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Cheng, Q., X. Chen, H. Wu, and Y. Du. "AB0042 THREE HEMATOLOGIC/IMMUNE SYSTEM-SPECIFIC EXPRESSED GENES ARE CONSIDERED AS THE POTENTIAL BIOMARKERS FOR THE DIAGNOSIS OF EARLY RHEUMATOID ARTHRITIS THROUGH BIOINFORMATICS ANALYSIS." Annals of the Rheumatic Diseases 80, Suppl 1 (May 19, 2021): 1053.1–1054. http://dx.doi.org/10.1136/annrheumdis-2021-eular.135.
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Background:Rheumatoid arthritis (RA) is a common chronic autoimmune connective tissue disease that mainly involves the joints. The incidence of RA is 5 to 10 per 1000 people[1]. Early diagnosis and treatment of RA can effectively prevent disease progression, joint damage, and other complications in 90% of patients[2]. At present, serum biomarkers used in the diagnosis of established RA are rheumatoid factor and anti-cyclic citrullinated peptide antibody[3]. However, early RA especially serum RF and anti-CCP antibody-negative is difficult to diagnose due to the lack of effective biomarkers. Therefore, it is vital to identify new and effective biomarkers for the early diagnosis and treatment of RA.Objectives:This study aimed to identify new biomarkers and mechanisms for RA disease progression at the transcriptome level through a combination of microarray and bioinformatics analyses.Methods:Microarray datasets for synovial tissue in RA or osteoarthritis (OA) were downloaded from the Gene Expression Omnibus (GEO) database, and differentially expressed genes (DEGs) were identified by R software. Tissue/organ-specific genes were recognized by BioGPS. Enrichment analyses were performed and protein-protein interaction (PPI) networks were constructed to understand the functions and enriched pathways of DEGs and to identify hub genes. Cytoscape was used to construct the co-expressed network and competitive endogenous RNA (ceRNA) networks. Biomarkers with high diagnostic value for the early diagnosis of RA were validated by GEO datasets. The ggpubr package was used to perform statistical analyses with Student’s t-test.Results:A total of 275 DEGs were identified between 16 RA samples and 10 OA samples from the datasets GSE77298 and GSE82107. Among these DEGs, 71 tissue/organ-specific expressed genes were recognized. Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analysis indicated that DEGs are mostly enriched in immune response, immune-related biological process, immune system, and cytokine signal pathways. Fifteen hub genes and gene cluster modules were identified by Cytoscape. Eight haematologic/immune system-specific expressed hub genes were verified by GEO datasets. GZMA, PRC1, and TTK may be biomarkers for diagnosis of early RA through combined the analysis of the verification results and the receiver operating characteristic (ROC) curve. NEAT1-miR-212-3p/miR-132-3p/miR-129-5p-TTK, XIST-miR-25-3p/miR-129-5p-GZMA, and TTK_hsa_circ_0077158- miR-212-3p/miR-132-3p/miR-129-5p-TTK might be potential RNA regulatory pathways to regulate the disease progression of early RA.Conclusion:This work identified three haematologic/immune system-specific expressed genes, namely, GZMA, PRC1, and TTK, as potential biomarkers for the early diagnosis and treatment of RA and provided insight into the mechanisms of disease development in RA at the transcriptome level. In addition, we proposed that NEAT1-miR-212-3p/miR-132-3p/miR-129-5p-TTK, XIST-miR-25-3p/miR-129-5p-GZMA, and TTK_hsa_circ_0077158-miR-212-3p/miR-132-3p/miR-129-5p-TTK are potential RNA regulatory pathways that control disease progression in early RA.References:[1]Smolen JS, Aletaha D, McInnes IB: Rheumatoid arthritis.Lancet 2016, 388:2023-2038.[2]Aletaha D, Smolen JS: Diagnosis and Management of Rheumatoid Arthritis: A Review.Jama 2018, 320:1360-1372.[3]Aletaha D, Neogi T, Silman AJ, Funovits J, Felson DT, Bingham CO, 3rd, Birnbaum NS, Burmester GR, Bykerk VP, Cohen MD, et al: 2010 Rheumatoid arthritis classification criteria: an American College of Rheumatology/European League Against Rheumatism collaborative initiative.Arthritis Rheum 2010, 62:2569-2581.Disclosure of Interests:None declared
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van Beek, Ellen M., Fiona Cochrane, A. Neil Barclay, and Timo K. van den Berg. "Signal Regulatory Proteins in the Immune System." Journal of Immunology 175, no. 12 (December 8, 2005): 7781–87. http://dx.doi.org/10.4049/jimmunol.175.12.7781.
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Yin, Junjie, Hong Yi, Xuewei Chen, and Jing Wang. "Post-Translational Modifications of Proteins Have Versatile Roles in Regulating Plant Immune Responses." International Journal of Molecular Sciences 20, no. 11 (June 8, 2019): 2807. http://dx.doi.org/10.3390/ijms20112807.
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To protect themselves from pathogens, plants have developed an effective innate immune system. Plants recognize pathogens and then rapidly alter signaling pathways within individual cells in order to achieve an appropriate immune response, including the generation of reactive oxygen species, callose deposition, and transcriptional reprogramming. Post-translational modifications (PTMs) are versatile regulatory changes critical for plant immune response processes. Significantly, PTMs are involved in the crosstalk that serves as a fine-tuning mechanism to adjust cellular responses to pathogen infection. Here, we provide an overview of PTMs that mediate defense signaling perception, signal transduction in host cells, and downstream signal activation.
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Çetin, Gonca, Sandro Klafack, Maja Studencka-Turski, Elke Krüger, and Frédéric Ebstein. "The Ubiquitin–Proteasome System in Immune Cells." Biomolecules 11, no. 1 (January 5, 2021): 60. http://dx.doi.org/10.3390/biom11010060.
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The ubiquitin–proteasome system (UPS) is the major intracellular and non-lysosomal protein degradation system. Thanks to its unique capacity of eliminating old, damaged, misfolded, and/or regulatory proteins in a highly specific manner, the UPS is virtually involved in almost all aspects of eukaryotic life. The critical importance of the UPS is particularly visible in immune cells which undergo a rapid and profound functional remodelling upon pathogen recognition. Innate and/or adaptive immune activation is indeed characterized by a number of substantial changes impacting various cellular processes including protein homeostasis, signal transduction, cell proliferation, and antigen processing which are all tightly regulated by the UPS. In this review, we summarize and discuss recent progress in our understanding of the molecular mechanisms by which the UPS contributes to the generation of an adequate immune response. In this regard, we also discuss the consequences of UPS dysfunction and its role in the pathogenesis of recently described immune disorders including cancer and auto-inflammatory diseases.
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Wilkinson, Melissa L., and Andrew J. Gow. "Effects of fatty acid nitroalkanes on signal transduction pathways and airway macrophage activation." Innate Immunity 27, no. 5 (July 2021): 353–64. http://dx.doi.org/10.1177/17534259211015330.
