev J, Sirota, Marina, and Neely, Jessica
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Biomedical and Clinical Sciences ,Immunology ,Prevention ,Biodefense ,Vaccine Related ,Autoimmune Disease ,Rare Diseases ,Biotechnology ,Clinical Research ,Aetiology ,2.1 Biological and endogenous factors ,Inflammatory and immune system ,Autoimmune diseases ,Autoimmunity ,Bioinformatics ,Rheumatology ,Biomedical and clinical sciences ,Health sciences - Abstract
Juvenile Dermatomyositis (JDM) is one of several childhood-onset autoimmune disorders characterized by a type I interferon response and autoantibodies. Treatment options are limited due to incomplete understanding of how the disease emerges from dysregulated cell states across the immune system. We therefore investigated the blood of JDM patients at different stages of disease activity using single-cell transcriptomics paired with surface protein expression. By immunophenotyping peripheral blood mononuclear cells, we observed skewing of the B cell compartment towards an immature naive state as a hallmark of JDM at diagnosis. Furthermore, we find that these changes in B cells are paralleled by T cell signatures suggestive of Th2-mediated inflammation that persist despite disease quiescence. We applied network analysis to reveal that hyperactivation of the type I interferon response in all immune populations is coordinated with previously masked cell states including dysfunctional protein processing in CD4+ T cells and regulation of cell death programming in NK, CD8+ T cells and gdT cells. Together, these findings unveil the coordinated immune dysregulation underpinning JDM and provide insight into strategies for restoring balance in immune function.
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- 2024
36. IL-22-dependent responses and their role during Citrobacter rodentium infection
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Melchior, Karine, Gerner, Romana R, Hossain, Suzana, Nuccio, Sean-Paul, Moreira, Cristiano Gallina, and Raffatellu, Manuela
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Medical Microbiology ,Biomedical and Clinical Sciences ,Biological Sciences ,Emerging Infectious Diseases ,Vaccine Related ,Digestive Diseases ,Biodefense ,Foodborne Illness ,Prevention ,Infectious Diseases ,2.1 Biological and endogenous factors ,Aetiology ,Infection ,Animals ,Interleukin-22 ,Citrobacter rodentium ,Interleukins ,Enterobacteriaceae Infections ,Mice ,Mice ,Knockout ,Mice ,Inbred C57BL ,Calgranulin B ,Pancreatitis-Associated Proteins ,Disease Models ,Animal ,Citrobacter ,mucosal immunity ,gut inflammation ,antimicrobial peptides ,Agricultural and Veterinary Sciences ,Medical and Health Sciences ,Microbiology ,Immunology ,Medical microbiology - Abstract
The mouse pathogen Citrobacter rodentium is utilized as a model organism for studying infections caused by the human pathogens enteropathogenic Escherichia coli (EPEC) and enterohemorrhagic E. coli (EHEC) and to elucidate mechanisms of mucosal immunity. In response to C. rodentium infection, innate lymphoid cells and T cells secrete interleukin (IL)-22, a cytokine that promotes mucosal barrier function. IL-22 plays a pivotal role in enabling mice to survive and recover from C. rodentium infection, although the exact mechanisms involved remain incompletely understood. Here, we investigated whether particular components of the host response downstream of IL-22 contribute to the cytokine's protective effects during C. rodentium infection. In line with previous research, mice lacking the IL-22 gene (Il22-/- mice) were highly susceptible to C. rodentium infection. To elucidate the role of specific antimicrobial proteins modulated by IL-22, we infected the following knockout mice: S100A9-/- (calprotectin), Lcn2-/- (lipocalin-2), Reg3b-/- (Reg3β), Reg3g-/- (Reg3γ), and C3-/- (C3). All knockout mice tested displayed a considerable level of resistance to C. rodentium infection, and none phenocopied the lethality observed in Il22-/- mice. By investigating another arm of the IL-22 response, we observed that C. rodentium-infected Il22-/- mice exhibited an overall decrease in gene expression related to intestinal barrier integrity as well as significantly elevated colonic inflammation, gut permeability, and pathogen levels in the spleen. Taken together, these results indicate that host resistance to lethal C. rodentium infection may depend on multiple antimicrobial responses acting in concert, or that other IL-22-regulated processes, such as tissue repair and maintenance of epithelial integrity, play crucial roles in host defense to attaching and effacing pathogens.