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Fatty acid nitroalkenes are reversibly-reactive electrophiles that are endogenously detectable at nM concentrations and display anti-inflammatory, pro-survival actions. These actions are elicited through the alteration of signal transduction proteins via a Michael addition on nucleophilic cysteine thiols. Nitrated fatty acids (NO2-FAs), like 9- or 10-nitro-octadec-9-enolic acid, will act on signal transduction proteins directly or on key regulatory proteins to cause an up-regulation or down-regulation of the protein’s expression, yielding an anti-inflammatory response. These responses have been characterized in many organ systems, such as the cardiovascular system, with the pulmonary system less well defined. Macrophages are one of the most abundant immune cells in the lung and are essential in maintaining lung homeostasis. Despite this, macrophages can play a role in both acute and chronic lung injury due to up-regulation of anti-inflammatory signal transduction pathways and down-regulation of pro-inflammatory pathways. Through their propensity to alter signal transduction pathways, NO2-FAs may be able to reduce macrophage activation during pulmonary injury. This review will focus on the implications of NO2-FAs on macrophage activation in the lung and the signal transduction pathways that may be altered, leading to reduced pulmonary injury.
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Cai, Guiquan, Xuan Yang, Ting Chen, Fangchun Jin, Jing Ding, and Zhenkai Wu. "Integrated bioinformatics analysis of potential pathway biomarkers using abnormal proteins in clubfoot." PeerJ 8 (January 20, 2020): e8422. http://dx.doi.org/10.7717/peerj.8422.
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Background As one of the most common major congenital distal skeletal abnormalities, congenital talipes equinovarus (clubfoot) affects approximately one in one thousandth newborns. Although several etiologies of clubfoot have been proposed and several genes have been identified as susceptible genes, previous studies did not further explore signaling pathways and potential upstream and downstream regulatory networks. Therefore, the aim of the present investigation is to explore abnormal pathways and their interactions in clubfoot using integrated bioinformatics analyses. Methods KEGG, gene ontology (GO), Reactome (REAC), WikiPathways (WP) or human phenotype ontology (HP) enrichment analysis were performed using WebGestalt, g:Profiler and NetworkAnalyst. Results A large number of signaling pathways were enriched e.g. signal transduction, disease, metabolism, gene expression (transcription), immune system, developmental biology, cell cycle, and ECM. Protein-protein interactions (PPIs) and gene regulatory networks (GRNs) analysis results indicated that extensive and complex interactions occur in these proteins, enrichment pathways, and TF-miRNA coregulatory networks. Transcription factors such as SOX9, CTNNB1, GLI3, FHL2, TGFBI and HOXD13, regulated these candidate proteins. Conclusion The results of the present study supported previously proposed hypotheses, such as ECM, genetic, muscle, neurological, skeletal, and vascular abnormalities. More importantly, the enrichment results also indicated cellular or immune responses to external stimuli, and abnormal molecular transport or metabolism may be new potential etiological mechanisms of clubfoot.
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Wang, Zhi W., Luciana Sarmento, Yuhuan Wang, Xia-qing Li, Vikas Dhingra, Tesfai Tseggai, Baoming Jiang, and Zhen F. Fu. "Attenuated Rabies Virus Activates, while Pathogenic Rabies Virus Evades, the Host Innate Immune Responses in the Central Nervous System." Journal of Virology 79, no. 19 (October 1, 2005): 12554–65. http://dx.doi.org/10.1128/jvi.79.19.12554-12565.2005.
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ABSTRACT Rabies virus (RV) induces encephalomyelitis in humans and animals. However, the pathogenic mechanism of rabies is not fully understood. To investigate the host responses to RV infection, we examined and compared the pathology, particularly the inflammatory responses, and the gene expression profiles in the brains of mice infected with wild-type (wt) virus silver-haired bat RV (SHBRV) or laboratory-adapted virus B2C, using a mouse genomic array (Affymetrix). Extensive inflammatory responses were observed in animals infected with the attenuated RV, but little or no inflammatory responses were found in mice infected with wt RV. Furthermore, attenuated RV induced the expression of the genes involved in the innate immune and antiviral responses, especially those related to the alpha/beta interferon (IFN-α/β) signaling pathways and inflammatory chemokines. For the IFN-α/β signaling pathways, many of the interferon regulatory genes, such as the signal transduction activation transducers and interferon regulatory factors, as well as the effector genes, for example, 2′-5′-oligoadenylate synthetase and myxovirus proteins, are highly induced in mice infected with attenuated RV. However, many of these genes were not up-regulated in mice infected with wt SHBRV. The data obtained by microarray analysis were confirmed by real-time PCR. Together, these data suggest that attenuated RV activates, while pathogenic RV evades, the host innate immune and antiviral responses.
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Naj, Xenia, Ann-Kathrin Hoffmann, Mirko Himmel, and Stefan Linder. "The Formins FMNL1 and mDia1 Regulate Coiling Phagocytosis of Borrelia burgdorferi by Primary Human Macrophages." Infection and Immunity 81, no. 5 (March 4, 2013): 1683–95. http://dx.doi.org/10.1128/iai.01411-12.
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ABSTRACTSpirochetes of theBorrelia burgdorferisensu latocomplex are the causative agent of Lyme borreliosis, a tick-borne infectious disease primarily affecting the skin, nervous system, and joints. During infection, macrophages and dendritic cells are the first immune cells to encounter invading borreliae. Phagocytosis and intracellular processing ofBorreliaby these cells is thus decisive for the eventual outcome of infection. Phagocytic uptake ofBorreliaby macrophages proceeds preferentially through coiling phagocytosis, which is characterized by actin-rich unilateral pseudopods that capture and enwrap spirochetes. Actin-dependent growth of these pseudopods necessitatesde novonucleation of actin filaments, which is regulated by actin-nucleating factors such as Arp2/3 complex. Here, we demonstrate that, in addition, also actin-regulatory proteins of the formin family are important for uptake of borreliae by primary human macrophages. Using immunofluorescence, live-cell imaging, and ratiometric analysis, we find specific enrichment of the formins FMNL1 and mDia1 at macrophage pseudopods that are in contact with borreliae. Consistently, small interfering RNA (siRNA)-mediated knockdown of FMNL1 or mDia1 leads to decreased formation ofBorrelia-induced pseudopods and to decreased internalization of borreliae by macrophages. Our results suggest that macrophage coiling phagocytosis is a complex process involving several actin nucleation/regulatory factors. They also point specifically to the formins mDia1 and FMNL1 as novel regulators of spirochete uptake by human immune cells.
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Hoefig, Kai P., and Vigo Heissmeyer. "Posttranscriptional regulation of T helper cell fate decisions." Journal of Cell Biology 217, no. 8 (April 23, 2018): 2615–31. http://dx.doi.org/10.1083/jcb.201708075.
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T helper cell subsets orchestrate context- and pathogen-specific responses of the immune system. They mostly do so by secreting specific cytokines that attract or induce activation and differentiation of other immune or nonimmune cells. The differentiation of T helper 1 (Th1), Th2, T follicular helper, Th17, and induced regulatory T cell subsets from naive T cells depends on the activation of intracellular signal transduction cascades. These cascades originate from T cell receptor and costimulatory receptor engagement and also receive critical input from cytokine receptors that sample the cytokine milieu within secondary lymphoid organs. Signal transduction then leads to the expression of subset-specifying transcription factors that, in concert with other transcription factors, up-regulate downstream signature genes. Although regulation of transcription is important, recent research has shown that posttranscriptional and posttranslational regulation can critically shape or even determine the outcome of Th cell differentiation. In this review, we describe how specific microRNAs, long noncoding RNAs, RNA-binding proteins, and ubiquitin-modifying enzymes regulate their targets to skew cell fate decisions.
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Pavlopoulou, Athanasia. "Cathelicidins Revisited." International Journal of Systems Biology and Biomedical Technologies 2, no. 2 (April 2013): 8–32. http://dx.doi.org/10.4018/ijsbbt.2013040102.
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Cathelicidins constitute important antimicrobial peptides of innate immunity. In order to elucidate the evolutionary history of cathelicidins, the author performed comprehensive phylogenetic analyses of cathelicidin homologs in all available genomes including those completed recently. The organization of cathelicidin genes, as well as the secondary and tertiary structures of the inferred proteins are conserved. Based on integrated genomic, structural, and functional data, the author identified the last common ancestor of the cathelicidin family in lampreys, thus tracing the evolutionary origin of cathelicidins 550 million years ago. The author’s data suggest that cathelicidins arose concordantly with the adaptive immune system, a new organismal function first acquired in lampreys. The appearance of cathelicidins at the junction of innate and adaptive immunity may explain their dual roles as signal transducing molecules and as antimicrobial peptide precursors. Conserved regulatory elements associated with functions of the immune system were identified in cathelicidin gene promoter sequences invariably from fishes to humans.
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Gatz, Christiane. "From Pioneers to Team Players: TGA Transcription Factors Provide a Molecular Link Between Different Stress Pathways." Molecular Plant-Microbe Interactions® 26, no. 2 (February 2013): 151–59. http://dx.doi.org/10.1094/mpmi-04-12-0078-ia.
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The plant immune system encompasses an arsenal of defense genes that is activated upon recognition of a pathogen. Appropriate adjustment of gene expression is mediated by multiple interconnected signal transduction cascades that finally control the activity of transcription factors. These sequence-specific DNA-binding proteins act at the interface between the DNA and the regulatory protein network. In 1989, tobacco TGA1a was cloned as the first plant transcription factor. Since then, multiple studies have shown that members of the TGA family play important roles in defense responses against biotrophic and necrotrophic pathogens and against chemical stress. Here, we review 22 years of research on TGA factors which have yielded both consistent and conflicting results.
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Chambers, Rebecca L., and John C. McDermott. "Molecular Basis of Skeletal Muscle Regeneration." Canadian Journal of Applied Physiology 21, no. 3 (June 1, 1996): 155–84. http://dx.doi.org/10.1139/h96-014.
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Skeletal muscle regeneration is a vital process with important implications for various muscle myopathies and adaptations to physiological overload. Few of the molecular regulatory proteins controlling this process have so far been identified. Several growth factors have defined effects on myogenic precursor cells and appear to also be involved during regeneration. In addition, factors that may be released by cells of the immune system may activate satellite cells during regeneration. Many of these growth factors are associated with signalling cascades which transmit information to the nucleus. The nuclear "receptors" that receive the incoming signals are transcription factors that interact with DNA regulatory sequences in order to modulate gene expression. Of the nuclear factors isolated so far, the immediate-early genes are associated with muscle precursor cell proliferation. This review aims to synthesize the extensive research on myogenic differentiation and relate this to research concerning the molecular regulation of skeletal muscle regeneration. Key words: satellite cells, growth factors, signal transduction, transcription factors, gene regulation, overload adaptation
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DAMIANO, Jason S., Vasco OLIVEIRA, Kate WELSH, and John C. REED. "Heterotypic interactions among NACHT domains: implications for regulation of innate immune responses." Biochemical Journal 381, no. 1 (June 22, 2004): 213–19. http://dx.doi.org/10.1042/bj20031506.
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Proteins of the NACHT [NAIP (neuronal apoptosis inhibitory protein), CIITA (MHC class II transcription activator), HET-E (incompatibility locus protein from Podospora anserina) and TP1 (telomerase-associated protein)] family may serve as critical pathogen-sensing and signal-transducing molecules within the innate immune system. In the present paper, we show that CLAN [CARD (caspase-recruitment domain), LRR (leucine-rich repeat) and NACHT domain-containing protein], a NACHT-containing protein originally demonstrated to bind and activate pro-caspase 1, is also capable of influencing the functions of other members of the NACHT family. Through heterotypic NACHT-domain interactions, CLAN was found to associate with Nod1, Nod2 and NAC [nucleotide-binding domain and CARD-containing protein; NALP1 (NACHT, LRR and PYRIN protein 1)] when co-expressed in HEK-293T (human embryonic kidney) cells. NF-κB (nuclear factor κB) reporter assays demonstrated that co-expression of either full-length CLAN or the NACHT domain of CLAN significantly inhibited NF-κB activation induced by Nod1 or Nod2 overexpression. In addition, co-expression of CLAN or the NACHT domain of CLAN with Nod1 or Nod2 inhibited the ability of these proteins to generate active IL-1β (interleukin 1β) through their association with pro-caspase 1. The NACHT domain of CLAN was demonstrated by co-immunoprecipitation experiments to bind all NACHT domains that were tested, including the NACHT domains from CLAN itself, Nod1, Nod2, cryopyrin, NAC, PAN2 {PAAD [pyrin, AIM (absent-in-melanoma), ASC (apoptosis-associated speck-like protein containing a CARD) and death-domain-like]- and NACHT-containing protein} and NAIP (neuronal apoptosis inhibitory protein). Finally, monocyte-expressed CLAN was found to associate with Nod2 following exposure to bacterial peptidoglycan, implying a regulatory role for interaction of these NACHT proteins in the innate immune response. These studies suggest that by mediating hetero-oligomerization, NACHT domains provide a means by which various NACHT-containing proteins may interact, creating protein-interaction networks that potentially modulate immune responses to invading pathogens.
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Correa, Ricardo G., Snezana Milutinovic, and John C. Reed. "Roles of NOD1 (NLRC1) and NOD2 (NLRC2) in innate immunity and inflammatory diseases." Bioscience Reports 32, no. 6 (October 15, 2012): 597–608. http://dx.doi.org/10.1042/bsr20120055.
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NOD1 {nucleotide-binding oligomerization domain 1; NLRC [NOD-LRR (leucine-rich repeat) family with CARD (caspase recruitment domain) 1]} and NOD2 (NLRC2) are among the most prominent members of the NLR (NOD-LRR) family –proteins that contain nucleotide-binding NACHT domains and receptor-like LRR domains. With over 20 members identified in humans, NLRs represent important components of the mammalian innate immune system, serving as intracellular receptors for pathogens and for endogenous molecules elaborated by tissue injury. NOD1 and NOD2 proteins operate as microbial sensors through the recognition of specific PG (peptidoglycan) constituents of bacteria. Upon activation, these NLR family members initiate signal transduction mechanisms that include stimulation of NF-κB (nuclear factor-κB), stress kinases, IRFs (interferon regulatory factors) and autophagy. Hereditary polymorphisms in the genes encoding NOD1 and NOD2 have been associated with an increasing number of chronic inflammatory diseases. In fact, potential roles for NOD1 and NOD2 in inflammatory disorders have been revealed by investigations using a series of animal models. In the present review, we describe recent experimental findings associating NOD1 and NOD2 with various autoimmune and chronic inflammatory disorders, and we discuss prospects for development of novel therapeutics targeting these NLR family proteins.
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Zhou, Xiaolu, Shanli Wu, Hongda Zhou, Mengyun Wang, Menghan Wang, Yan Lü, Zhongyi Cheng, Jiacui Xu, and Yongxing Ai. "Marek’s Disease Virus Regulates the Ubiquitylome of Chicken CD4+ T Cells to Promote Tumorigenesis." International Journal of Molecular Sciences 20, no. 9 (April 28, 2019): 2089. http://dx.doi.org/10.3390/ijms20092089.