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- 2024
37. Mycobacterium tuberculosis resides in lysosome-poor monocyte-derived lung cells during chronic infection.
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Zheng, Weihao, Chang, I-Chang, Limberis, Jason, Budzik, Jonathan M, Zha, Beth Shoshana, Howard, Zachary, Chen, Lucas, and Ernst, Joel D
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Biochemistry and Cell Biology ,Biomedical and Clinical Sciences ,Biological Sciences ,Rare Diseases ,Infectious Diseases ,Lung ,Tuberculosis ,Aetiology ,2.1 Biological and endogenous factors ,Infection ,Good Health and Well Being ,Monocytes ,Lysosomes ,Macrophages ,Alveolar ,Animals ,Mice ,Inbred C57BL ,Humans ,Mice ,Mycobacterium tuberculosis ,Tuberculosis ,Pulmonary ,Chronic Disease ,Basic Helix-Loop-Helix Leucine Zipper Transcription Factors ,Microbiology ,Immunology ,Medical Microbiology ,Virology ,Medical microbiology - Abstract
Mycobacterium tuberculosis (Mtb) infects lung myeloid cells, but the specific Mtb-permissive cells and host mechanisms supporting Mtb persistence during chronic infection are incompletely characterized. We report that after the development of T cell responses, CD11clo monocyte-derived cells harbor more live Mtb than alveolar macrophages (AM), neutrophils, and CD11chi monocyte-derived cells. Transcriptomic and functional studies revealed that the lysosome pathway is underexpressed in this highly permissive subset, characterized by less lysosome content, acidification, and proteolytic activity than AM, along with less nuclear TFEB, a regulator of lysosome biogenesis. Mtb infection does not drive lysosome deficiency in CD11clo monocyte-derived cells but promotes recruitment of monocytes that develop into permissive lung cells, mediated by the Mtb ESX-1 secretion system. The c-Abl tyrosine kinase inhibitor nilotinib activates TFEB and enhances lysosome functions of macrophages in vitro and in vivo, improving control of Mtb infection. Our results suggest that Mtb exploits lysosome-poor lung cells for persistence and targeting lysosome biogenesis is a potential host-directed therapy for tuberculosis.
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- 2024
38. What a Clinician Needs to Know About Genome Editing: Status and Opportunities for Inborn Errors of Immunity
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Mudde, Anne CA, Kuo, Caroline Y, Kohn, Donald B, and Booth, Claire
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Medical Biotechnology ,Biomedical and Clinical Sciences ,Pediatric ,Genetics ,Stem Cell Research ,Biotechnology ,Regenerative Medicine ,Gene Therapy ,Development of treatments and therapeutic interventions ,5.2 Cellular and gene therapies ,Inflammatory and immune system ,Humans ,Gene Editing ,Genetic Therapy ,Animals ,CRISPR-Cas Systems ,Agammaglobulinemia ,Severe Combined Immunodeficiency ,Hematopoietic Stem Cell Transplantation ,Gene editing ,Inborn errors of immunity ,CRISPR/Cas ,Prime editing ,Base editing ,Immunology - Abstract
During the past 20 years, gene editing has emerged as a novel form of gene therapy. Since the publication of the first potentially therapeutic gene editing platform for genetic disorders, increasingly sophisticated editing technologies have been developed. As with viral vector-mediated gene addition, inborn errors of immunity are excellent candidate diseases for a corrective autologous hematopoietic stem cell gene editing strategy. Research on gene editing for inborn errors of immunity is still entirely preclinical, with no trials yet underway. However, with editing techniques maturing, scientists are investigating this novel form of gene therapy in context of an increasing number of inborn errors of immunity. Here, we present an overview of these studies and the recent progress moving these technologies closer to clinical benefit.
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- 2024
39. Interferon-β deficiency alters brain response to chronic HIV-1 envelope protein exposure in a transgenic model of NeuroHIV
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Singh, Hina, Koury, Jeffrey, Maung, Ricky, Roberts, Amanda J, and Kaul, Marcus
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Biomedical and Clinical Sciences ,Biological Psychology ,Immunology ,Medical Microbiology ,Psychology ,Genetics ,Sexually Transmitted Infections ,Behavioral and Social Science ,Brain Disorders ,Basic Behavioral and Social Science ,Acquired Cognitive Impairment ,Neurodegenerative ,Mental Health ,Women's Health ,Infectious Diseases ,Neurosciences ,HIV/AIDS ,Underpinning research ,1.1 Normal biological development and functioning ,Mental health ,Neurological ,Animals ,Female ,Male ,Mice ,Brain ,HIV Infections ,HIV-1 ,Interferon-beta ,Mice ,Transgenic ,Interferon beta ,IFN beta knockout ,HIVgp120-transgenic ,HIV associated neurocognitive disorder ,Behavior deficits ,P38 MAPK ,ERK1/2 signaling ,Sexual dimorphism ,IFNβ knockout ,Neurology & Neurosurgery ,Biological psychology - Abstract
Human immunodeficiency virus-1 (HIV-1) infects the central nervous system (CNS) and causes HIV-associated neurocognitive disorders (HAND) in about half of the population living with the virus despite combination anti-retroviral therapy (cART). HIV-1 activates the innate immune system, including the production of type 1 interferons (IFNs) α and β. Transgenic mice expressing HIV-1 envelope glycoprotein gp120 (HIVgp120tg) in the CNS develop memory impairment and share key neuropathological features and differential CNS gene expression with HIV patients, including the induction of IFN-stimulated genes (ISG). Here we show that knocking out IFNβ (IFNβKO) in HIVgp120tg and non-tg control mice impairs recognition and spatial memory, but does not affect anxiety-like behavior, locomotion, or vision. The neuropathology of HIVgp120tg mice is only moderately affected by the KO of IFNβ but in a sex-dependent fashion. Notably, in cerebral cortex of IFNβKO animals presynaptic terminals are reduced in males while neuronal dendrites are reduced in females. The IFNβKO results in the hippocampal CA1 region of both male and female HIVgp120tg mice in an ameliorated loss of neuronal presynaptic terminals but no protection of neuronal dendrites. Only female IFNβ-deficient HIVgp120tg mice display diminished microglial activation in cortex and hippocampus and increased astrocytosis in hippocampus compared to their IFNβ-expressing counterparts. RNA expression for some immune genes and ISGs is also affected in a sex-dependent way. The IFNβKO abrogates or diminishes the induction of MX1, DDX58, IRF7 and IRF9 in HIVgp120tg brains of both sexes. Expression analysis of neurotransmission related genes reveals an influence of IFNβ on multiple components with more pronounced changes in IFNβKO females. In contrast, the effects of IFNβKO on MAPK activities are independent of sex with pronounced reduction of active ERK1/2 but also of active p38 in the HIVgp120tg brain. In summary, our findings show that the absence of IFNβ impairs memory dependent behavior and modulates neuropathology in HIVgp120tg brains, indicating that its absence may facilitate development of HAND. Moreover, our data suggests that endogenous IFNβ plays a vital role in maintaining neuronal homeostasis and memory function.