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Ubiquitination and deubiquitination of cellular proteins are reciprocal reactions catalyzed by ubiquitination-related enzymes and deubiquitinase (DUB) which regulate almost all cellular processes. Marek’s disease virus (MDV) encodes a viral DUB that plays an important role in the MDV pathogenicity. Chicken CD4+ T-cell lymphoma induced by MDV is a key contributor to multiple visceral tumors and immunosuppression of chickens with Marek’s disease (MD). However, alterations in the ubiquitylome of MDV-induced T lymphoma cells are still unclear. In this study, a specific antibody against K-ε-GG was used to isolate ubiquitinated peptides from CD4+ T cells and MD T lymphoma cells. Mass spectrometry was used to compare and analyze alterations in the ubiquitylome. Our results showed that the ubiquitination of 717 and 778 proteins was significantly up- and downregulated, respectively, in T lymphoma cells. MDV up- and downregulated ubiquitination of a similar percentage of proteins. The ubiquitination of transferases, especially serine/threonine kinases, was the main regulatory target of MDV. Compared with CD4+ T cells of the control group, MDV mainly altered the ubiquitylome associated with the signal transduction, immune system, cancer, and infectious disease pathways in T lymphoma cells. In these pathways, the ubiquitination of CDK1, IL-18, PRKCB, ETV6, and EST1 proteins was significantly up- or downregulated as shown by immunoblotting. The current study revealed that the MDV infection could exert a significant influence on the ubiquitylome of CD4+ T cells.
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Smith, Rosemary E., Vanshree Patel, Sandra D. Seatter, Maureen R. Deehan, Marion H. Brown, Gareth P. Brooke, Helen S. Goodridge, et al. "A novel MyD-1 (SIRP-1α) signaling pathway that inhibits LPS-induced TNFα production by monocytes." Blood 102, no. 7 (October 1, 2003): 2532–40. http://dx.doi.org/10.1182/blood-2002-11-3596.
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Abstract MyD-1 (CD172) is a member of the family of signal regulatory phosphatase (SIRP) binding proteins, which is expressed on human CD14+ monocytes and dendritic cells. We now show a novel role for MyD-1 in the regulation of the innate immune system by pathogen products such as lipopolysaccharide (LPS), purified protein derivative (PPD), and Zymosan. Specifically, we demonstrate that ligation of MyD-1 on peripheral blood mononuclear cells (PBMCs) inhibits tumor necrosis factor alpha (TNFα) secretion but has no effect on other cytokines induced in response to each of these products. In an attempt to understand the molecular mechanisms underlying this surprisingly selective effect we investigated signal transduction pathways coupled to MyD-1. Ligation of the SIRP was found to recruit the tyrosine phosphatase SHP-2 and promote sequential activation of phosphatidylinositol (PI) 3-kinase, phospholipase D, and sphingosine kinase. Inhibition of LPS-induced TNFα secretion by MyD-1 appears to be mediated by this pathway, as the PI 3-kinase inhibitor wortmannin restores normal LPS-driven TNFα secretion. MyD-1-coupling to this PI 3-kinase-dependent signaling pathway may therefore present a novel target for the development of therapeutic strategies for combating TNFα production and consequent inflammatory disease. (Blood. 2003;102:2532-2540)
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Wei, Tzu-Hsuan, and Ching-Liang Hsieh. "Effect of Acupuncture on the p38 Signaling Pathway in Several Nervous System Diseases: A Systematic Review." International Journal of Molecular Sciences 21, no. 13 (June 30, 2020): 4693. http://dx.doi.org/10.3390/ijms21134693.
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Acupuncture is clinically used to treat various diseases and exerts positive local and systemic effects in several nervous system diseases. Advanced molecular and clinical studies have continually attempted to decipher the mechanisms underlying these effects of acupuncture. While a growing understanding of the pathophysiology underlying several nervous system diseases shows it to be related to inflammation and impair cell regeneration after ischemic events, the relationship between the therapeutic mechanism of acupuncture and the p38 MAPK signal pathway has yet to be elucidated. This review discusses the latest advancements in the identification of the effect of acupuncture on the p38 signaling pathway in several nervous system diseases. We electronically searched databases including PubMed, Embase, and the Cochrane Library from their inception to April 2020, using the following keywords alone or in various combinations: “acupuncture”, “p38 MAPK pathway”, “signaling”, “stress response”, “inflammation”, “immune”, “pain”, “analgesic”, “cerebral ischemic injury”, “epilepsy”, “Alzheimer’s disease”, “Parkinson’s disease”, “dementia”, “degenerative”, and “homeostasis”. Manual acupuncture and electroacupuncture confer positive therapeutic effects by regulating proinflammatory cytokines, ion channels, scaffold proteins, and transcription factors including TRPV1/4, Nav, BDNF, and NADMR1; consequently, p38 regulates various phenomena including cell communication, remodeling, regeneration, and gene expression. In this review article, we found the most common acupoints for the relief of nervous system disorders including GV20, GV14, ST36, ST37, and LI4. Acupuncture exhibits dual regulatory functions of activating or inhibiting different p38 MAPK pathways, contributing to an overall improvement of clinical symptoms and function in several nervous system diseases.
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Lacey, Derek, Peter Hickey, Benedicta D. Arhatari, Lorraine A. O’Reilly, Leona Rohrbeck, Helen Kiriazis, Xiao-Jun Du, and Philippe Bouillet. "Spontaneous retrotransposon insertion into TNF 3′UTR causes heart valve disease and chronic polyarthritis." Proceedings of the National Academy of Sciences 112, no. 31 (July 20, 2015): 9698–703. http://dx.doi.org/10.1073/pnas.1508399112.
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Rheumatoid arthritis (RA) and ankylosing spondylitis (AS) are chronic inflammatory diseases that together affect 2–3% of the population. RA and AS predominantly involve joints, but heart disease is also a common feature in RA and AS patients. Here we have studied a new spontaneous mutation that causes severe polyarthritis in bone phenotype spontaneous mutation 1 (BPSM1) mice. In addition to joint destruction, mutant mice also develop aortic root aneurism and aorto-mitral valve disease that can be fatal depending on the genetic background. The cause of the disease is the spontaneous insertion of a retrotransposon into the 3′ untranslated region (3′UTR) of the tumor necrosis factor (TNF), which triggers its strong overexpression in myeloid cells. We found that several members of a family of RNA-binding, CCCH-containing zinc-finger proteins control TNF expression through its 3′UTR, and we identified a previously unidentified regulatory element in the UTR. The disease in BPSM1 mice is independent of the adaptive immune system and does not appear to involve inflammatory cytokines other than TNF. To our knowledge, this is the first animal model showing both polyarthritis and heart disease as a direct result of TNF deregulation. These results emphasize the therapeutic potential of anti-TNF drugs for the treatment of heart valve disease and identify potential therapeutic targets to control TNF expression and inflammation.
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Das, Sudip, Claudia Lindemann, Bernadette C. Young, Julius Muller, Babett Österreich, Nicola Ternette, Ann-Cathrin Winkler, et al. "Natural mutations in aStaphylococcus aureusvirulence regulator attenuate cytotoxicity but permit bacteremia and abscess formation." Proceedings of the National Academy of Sciences 113, no. 22 (May 16, 2016): E3101—E3110. http://dx.doi.org/10.1073/pnas.1520255113.