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- 2024
40. Development and validation of a risk scoring system to identify patients with lupus nephritis in electronic health record data
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Izadi, Zara, Gianfrancesco, Milena, Anastasiou, Christine, Schmajuk, Gabriela, and Yazdany, Jinoos
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Biomedical and Clinical Sciences ,Clinical Sciences ,Immunology ,Lupus ,Patient Safety ,Women's Health ,Networking and Information Technology R&D (NITRD) ,Autoimmune Disease ,Clinical Research ,Good Health and Well Being ,Humans ,Lupus Nephritis ,Electronic Health Records ,Female ,Male ,Adult ,Middle Aged ,International Classification of Diseases ,Logistic Models ,Risk Assessment ,Lupus Erythematosus ,Systemic ,Epidemiology ,Antibodies ,Antirheumatic Agents ,Clinical sciences - Abstract
ObjectiveAccurate identification of lupus nephritis (LN) cases is essential for patient management, research and public health initiatives. However, LN diagnosis codes in electronic health records (EHRs) are underused, hindering efficient identification. We investigated the current performance of International Classification of Diseases (ICD) codes, 9th and 10th editions (ICD9/10), for identifying prevalent LN, and developed scoring systems to increase identification of LN that are adaptable to settings with and without LN ICD codes.MethodsTraining and test sets derived from EHR data from a large health system. An external set comprised data from the EHR of a second large health system. Adults with ICD9/10 codes for SLE were included. LN cases were ascertained through manual chart reviews conducted by rheumatologists. Two definitions of LN were used: strict (definite LN) and inclusive (definite, potential or diagnostic uncertainty). Gradient boosting models including structured EHR fields were used for predictor selection. Two logistic regression-based scoring systems were developed ('LN-Code' included LN ICD codes and 'LN-No Code' did not), calibrated and validated using standard performance metrics.ResultsA total of 4152 patients from University of California San Francisco Medical Center and 370 patients from Zuckerberg San Francisco General Hospital and Trauma Center met the eligibility criteria. Mean age was 50 years, 87% were female. LN diagnosis codes demonstrated low sensitivity (43-73%) but high specificity (92-97%). LN-Code achieved an area under the curve (AUC) of 0.93 and a sensitivity of 0.88 for identifying LN using the inclusive definition. LN-No Code reached an AUC of 0.91 and a sensitivity of 0.95 (0.97 for the strict definition). Both scoring systems had good external validity, calibration and performance across racial and ethnic groups.ConclusionsThis study quantified the underutilisation of LN diagnosis codes in EHRs and introduced two adaptable scoring systems to enhance LN identification. Further validation in diverse healthcare settings is essential to ensure their broader applicability.
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- 2024
41. Chronic SIV-induced neuroinflammation disrupts CCR7+CD4+ T cell immunosurveillance in the rhesus macaque brain
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Elizaldi, Sonny R, Hawes, Chase E, Verma, Anil, Lakshmanappa, Yashavanth Shaan, Dinasarapu, Ashok R, Schlegel, Brent T, Rajasundaram, Dhivyaa, Li, Jie, Durbin-Johnson, Blythe P, Ma, Zhong-Min, Pal, Pabitra B, Beckman, Danielle, Ott, Sean, Raeman, Reben, Lifson, Jeffrey, Morrison, John H, and Iyer, Smita S
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Medical Microbiology ,Biomedical and Clinical Sciences ,Immunology ,Infectious Diseases ,Genetics ,Human Genome ,HIV/AIDS ,Neurosciences ,Sexually Transmitted Infections ,1.1 Normal biological development and functioning ,Underpinning research ,Animals ,Macaca mulatta ,Simian Acquired Immunodeficiency Syndrome ,Simian Immunodeficiency Virus ,CD4-Positive T-Lymphocytes ,Receptors ,CCR7 ,Brain ,Neuroinflammatory Diseases ,Immunologic Surveillance ,Simian immunodeficiency virus ,AIDS/HIV ,Adaptive immunity ,Inflammation ,Neurological disorders ,T cells ,Medical and Health Sciences ,Biological sciences ,Biomedical and clinical sciences ,Health sciences - Abstract
CD4+ T cells survey and maintain immune homeostasis in the brain, yet their differentiation states and functional capabilities remain unclear. Our approach, combining single-cell transcriptomic analysis, ATAC-Seq, spatial transcriptomics, and flow cytometry, revealed a distinct subset of CCR7+ CD4+ T cells resembling lymph node central memory (TCM) cells. We observed chromatin accessibility at the CCR7, CD28, and BCL-6 loci, defining molecular features of TCM. Brain CCR7+ CD4+ T cells exhibited recall proliferation and interleukin-2 production ex vivo, showcasing their functional competence. We identified the skull bone marrow as a local niche for these cells alongside CNS border tissues. Sequestering TCM cells in lymph nodes using FTY720 led to reduced CCR7+ CD4+ T cell frequencies in the cerebrospinal fluid, accompanied by increased monocyte levels and soluble markers indicating immune activation. In macaques chronically infected with SIVCL757 and experiencing viral rebound due to cessation of antiretroviral therapy, a decrease in brain CCR7+ CD4+ T cells was observed, along with increased microglial activation and initiation of neurodegenerative pathways. Our findings highlight a role for CCR7+ CD4+ T cells in CNS immune surveillance, and their decline during chronic SIV highlights their responsiveness to neuroinflammation.