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Staphylococcus aureusis a major bacterial pathogen, which causes severe blood and tissue infections that frequently emerge by autoinfection with asymptomatically carried nose and skin populations. However, recent studies report that bloodstream isolates differ systematically from those found in the nose and skin, exhibiting reduced toxicity toward leukocytes. In two patients, an attenuated toxicity bloodstream infection evolved from an asymptomatically carried high-toxicity nasal strain by loss-of-function mutations in the gene encoding the transcription factor repressor of surface proteins (rsp). Here, we report thatrspknockout mutants lead to global transcriptional and proteomic reprofiling, and they exhibit the greatest signal in a genome-wide screen for genes influencingS. aureussurvival in human cells. This effect is likely to be mediated in part viaSSR42, a long-noncoding RNA. We show thatrspcontrolsSSR42 expression, is induced by hydrogen peroxide, and is required for normal cytotoxicity and hemolytic activity. Rsp inactivation in laboratory- and bacteremia-derived mutants attenuates toxin production, but up-regulates other immune subversion proteins and reduces lethality during experimental infection. Crucially, inactivation ofrsppreserves bacterial dissemination, because it affects neither formation of deep abscesses in mice nor survival in human blood. Thus, we have identified a spontaneously evolving, attenuated-cytotoxicity, nonhemolyticS. aureusphenotype, controlled by a pleiotropic transcriptional regulator/noncoding RNA virulence regulatory system, capable of causingS. aureusbloodstream infections. Such a phenotype could promote deep infection with limited early clinical manifestations, raising concerns that bacterial evolution within the human body may contribute to severe infection.
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MacKenzie, Kirsty F., Derek A. Wallace, Elaine V. Hill, Diana F. Anthony, David J. P. Henderson, Daniel M. Houslay, J. Simon C. Arthur, George S. Baillie, and Miles D. Houslay. "Phosphorylation of cAMP-specific PDE4A5 (phosphodiesterase-4A5) by MK2 (MAPKAPK2) attenuates its activation through protein kinase A phosphorylation." Biochemical Journal 435, no. 3 (April 13, 2011): 755–69. http://dx.doi.org/10.1042/bj20101184.
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cAMP-specific PDE (phosphodiesterase) 4 isoforms underpin compartmentalized cAMP signalling in mammalian cells through targeting to specific signalling complexes. Their importance is apparent as PDE4 selective inhibitors exert profound anti-inflammatory effects and act as cognitive enhancers. The p38 MAPK (mitogen-activated protein kinase) signalling cascade is a key signal transduction pathway involved in the control of cellular immune, inflammatory and stress responses. In the present study, we show that PDE4A5 is phosphorylated at Ser147, within the regulatory UCR1 (ultraconserved region 1) domain conserved among PDE4 long isoforms, by MK2 (MAPK-activated protein kinase 2, also called MAPKAPK2). Phosphorylation by MK2, although not altering PDE4A5 activity, markedly attenuates PDE4A5 activation through phosphorylation by protein kinase A. This modification confers the amplification of intracellular cAMP accumulation in response to adenylate cyclase activation by attenuating a major desensitization system to cAMP. Such reprogramming of cAMP accumulation is recapitulated in wild-type primary macrophages, but not MK2/3-null macrophages. Phosphorylation by MK2 also triggers a conformational change in PDE4A5 that attenuates PDE4A5 interaction with proteins whose binding involves UCR2, such as DISC1 (disrupted in schizophrenia 1) and AIP (aryl hydrocarbon receptor-interacting protein), but not the UCR2-independent interacting scaffold protein β-arrestin. Long PDE4 isoforms thus provide a novel node for cross-talk between the cAMP and p38 MAPK signalling systems at the level of MK2.
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Gilani, Syed Amir. "THE FUTURE OF BODY IMPLANTS." Asian Journal of Allied Health Sciences (AJAHS) 5, no. 1 (March 20, 2021): 2–3. http://dx.doi.org/10.52229/ajahs.v5i1.802.
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There are around 415 million people suffering from diabetes around the globe, and they don't need to get their finger punctured every time their blood sugar is to be monitored or insulin to be delivered, thanks to the magical “Insulin Pumps”. All these tiny machines have is a needle and a small pump, the system is able to monitor the glucose levels, provide information to the pump and then determine the amount of insulin to be injected through the needle. But they have a catch: they're temporary. Within a few days, glucose sensors have to be moved and replaced. And it's not just glucose monitors and insulin pumps that have this problem, but all bodily implants, at different time scales. Plastic prosthetic knees have to be replaced after about 20 years. Other implants, such as those used for cosmetic reasons, can meet the same fate in about 10. That isn't just a nuisance: it can be expensive and risky. This inconvenience happens because of our bodies' immune systems. Honed by several hundred million years of evolution, these defensive fronts have become exceptionally good at identifying foreign objects. Our immune systems boast an impressivearsenal of tools to tackle, intercept, and destroy anything they believe shouldn't be there. But the consequence of this constant surveillance is that our bodies treat helpful implants, like insulin pumps, with the same suspicion as they would a harmful virus or bacteria. As soon as the insulin pump has been implanted in the skin, its presence triggers what's known as a “foreign body response.” This starts with free-floating proteins that stick themselves to the surface of the implant. Those proteins include antibodies, which attempt to neutralize the new object and send out a signal that calls other immune cells to the site to strengthen the attack. Early-responding inflammatory cells, like neutrophils and macrophages, respond to the emergency call. The needle of the pump is labeled as foreign object and attacked with tiny grains that are filled with enzymes, they try t deteriorate the surface of the insulin pump's needle. Macrophages secrete enzymes too, together with nitric oxide radicals, which create a chemical reaction that degrades the object over time. If the macrophages are unable to dispatch the foreign body rapidly, they fuse together, forming a mass of cells called a “giant cell.” At the same time, cells called fibroblasts travel to the site and begin to deposit layers of dense connective tissue. Those enclose the needle that the pump uses to deliver insulin and test for glucose levels. Over time this scaffolding builds up, forming a scar around the implant. The scar functions as an almost impenetrable wall that might start to block vital interactions between the body and the implant. For example, scarring around pacemakers (an electrically charged medical device to control heartbeat) can interrupt the electrical transmission that's crucial for their functioning. With time due to stress and workload, Synthetic knee joints might give out particles that trigger immune cells to come into action and inflame around these fragments. Unfortunately the work of immune system attack might sometime be fatal and endanger life. Research work is underway to trick the immune system into accepting the new devices that are introduced into our bodily tissues. There are implants coated with certain chemicals and drugs that somewhat downplay the response of immune system. Those basically make the implants invisible to the immune system. More implants are being made out of natural materials and in forms that directly mimic issues, so that the body launches a weaker attack than it would if it came across a completely artificial implant. Some medical treatments involve implants designed to regenerate lost or damaged tissues. In those cases, the implant is designed to contain ingredients that will release specific signals, and carefully tailor to bodies' immune reactions. In the future, this way of working alongside the immune system could help develop completely artificial organs, totally integrative prostheses, and self-healing wound therapies. These treatments might one day revolutionize medicine and transform, forever, thebodies we live in.
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Rodriguez, Kenny R., and Curt M. Horvath. "Paramyxovirus V Protein Interaction with the Antiviral Sensor LGP2 Disrupts MDA5 Signaling Enhancement but Is Not Relevant to LGP2-Mediated RLR Signaling Inhibition." Journal of Virology 88, no. 14 (May 14, 2014): 8180–88. http://dx.doi.org/10.1128/jvi.00737-14.
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ABSTRACTThe interferon antiviral system is a primary barrier to virus replication triggered upon recognition of nonself RNAs by the cytoplasmic sensors encoded by retinoic acid-inducible gene I (RIG-I), melanoma differentiation-associated gene 5 (MDA5), and laboratory of genetics and physiology gene 2 (LGP2). Paramyxovirus V proteins are interferon antagonists that can selectively interact with MDA5 and LGP2 through contact with a discrete helicase domain region. Interaction with MDA5, an activator of antiviral signaling, disrupts interferon gene expression and antiviral responses. LGP2 has more diverse reported roles as both a coactivator of MDA5 and a negative regulator of both RIG-I and MDA5. This functional dichotomy, along with the concurrent interference with both cellular targets, has made it difficult to assess the unique consequences of V protein interaction with LGP2. To directly evaluate the impact of LGP2 interference, MDA5 and LGP2 variants unable to be recognized by measles virus and parainfluenza virus 5 (PIV5) V proteins were tested in signaling assays. Results indicate that interaction with LGP2 specifically prevents coactivation of MDA5 signaling and that LGP2's negative regulatory capacity was not affected. V proteins only partially antagonize RIG-I at high concentrations, and their expression had no additive effects on LGP2-mediated negative regulation. However, conversion of RIG-I to a direct V protein target was accomplished by only two amino acid substitutions that allowed both V protein interaction and efficient interference. These results clarify the unique consequences of MDA5 and LGP2 interference by paramyxovirus V proteins and help resolve the distinct roles of LGP2 in both activation and inhibition of antiviral signal transduction.IMPORTANCEParamyxovirus V proteins interact with two innate immune receptors, MDA5 and LGP2, but not RIG-I. V proteins prevent MDA5 from signaling to the beta interferon promoter, but the consequences of LGP2 targeting are poorly understood. As the V protein targets MDA5 and LGP2 simultaneously, and LGP2 is both a positive and negative regulator of both MDA5 and RIG-I, it has been difficult to evaluate the specific advantages conferred by LGP2 targeting. Experiments with V-insensitive proteins revealed that the primary outcome of LGP2 interference is suppression of its ability to synergize with MDA5. LGP2's negative regulation of MDA5 and RIG-I remains intact irrespective of V protein interaction. Complementary experiments demonstrate that RIG-I can be converted to V protein sensitivity by two amino acid substitutions. These findings clarify the functions of LGP2 as a positive regulator of MDA5 signaling, demonstrate the basis for V-mediated LGP2 targeting, and broaden our understanding of paramyxovirus-host interactions.
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Cheng, Q., M. Chen, X. Chen, X. Chen, H. Wu, and Y. Du. "POS0416 NOVEL LONG NON-CODING RNA EXPRESSION PROFILE OF PERIPHERAL BLOOD MONOUCLEAR CELL REVEALED POTENTIAL BIOMARKERS AND REGULATORY MECHANISM IN SYSTEMIC LUPUS ERYTHEMATOSUS." Annals of the Rheumatic Diseases 80, Suppl 1 (May 19, 2021): 437.1–437. http://dx.doi.org/10.1136/annrheumdis-2021-eular.129.
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Background:Systemic lupus erythematosus (SLE) is a complex and heterogeneous autoimmune disease, usually involving multiple systems of the whole body (1). A variety of factors can affect SLE, such as genetic, environmental, immunoregulatory, hormonal and epigenetic (2). Long non-coding RNA is a type of RNA greater than 200 nucleotides that does not encode proteins. With the development of research, lncRNA gradually becomes the key regulator of gene expression in the immune system (3). Studies have shown that several lncRNAs, such as NEAT1 and GAS5 are dysregulated in SLE and are involved in the pathogenesis of SLE (4,5). These results suggest that lncRNA can be used as a potential biomarker for disease diagnosis and treatment. However, our current understanding of SLE related lncRNAS is still limited.Objectives:The purpose of this study was to find new lncRNAs in peripheral blood monouclear cells of SLE patients by transcriptome sequencing and explore their potential as biomarkers and their correlation with clinical features.Methods:Transcriptome sequencing was used to screen differentially expressed lncRNAs (DELs) and mRNAs (DEMs). DAVID and WebGestalt were used to perform enrichment analysis. Cytoscape was used to constructed protein-protein network, co-expression network and competitive endogenous RNA network to reveal the regulatory mechanism of lncRNAs in transcriptome level. The expression of these selected lncRNAs in SLE patients and healthy controls were verified by qPCR.Results:A toal of 1737 DELs and 4078 DEMs were identified between 5 SLE patients and 5 healthy controls. Most of upregulated genes were enriched in defense and immune response, while downregulated genes were mainly enriched in SLE related pathways. Topology network analysis reveal the regulatory mechanism of lncRNAs in transcriptome level including directly acting on mRNA or indirectly affecting gene expression after acting on miRNA. Ten lncRNAs and eight genes was verified by qPCR in bigger samples including 77 SLE patients and 25 healthy controls. LncRNA NONHSAT101022.2 was significantly downregulated in SLE patients (p=0.001) and the expression of NONHSAT101022.2 showed a significant negative correlation with SLE disease activity index (SLEDAI, r=-0.3592, p=0.0013).Conclusion:In this work, we identified a large number of mRNAs and novel lncRNAs by transcriptome sequence. The function and regulatory mechanism of these lncRNAs were analyzed by bioinformatics methods. LncRNA NONHSAT101022.2 is significantly downregulated in SLE patients and significantly related to the activity and severity of disease. Additionally, we put forward that NONHSAT101022.2 may enhance the signal transduction of β2-AR by cis-regulating its target gene, LMBRD2, which induces NK cells to produce high levels of IFN-γ, thereby exacerbating SLE.References:[1]Carter EE, Barr SG, Clarke AE. The global burden of SLE: prevalence, health disparities and socioeconomic impact. Nat Rev Rheumatol. 2016;12(10):605-20.[2]Han EC. Systemic lupus erythematosus. N Engl J Med. 2012;366(6):573-4; author reply.[3]Chen YG, Satpathy AT, Chang HY. Gene regulation in the immune system by long noncoding RNAs. Nat Immunol. 2017;18(9):962-72.[4]Zhang F, Wu L, Qian J, Qu B, Xia S, La T, et al. Identification of the long noncoding RNA NEAT1 as a novel inflammatory regulator acting through MAPK pathway in human lupus. Journal of autoimmunity. 2016;75:96-104.[5]Liu Q, Deng Y, Li C, Xie H, Liu Q, Ming S, et al. LncRNA GAS5 suppresses CD4(+) T cell activation by upregulating E4BP4 via inhibiting miR-92a-3p in systemic lupus erythematosus. Immunol Lett. 2020;227:41-7.Disclosure of Interests:None declared
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Yamamoto, Ryo, Momoko Nishikori, Toshio Kitawaki, Tomomi Sakai, Masakatsu Hishizawa, Masaharu Tashima, Tadakazu Kondo, Katsuyuki Ohmori, and Takashi Uchiyama. "PD-1/PD-1-Ligand Interaction Contributes to Immunosuppressive Microenvironment of Hodgkin Lymphoma." Blood 110, no. 11 (November 16, 2007): 379. http://dx.doi.org/10.1182/blood.v110.11.379.379.