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- 2024
42. Integrated longitudinal multiomics study identifies immune programs associated with acute COVID-19 severity and mortality
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Gygi, Jeremy P, Maguire, Cole, Patel, Ravi K, Shinde, Pramod, Konstorum, Anna, Shannon, Casey P, Xu, Leqi, Hoch, Annmarie, Jayavelu, Naresh Doni, Haddad, Elias K, Network, IMPACC, Reed, Elaine F, Kraft, Monica, McComsey, Grace A, Metcalf, Jordan P, Ozonoff, Al, Esserman, Denise, Cairns, Charles B, Rouphael, Nadine, Bosinger, Steven E, Kim-Schulze, Seunghee, Krammer, Florian, Rosen, Lindsey B, van Bakel, Harm, Wilson, Michael, Eckalbar, Walter L, Maecker, Holden T, Langelier, Charles R, Steen, Hanno, Altman, Matthew C, Montgomery, Ruth R, Levy, Ofer, Melamed, Esther, Pulendran, Bali, Diray-Arce, Joann, Smolen, Kinga K, Fragiadakis, Gabriela K, Becker, Patrice M, Sekaly, Rafick P, Ehrlich, Lauren IR, Fourati, Slim, Peters, Bjoern, Kleinstein, Steven H, and Guan, Leying
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Biomedical and Clinical Sciences ,Immunology ,Clinical Research ,Rare Diseases ,2.1 Biological and endogenous factors ,Aetiology ,Good Health and Well Being ,Humans ,COVID-19 ,Male ,Longitudinal Studies ,SARS-CoV-2 ,Female ,Middle Aged ,Severity of Illness Index ,Aged ,Adult ,Cytokines ,Multiomics ,IMPACC Network ,Adaptive immunity ,Innate immunity ,Medical and Health Sciences ,Biological sciences ,Biomedical and clinical sciences ,Health sciences - Abstract
BACKGROUNDPatients hospitalized for COVID-19 exhibit diverse clinical outcomes, with outcomes for some individuals diverging over time even though their initial disease severity appears similar to that of other patients. A systematic evaluation of molecular and cellular profiles over the full disease course can link immune programs and their coordination with progression heterogeneity.METHODSWe performed deep immunophenotyping and conducted longitudinal multiomics modeling, integrating 10 assays for 1,152 Immunophenotyping Assessment in a COVID-19 Cohort (IMPACC) study participants and identifying several immune cascades that were significant drivers of differential clinical outcomes.RESULTSIncreasing disease severity was driven by a temporal pattern that began with the early upregulation of immunosuppressive metabolites and then elevated levels of inflammatory cytokines, signatures of coagulation, formation of neutrophil extracellular traps, and T cell functional dysregulation. A second immune cascade, predictive of 28-day mortality among critically ill patients, was characterized by reduced total plasma Igs and B cells and dysregulated IFN responsiveness. We demonstrated that the balance disruption between IFN-stimulated genes and IFN inhibitors is a crucial biomarker of COVID-19 mortality, potentially contributing to failure of viral clearance in patients with fatal illness.CONCLUSIONOur longitudinal multiomics profiling study revealed temporal coordination across diverse omics that potentially explain the disease progression, providing insights that can inform the targeted development of therapies for patients hospitalized with COVID-19, especially those who are critically ill.TRIAL REGISTRATIONClinicalTrials.gov NCT04378777.FUNDINGNIH (5R01AI135803-03, 5U19AI118608-04, 5U19AI128910-04, 4U19AI090023-11, 4U19AI118610-06, R01AI145835-01A1S1, 5U19AI062629-17, 5U19AI057229-17, 5U19AI125357-05, 5U19AI128913-03, 3U19AI077439-13, 5U54AI142766-03, 5R01AI104870-07, 3U19AI089992-09, 3U19AI128913-03, and 5T32DA018926-18); NIAID, NIH (3U19AI1289130, U19AI128913-04S1, and R01AI122220); and National Science Foundation (DMS2310836).
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- 2024
43. CHMP2A regulates broad immune cell-mediated antitumor activity in an immunocompetent in vivo head and neck squamous cell carcinoma model
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Yun, Jiyoung, Saddawi-Konefka, Robert, Goldenson, Benjamin, Al-Msari, Riyam, Bernareggi, Davide, Thangaraj, Jaya L, Tang, Shiqi, Patel, Sonam H, Luna, Sarah M, Gutkind, J Silvio, and Kaufman, Dan
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Biomedical and Clinical Sciences ,Oncology and Carcinogenesis ,Immunology ,Dental/Oral and Craniofacial Disease ,Immunotherapy ,Rare Diseases ,Genetics ,Cancer ,2.1 Biological and endogenous factors ,5.1 Pharmaceuticals ,Good Health and Well Being ,Animals ,Humans ,Mice ,Cell Line ,Tumor ,Disease Models ,Animal ,Head and Neck Neoplasms ,Immunocompetence ,Killer Cells ,Natural ,Squamous Cell Carcinoma of Head and Neck ,Immunity ,Innate ,Immunotherapy ,Adoptive ,Myeloid-Derived Suppressor Cells ,Oncology and carcinogenesis - Abstract
BackgroundNatural killer (NK) cells are key effector cells of antitumor immunity. However, tumors can acquire resistance programs to escape NK cell-mediated immunosurveillance. Identifying mechanisms that mediate this resistance enables us to define approaches to improve immune-mediate antitumor activity. In previous studies from our group, a genome-wide CRISPR-Cas9 screen identified Charged Multivesicular Body Protein 2A (CHMP2A) as a novel mechanism that mediates tumor intrinsic resistance to NK cell activity.MethodsHere, we use an immunocompetent mouse model to demonstrate that CHMP2A serves as a targetable regulator of not only NK cell-mediated immunity but also other immune cell populations. Using the recently characterized murine 4MOSC model system, a syngeneic, tobacco-signature murine head and neck squamous cell carcinoma model, we deleted mCHMP2A using CRISPR/Cas9-mediated knock-out (KO), following orthotopic transplantation into immunocompetent hosts.ResultsWe found that mCHMP2A KO in 4MOSC1 cells leads to more potent NK-mediated tumor cell killing in vitro in these tumor cells. Moreover, following orthotopic transplantation, KO of mCHMP2A in 4MOSC1 cells, but not the more immune-resistant 4MOSC2 cells enables both T cells and NK cells to better mediate antitumor activity compared with wild type (WT) tumors. However, there was no difference in tumor development between WT and mCHMP2A KO 4MOSC1 or 4MOSC2 tumors when implanted in immunodeficient mice. Mechanistically, we find that mCHMP2A KO 4MOSC1 tumors transplanted into the immunocompetent mice had significantly increased CD4+T cells, CD8+T cells. NK cell, as well as fewer myeloid-derived suppressor cells (MDSC).ConclusionsTogether, these studies demonstrate that CHMP2A is a targetable inhibitor of cellular antitumor immunity.
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- 2024
44. A critical role for Macrophage-derived Cysteinyl-Leukotrienes in HIV-1 induced neuronal injury
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Yuan, Nina Y, Medders, Kathryn E, Sanchez, Ana B, Shah, Rohan, de Rozieres, Cyrus M, Ojeda-Juárez, Daniel, Maung, Ricky, Williams, Roy, Gelman, Benjamin B, Baaten, Bas J, Roberts, Amanda J, and Kaul, Marcus
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Medical Microbiology ,Biomedical and Clinical Sciences ,Immunology ,Acquired Cognitive Impairment ,Sexually Transmitted Infections ,Infectious Diseases ,Neurodegenerative ,Neurosciences ,HIV/AIDS ,Brain Disorders ,2.1 Biological and endogenous factors ,Aetiology ,Infection ,Neurological ,Mice ,Humans ,Animals ,HIV-1 ,Macrophages ,Leukotrienes ,Neurons ,p38 Mitogen-Activated Protein Kinases ,Mice ,Transgenic ,HIV Infections ,Cysteine ,HIV ,Neurotoxicity ,Cysteinyl leukotrienes ,Knockout ,HIVgp120-transgenic ,HIV associated neurocognitive disorder ,Behavior deficits ,P38 MAPK ,ERK1/2 signaling ,Psychology ,Neurology & Neurosurgery ,Biological psychology - Abstract
Macrophages (MΦ) infected with human immunodeficiency virus (HIV)-1 or activated by its envelope protein gp120 exert neurotoxicity. We found previously that signaling via p38 mitogen-activated protein kinase (p38 MAPK) is essential to the neurotoxicity of HIVgp120-stimulated MΦ. However, the associated downstream pathways remained elusive. Here we show that cysteinyl-leukotrienes (CysLT) released by HIV-infected or HIVgp120 stimulated MΦ downstream of p38 MAPK critically contribute to neurotoxicity. SiRNA-mediated or pharmacological inhibition of p38 MAPK deprives MΦ of CysLT synthase (LTC4S) and, pharmacological inhibition of the cysteinyl-leukotriene receptor 1 (CYSLTR1) protects cerebrocortical neurons against toxicity of both gp120-stimulated and HIV-infected MΦ. Components of the CysLT pathway are differentially regulated in brains of HIV-infected individuals and a transgenic mouse model of NeuroHIV (HIVgp120tg). Moreover, genetic ablation of LTC4S or CysLTR1 prevents neuronal damage and impairment of spatial memory in HIVgp120tg mice. Altogether, our findings suggest a novel critical role for cysteinyl-leukotrienes in HIV-associated brain injury.