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Abstract Programmed death-1 (PD-1), a member of the CD28 costimulatory receptor superfamily, inhibits T cell activity by providing a second signal to T cells in conjunction with signaling through the T-cell receptor. PD-1/PD-1 ligand (PD-L) signaling system is indicated to be involved in the functional impairment of T cells such as in chronic viral infection or tumor immune evasion. We hypothesized that this signaling system is also involved in the pathogenesis of Hodgkin lymphoma (HL). We examined expression of B7-H1 and B7-DC, two known PD-Ls, in lymphoid cell lines using RT-PCR and flow cytometry. They were expressed in HL and several T-cell lines, whereas most B-NHL lines lacked their expression. Immunohistochemical staining of HL tissues demonstrated that PD-Ls were also expressed in primary H/RS cells. As gene expression of B7-H1 and B7-DC was increased in Epstein-Barr virus (EBV)-transformed lymphoblastoid B-cell lines, we examined the effect of EBV latent membrane proteins on their gene regulation. By luciferase reporter assay, both LMP1 and LMP2A were shown to enhance promoter activity of B7-H1 and B7-DC genes. This finding implies that in cases of EBV-positive HL, latent membrane proteins may help H/RS cells escape from host immune surveillance by upregulating PD-L gene expression. We next analyzed PD-1 expression of tumor-infiltrating T cells of HL tissue samples by flow cytometry, and found that PD-1+ cells were elevated markedly in these cells. As HL patients are well recognized as having defective cellular immunity, we compared PD-1 expression level in peripheral blood T cells of HL patients with those of healthy volunteers and B-NHL patients. PD-1 was significantly elevated in peripheral T cells of HL patients compared to the other two groups. PD-1+ T cells were highest in patients with active disease, and tended to decline along with treatment. Although regulatory T cells are reported to play a part in the pathogenesis of HL, FOXP3+ T cells were not significantly elevated in peripheral T cells of HL patients, and PD-1+ T cells did not overlap with these regulatory population. To elucidate whether the PD-1/PD-L signaling pathway is functional in the immunosuppressive microenvironment of HL, we finally examined the effect of blockade of this pathway. After culturing bulk HL tumor cells with anti-PD-L blocking antibodies, IFN-γ production was measured by ELISA. Blockade of PD-Ls augmented IFN-γ production of HL-infiltrating T cells. We concluded that anti-tumor activity of HL-infiltrating T cells was inhibited via the PD-1/PD-L pathway, and this inhibition could be successfully relieved by PD-L blockade. Taken together, our observations indicate that “T-cell exhaustion” is essential to the pathogenesis of HL, and tumor-infiltrating T cells around H/RS cells seem to be kept in balance by this inhibitory signaling. Our findings provide a potentially effective and clinically applicable strategy for the immunotherapy of HL.
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Hurtado-Ziola, Nancy, Justin L. Sonnenburg, and Ajit Varki. "Differential Expression and Function of the CD33-Related Siglecs between Humans and Great Apes." Blood 104, no. 11 (November 16, 2004): 1466. http://dx.doi.org/10.1182/blood.v104.11.1466.1466.
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Abstract The Siglecs (Sialic acid-binding Immunoglobulin Superfamily Lectins) are a recently discovered family of mammalian glycan-binding proteins that have been shown to recognize the terminal sialic acids of glycoproteins and glycolipids. The CD33-Related Siglecs (CD33rSiglecs, namely Siglec-3, -5 through -11 and -XII in humans) are a subgroup of these molecules, which are thought to be primarily expressed on cells of the innate immune system. All CD33rSiglecs are type-1 transmembrane proteins with an N-terminal sialic acid-recognizing V-set domain followed by a variable number of C-2 set domains, a transmembrane region and a cytosolic C-terminal domain that usually has two tyrosine-based signaling motifs, one of which conforms to a canonical negative regulatory ITIM motif. Although the true function of the CD33rSiglecs has yet to be discovered, available data are most consistent with an inhibitory signaling role in the innate immune response, mediated by recognition of host sialic acids as “self”. CD33rSiglecs also interact with sialic acids on the same cell surface, typically resulting in “masking” of their sialic acid-binding sites. Our recent studies have shown that humans and non-human primates have a similar clustered localization of CD33rSiglec genes, and that true orthologs can generally be identified within each cluster (Angata et al., PNAS, in press). However, humans no longer express CMP-sialic acid hydroxylase (CMAH) the enzyme required to generate one of the potential CD33rSiglec sialic acid ligands called N-glycolylneuraminic acid (Neu5Gc), from its precursor N-acetylneuraminic acid (Neu5Ac). This genetic change occurred after our last common ancestor with the great apes, and dramatically altered the “Sialome” (the sialic acid makeup of a specific species) of humans when compared to that of the great apes. While great ape blood cells express about equal amounts of Neu5Ac and Neu5Gc, human blood cells express almost exclusively Neu5Ac. We also recently discovered that preferential recognition of Neu5Gc is the ancestral condition of most or all of the great ape (chimpanzee and gorilla) CD33rSiglecs (Sonnenburg JL, Altheide TK, Varki A. Glycobiology.14:339–46, 2004). We therefore reasoned that the sudden and major change in the sialome of our hominid ancestors could have had a significant impact on the evolution, binding specificities and expression patterns of CD33rSiglecs. Indeed, we have found that all human CD33rSiglecs can recognize both Neu5Ac and Neu5Gc. This presumably represents an evolutionarily-selected “relaxation” in binding specificity that was necessary to “remask” the Siglecs that had lost their Neu5Gc ligands. Also, there are differences in CD33rSiglec expression on monocytes and neutrophils between humans and great apes (chimp, bonobo, gorilla and orangutan). Furthermore, while great ape cells often show multiple populations with different signal intensities, humans express a single bright peak for each Siglec in flow cytometry. Surprisingly, while humans showed almost no CD33rSiglec expression on lymphocytes, the great apes show a moderate to high expression of some Siglecs on these cells. Total leukocyte expression of some CD33rSiglecs also shows differences between humans and great apes. Overall, CD33rSiglecs appear to be rapidly evolving in primates, with an apparent further acceleration of changes in humans. Additional studies are needed to define the mechanistic details, as well as the implications for human health and disease.
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Blanton, Wanda P., Fangnian Wang, Hongsheng Liu, Paul Romesser, Douglas Faller, and Gerald Denis. "The Dual Bromodomain Protein Brd2 Controls Primary B Cell Mitogenesis and Cell Cycle in Mice Reconstituted with Lentivirus-Transduced HSCs." Blood 112, no. 11 (November 16, 2008): 2465. http://dx.doi.org/10.1182/blood.v112.11.2465.2465.