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- 2024
45. Mortality in adults with sickle cell disease: Results from the sickle cell disease implementation consortium (SCDIC) registry
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Njoku, Franklin, Pugh, Norma, Brambilla, Donald, Kroner, Barbara, Shah, Nirmish, Treadwell, Marsha, Gibson, Robert, Hsu, Lewis L, Gordeuk, Victor R, Glassberg, Jeffrey, Hankins, Jane S, Kutlar, Abdullah, King, Allison A, and Kanter, Julie
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Biomedical and Clinical Sciences ,Clinical Sciences ,Clinical Research ,Lung ,Prevention ,Sickle Cell Disease ,Rare Diseases ,Hematology ,Clinical Trials and Supportive Activities ,2.1 Biological and endogenous factors ,2.4 Surveillance and distribution ,Aetiology ,Good Health and Well Being ,Humans ,Hypertension ,Pulmonary ,Anemia ,Sickle Cell ,Retrospective Studies ,Prospective Studies ,Research Design ,Adult ,Cardiorespiratory Medicine and Haematology ,Immunology ,Cardiovascular medicine and haematology - Abstract
The cause of death in people affected by sickle cell disease (SCD) is often challenging to define as prior studies have used retrospective or administrative data for analysis. We used a prospective longitudinal registry to assess mortality and clinical co-morbidities among subjects enrolled in the Sickle Cell Disease Implementation Consortium (SCDIC) registry. At enrollment, we collected the following data: patient-reported demographics, SCD phenotype, baseline laboratory values, comorbidities, and current medications. Subjects were followed for a median of 4.7 years before the present analysis. The relationship of clinical co-morbidities (at time of enrollment) to mortality was determined using survival analysis, adjusting for SCD phenotype and gender. There was a total of 2439 people with SCD enrolled in the SCDIC registry. One hundred and twenty-eight participants (5%) died during the observation period (2017-2022). Six people died from trauma and were excluded from further analysis. Proximate cause of death was unwitnessed in 17% of the deaths, but commonest causes of death include cardiac (18%), acute chest or respiratory failure (11%), sudden unexplained death (8%). Enrollment characteristics of the individuals who died (n = 122) were compared to those of survivors (n = 2317). Several co-morbidities at enrollment increased the odds of death on univariate analysis. All co-morbidities were included in a multivariable model. After backward elimination, iron overload, pulmonary hypertension, and depression, remained statistically significant predictors of the risk of death. SCD reduces life expectancy. Improved comprehensive and supportive care to prevent end-organ damage and address comorbidities is needed for this population.
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- 2024
46. Survival and Functional Integration of Human Embryonic Stem Cell–Derived Retinal Organoids After Shipping and Transplantation into Retinal Degeneration Rats
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Lin, Bin, Singh, Ratnesh K, Seiler, Magdalene J, and Nasonkin, Igor O
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Biological Sciences ,Bioengineering ,Stem Cell Research - Embryonic - Human ,Stem Cell Research ,Regenerative Medicine ,Transplantation ,Neurosciences ,Eye Disease and Disorders of Vision ,Development of treatments and therapeutic interventions ,5.2 Cellular and gene therapies ,Eye ,Animals ,Human Embryonic Stem Cells ,Retinal Degeneration ,Humans ,Organoids ,Rats ,Retina ,Cell Differentiation ,Stem Cell Transplantation ,Cell Survival ,Tomography ,Optical Coherence ,retinal degeneration ,cell therapy ,retinal organoids ,tissue replacement ,subretinal transplantation ,synaptic integration ,Technology ,Medical and Health Sciences ,Developmental Biology ,Immunology ,Biological sciences - Abstract
Because derivation of retinal organoids (ROs) and transplantation are frequently split between geographically distant locations, we developed a special shipping device and protocol capable of the organoids' delivery to any location. Human embryonic stem cell (hESC)-derived ROs were differentiated from the hESC line H1 (WA01), shipped overnight to another location, and then transplanted into the subretinal space of blind immunodeficient retinal degeneration (RD) rats. Development of transplants was monitored by spectral-domain optical coherence tomography. Visual function was accessed by optokinetic tests and superior colliculus (SC) electrophysiology. Cryostat sections through transplants were stained with hematoxylin and eosin; or processed for immunohistochemistry to label human donor cells, retinal cell types, and synaptic markers. After transplantation, ROs integrated into the host RD retina, formed functional photoreceptors, and improved vision in rats with advanced RD. The survival and vision improvement are comparable with our previous results of hESC-ROs without a long-distance delivery. Furthermore, for the first time in the stem cell transplantation field, we demonstrated that the response heatmap on the SC showed a similar shape to the location of the transplant in the host retina, which suggested the point-to-point projection of the transplant from the retina to SC. In conclusion, our results showed that using our special device and protocol, the hESC-derived ROs can be shipped over long distance and are capable of survival and visual improvement after transplantation into the RD rats. Our data provide a proof-of-concept for stem cell replacement as a therapy for RD patients.
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- 2024
47. Live-attenuated virus vaccine defective in RNAi suppression induces rapid protection in neonatal and adult mice lacking mature B and T cells
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Chen, Gang, Han, Qingxia, Li, Wan-Xiang, Hai, Rong, and Ding, Shou-Wei
- Subjects
Medical Microbiology ,Biomedical and Clinical Sciences ,Immunology ,Emerging Infectious Diseases ,Infectious Diseases ,Prevention ,Biotechnology ,Rare Diseases ,Immunization ,Vaccine Related ,Aetiology ,3.4 Vaccines ,2.1 Biological and endogenous factors ,Prevention of disease and conditions ,and promotion of well-being ,Infection ,Good Health and Well Being ,Animals ,Humans ,Mice ,T-Lymphocytes ,RNA Interference ,Vaccines ,Attenuated ,Viral Vaccines ,Viruses ,Homeodomain Proteins ,Influenza Vaccines ,Antibodies ,Viral ,virus ,vaccine ,influenza ,RNAi - Abstract
Global control of infectious diseases depends on the continuous development and deployment of diverse vaccination strategies. Currently available live-attenuated and killed virus vaccines typically take a week or longer to activate specific protection by the adaptive immunity. The mosquito-transmitted Nodamura virus (NoV) is attenuated in mice by mutations that prevent expression of the B2 viral suppressor of RNA interference (VSR) and consequently, drastically enhance in vivo production of the virus-targeting small-interfering RNAs. We reported recently that 2 d after immunization with live-attenuated VSR-disabled NoV (NoVΔB2), neonatal mice become fully protected against lethal NoV challenge and develop no detectable infection. Using Rag1-/- mice that produce no mature B and T lymphocytes as a model, here we examined the hypothesis that adaptive immunity is dispensable for the RNAi-based protective immunity activated by NoVΔB2 immunization. We show that immunization of both neonatal and adult Rag1-/- mice with live but not killed NoVΔB2 induces full protection against NoV challenge at 2 or 14 d postimmunization. Moreover, NoVΔB2-induced protective antiviral immunity is virus-specific and remains effective in adult Rag1-/- mice 42 and 90 d after a single-shot immunization. We conclude that immunization with the live-attenuated VSR-disabled RNA virus vaccine activates rapid and long-lasting protective immunity against lethal challenges by a distinct mechanism independent of the adaptive immunity mediated by B and T cells. Future studies are warranted to determine whether additional animal and human viruses attenuated by VSR inactivation induce similar protective immunity in healthy and adaptive immunity-compromised individuals.
- Published
- 2024
48. Spatiotemporal architecture of immune cells and cancer-associated fibroblasts in high-grade serous ovarian carcinoma
- Author
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Xu, Alexander M, Haro, Marcela, Walts, Ann E, Hu, Ye, John, Joshi, Karlan, Beth Y, Merchant, Akil, and Orsulic, Sandra
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Biomedical and Clinical Sciences ,Oncology and Carcinogenesis ,Immunology ,Ovarian Cancer ,Cancer ,Rare Diseases ,Prevention ,Female ,Humans ,Cancer-Associated Fibroblasts ,Neoplasm Recurrence ,Local ,Antineoplastic Agents ,Ovarian Neoplasms ,Recurrence ,Tumor Microenvironment - Abstract
High-grade serous ovarian carcinoma (HGSOC), the deadliest form of ovarian cancer, is typically diagnosed after it has metastasized and often relapses after standard-of-care platinum-based chemotherapy, likely due to advanced tumor stage, heterogeneity, and immune evasion and tumor-promoting signaling from the tumor microenvironment. To understand how spatial heterogeneity contributes to HGSOC progression and early relapse, we profiled an HGSOC tissue microarray of patient-matched longitudinal samples from 42 patients. We found spatial patterns associated with early relapse, including changes in T cell localization, malformed tertiary lymphoid structure (TLS)-like aggregates, and increased podoplanin-positive cancer-associated fibroblasts (CAFs). Using spatial features to compartmentalize the tissue, we found that plasma cells distribute in two different compartments associated with TLS-like aggregates and CAFs, and these distinct microenvironments may account for the conflicting reports about the role of plasma cells in HGSOC prognosis.
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- 2024
49. Minnelide suppresses GVHD and enhances survival while maintaining GVT responses.
- Author
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Copsel, Sabrina, Garrido, Vanessa, Barreras, Henry, Bader, Cameron, Pfeiffer, Brent, Mateo-Victoriano, Beatriz, Wolf, Dietlinde, Gallardo, Miguel, Paczesny, Sophie, Benjamin, Cara, Villarino, Alejandro, Saluja, Ashok, Levy, Robert, and Komanduri, Krishna
- Subjects
Cellular immune response ,Immunology ,Stem cell transplantation ,Transplantation ,Graft vs Host Disease ,Animals ,Mice ,Hematopoietic Stem Cell Transplantation ,Diterpenes ,Epoxy Compounds ,Phenanthrenes ,Humans ,Transplantation ,Homologous ,Female ,Cyclophosphamide ,Disease Models ,Animal ,Graft vs Leukemia Effect ,Mice ,Inbred C57BL ,Male - Abstract
Allogeneic hematopoietic stem cell transplantation (aHSCT) can cure patients with otherwise fatal leukemias and lymphomas. However, the benefits of aHSCT are limited by graft-versus-host disease (GVHD). Minnelide, a water-soluble analog of triptolide, has demonstrated potent antiinflammatory and antitumor activity in several preclinical models and has proven both safe and efficacious in clinical trials for advanced gastrointestinal malignancies. Here, we tested the effectiveness of Minnelide in preventing acute GVHD as compared with posttransplant cyclophosphamide (PTCy). Strikingly, we found Minnelide improved survival, weight loss, and clinical scores in an MHC-mismatched model of aHSCT. These benefits were also apparent in minor MHC-matched aHSCT and xenogeneic HSCT models. Minnelide was comparable to PTCy in terms of survival, GVHD clinical score, and colonic length. Notably, in addition to decreased donor T cell infiltration early after aHSCT, several regulatory cell populations, including Tregs, ILC2s, and myeloid-derived stem cells in the colon were increased, which together may account for Minnelides GVHD suppression after aHSCT. Importantly, Minnelides GVHD prevention was accompanied by preservation of graft-versus-tumor activity. As Minnelide possesses anti-acute myeloid leukemia (anti-AML) activity and is being applied in clinical trials, together with the present findings, we conclude that this compound might provide a new approach for patients with AML undergoing aHSCT.
- Published
- 2024
50. CRISPR-Cas9 screen of E3 ubiquitin ligases identifies TRAF2 and UHRF1 as regulators of HIV latency in primary human T cells
- Author
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Rathore, Ujjwal, Haas, Paige, Kumar, Vigneshwari Easwar, Hiatt, Joseph, Haas, Kelsey M, Bouhaddou, Mehdi, Swaney, Danielle L, Stevenson, Erica, Zuliani-Alvarez, Lorena, McGregor, Michael J, Turner-Groth, Autumn, Olwal, Charles Ochieng', Bediako, Yaw, Braberg, Hannes, Soucheray, Margaret, Ott, Melanie, Eckhardt, Manon, Hultquist, Judd F, Marson, Alexander, Kaake, Robyn M, and Krogan, Nevan J
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Medical Microbiology ,Biomedical and Clinical Sciences ,Immunology ,HIV/AIDS ,Clinical Research ,Infectious Diseases ,Health Disparities ,Sexually Transmitted Infections ,Genetics ,Minority Health ,2.2 Factors relating to the physical environment ,2.1 Biological and endogenous factors ,Aetiology ,Infection ,Humans ,CCAAT-Enhancer-Binding Proteins ,CD4-Positive T-Lymphocytes ,CRISPR-Cas Systems ,HIV Infections ,TNF Receptor-Associated Factor 2 ,Ubiquitin-Protein Ligases ,Ubiquitins ,Virus Latency ,Virus Replication ,HIV ,human immunodeficiency virus ,ubiquitin E3 ligases ,HIV latency ,CRISPR screen ,resting primary T cells ,Microbiology ,Biochemistry and cell biology ,Medical microbiology - Abstract
During HIV infection of CD4+ T cells, ubiquitin pathways are essential to viral replication and host innate immune response; however, the role of specific E3 ubiquitin ligases is not well understood. Proteomics analyses identified 116 single-subunit E3 ubiquitin ligases expressed in activated primary human CD4+ T cells. Using a CRISPR-based arrayed spreading infectivity assay, we systematically knocked out 116 E3s from activated primary CD4+ T cells and infected them with NL4-3 GFP reporter HIV-1. We found 10 E3s significantly positively or negatively affected HIV infection in activated primary CD4+ T cells, including UHRF1 (pro-viral) and TRAF2 (anti-viral). Furthermore, deletion of either TRAF2 or UHRF1 in three JLat models of latency spontaneously increased HIV transcription. To verify this effect, we developed a CRISPR-compatible resting primary human CD4+ T cell model of latency. Using this system, we found that deletion of TRAF2 or UHRF1 initiated latency reactivation and increased virus production from primary human resting CD4+ T cells, suggesting these two E3s represent promising targets for future HIV latency reversal strategies.ImportanceHIV, the virus that causes AIDS, heavily relies on the machinery of human cells to infect and replicate. Our study focuses on the host cell's ubiquitination system which is crucial for numerous cellular processes. Many pathogens, including HIV, exploit this system to enhance their own replication and survival. E3 proteins are part of the ubiquitination pathway that are useful drug targets for host-directed therapies. We interrogated the 116 E3s found in human immune cells known as CD4+ T cells, since these are the target cells infected by HIV. Using CRISPR, a gene-editing tool, we individually removed each of these enzymes and observed the impact on HIV infection in human CD4+ T cells isolated from healthy donors. We discovered that 10 of the E3 enzymes had a significant effect on HIV infection. Two of them, TRAF2 and UHRF1, modulated HIV activity within the cells and triggered an increased release of HIV from previously dormant or "latent" cells in a new primary T cell assay. This finding could guide strategies to perturb hidden HIV reservoirs, a major hurdle to curing HIV. Our study offers insights into HIV-host interactions, identifies new factors that influence HIV infection in immune cells, and introduces a novel methodology for studying HIV infection and latency in human immune cells.
- Published
- 2024
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