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Abstract Transcriptional control of cellular proliferation and differentiation is critically important in hematopoiesis; specifically, the role of chromatin-dependent regulatory processes in this context is poorly understood. The human BRD2 proto-oncogene encodes a double bromodomain protein that binds to acetylated histone H4 in chromatin and is located within the MHC class II locus, suggesting Brd2 plays a role in immunity. However, BRD2 shares no sequence similarity with other MHC genes, nor is Brd2 involved in antigen processing, but rather it plays a role in mitogenic signal transduction. We have previously found that whole-body knockout of Brd2 is lethal to mice. However, when Brd2 was expressed constitutively in the B cells of transgenic mice, Brd2 binds E2F proteins, histone acetylases and Swi/Snf complexes, and co-activates cyclin A leading to B cell lymphoma and leukemia. Importantly, elevated levels of Brd2 have been reported in primary malignant B cells from human and mouse. We therefore hypothesize that Brd2 multiprotein complexes, working through chromatin modification, are crucial in the control of the cell cycle and in the mitogen responsiveness and proliferation of the B cell compartment. To study the effects of Brd2 in B cell development and proliferation, we performed bone marrow transplants of hematopoietic stem cells in a chimeric mouse model. Hematopoietic stem cells were sorted from CD45.1 donor mice with the characteristic ‘side population’ profile by flow cytometry and transduced with lentivirus containing vectors for Brd2 overexpression, shRNA knockdown, or control vectors. Recipient CD45.2 mice were lethally irradiated and a functional immune system was successfully reconstituted with donor cells and CD45.2 competitor BM cells. Mice were immunophenotyped and functional B cell mitogenic capacity was examined by BrdU incorporation into LPS-stimulated B cells. We found that in the spleen, Brd2 expression dramatically expands the CD45.1 (but not CD45.2) B cell compartment at the expense of T cells and renders B cells mitogenically hypersensitive. Compared with control, there was an increase in BrdU incorporation at 24 and 48 hours (29.8% v. 43.5% at T=24 h; 56.9% v. 66.7% at T=48 h). Preliminary results also suggest that B cell development was skewed in the bone marrow and periphery towards B1a phenotype. Moreover, downregulation of Brd2 via shRNA blocked cyclin A transcription and completely arrested B cell development and proliferation. Taken together, these data suggest that Brd2, through epigenetic regulation of the cell cycle, plays an important role in B-lymphopoiesis, proliferation, and stimulation.
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Knowles, Lynn M., Daniela Lessig, Martin Bernard, Eva C. Schwarz, Hermann Eichler, and Jan Pilch. "Macrophage Polarization Is Impaired in Hemophilia." Blood 132, Supplement 1 (November 29, 2018): 2499. http://dx.doi.org/10.1182/blood-2018-99-117111.
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Abstract Macrophages are master regulators of inflammation and wound healing. As such they play an important role in hemophilia, which is commonly associated with delayed tissue regeneration and bleeding-induced joint inflammation. The objective of this study is to determine if macrophage function is deregulated in hemophilia and whether this affects the physiological balance of tissue regeneration and inflammation. For this study, we analyzed monocytes and plasma from a cohort of 26 adult patients with hemophilia A or B that visited our clinic for their annual routine check-up. Patients with acute bleeding events were excluded. The majority of patients had severe forms of hemophilia with factor VIII or IX activity < 1% and, therefore, received prophylactic factor replacement therapy (recombinant or plasmatic) but we also included patients with moderate to mild hemophilia, which were only treated in case of bleeding. Corresponding control samples stemmed from healthy male individuals that we recruited randomly from our blood donor center. To assess macrophage differentiation, we isolated monocytes from the peripheral blood of hemophilia patients as well as healthy controls and began treatment with M-CSF or GM-CSF for 7 days. Macrophage differentiation was confirmed by phase contrast and fluorescence microscopy, which revealed a spread and elongated cell phenotype in donor monocytes in the presence of M-CSF and, to a lesser extent, GM-CSF. Hemophilia monocytes, on the other hand, failed to spread properly in response to either of the cytokines suggesting that macrophage polarization is diminished in patients with reduced activity of coagulation factor VIII or IX. As hemophilia macrophages failed to spread in response to M-CSF, they also failed to express TNFα and CD163, which are macrophage differentiation markers typically induced by M-CSF. In contrast, GM-CSF-induced differentiation was only mildly suppressed suggesting that hemophilia macrophages specifically resist the differentiating stimulus of M-CSF. Consequently, we experienced a significant impairment in M-CSF-induced regenerative macrophage functions such as clot infiltration and red blood cell phagocytosis in hemophilia. Intriguingly, while monocyte invasion was impaired, protein expression in response to M-CSF was regained with respect to CD163 and CD206 after embedding hemophilia monocytes in clotted plasma from healthy blood donors suggesting that a functioning coagulation system has positive effects on regenerative macrophage functions. The inability of hemophilia macrophages to promote M-CSF-mediated signals correlates with a marked down regulation of the M-CSF receptor CSF-1R on hemophilia monocytes as determined in citrated whole blood by flow cytometry. Alongside with a modest reduction of GM-CSF-R, we also detected a substantial reduction of CD163 and Tie2, which are specifically expressed on regenerative monocytes/macrophages, suggesting that clotting deficiencies impair the immune function either directly or indirectly. To further analyze the immune status of hemophilia patients, we performed a cytokine array on plasma samples from hemophiliacs versus healthy blood donors, which revealed the down regulation of a large spectrum of anti-inflammatory and regenerative cytokines in the blood of hemophilia patients. Among the few cytokines upregulated in the blood of hemophiliacs, the adipokine leptin was the most prominent (6-fold, hemophiliac vs. donor). Since leptin has been shown to cause deregulation of the innate immunity, we treated the human monocyte cell line THP1 with recombinant leptin and found a significant inhibitory effect of M-CSF-induced spreading and clot invasion. Therefore, these data suggest that high leptin levels in the blood can reiterate the changes in monocyte function we observed in hemophilia. Together, we conclude that macrophage differentiation is deregulated in hemophilia as a result of resistance towards the cytokine M-CSF. Consequently, hemophilia macrophages are unable to properly perform regenerative functions such as clot invasion and red blood cell phagocytosis. The hemophilic monocyte/macrophage phenotype we describe can be induced by high levels of leptin and mitigated by correcting the clotting dysfunction suggesting a two prone approach to prevent delayed wound healing and persistent inflammation in hemophilia. Disclosures No relevant conflicts of interest to declare.
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Myklebust, June H., Jonathan M. Irish, Roch Houot, Joshua Brody, Debra K. Czerwinski, Ash A. Alizadeh, Arne Kolstad, and Ronald Levy. "A Subpopulation of Follicular Lymphoma Tumor Infiltrating T Cells Shows Suppressed Common Gamma Chain Cytokine Signaling." Blood 114, no. 22 (November 20, 2009): 759. http://dx.doi.org/10.1182/blood.v114.22.759.759.
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Abstract Abstract 759 Introduction: Tumor infiltrating T cells present within biopsy specimens of human B cell non-Hodgkin's lymphomas (NHL) provide a valuable opportunity to examine immune system function in the presence of cancer. We recently used flow cytometry to characterize signaling in subpopulations of tumor samples from patients with follicular lymphoma (FL). In FL, we identified a novel lymphoma cell subset with impaired B cell antigen receptor (BCR) signaling, the prevalence of which correlated with adverse clinical outcome. Here, we turned our attention to signaling differences in subsets of the tumor-infiltrating T cells from FL and two other NHLs, diffuse large B cell lymphoma (DLBCL) and mantle cell lymphoma (MCL). Signaling differences that distinguish the tumor infiltrating T cells from each malignancy might be expected to be a reflection of the specific disease microenvironment, whereas T cell signaling differences distinguishing cases of the same malignancy might be related to the biology of each patient's tumor. Methods: Single cell flow cytometry measurements of signaling were acquired for samples of DLBCL (N=13), MCL (N=20), and FL (N=14). Phosphorylation of 14 signaling proteins was measured under 12 stimulation conditions in every cell, including lymphoma B cells and tumor-infiltrating T cells within the same specimen. Stimulation conditions included those that were B cell specific (BCR crosslinking, CD40 ligand), T cell specific (IL-7), and those that stimulated both B and T cells (IL-4, IL-10, IL-21, PMA + ionomycin, and IFN-γ). Results: Striking differences were observed in the signaling responses of tumor infiltrating T cells. T cells infiltrating FL patient samples showed significantly lower responses to cytokines where signal transduction is mediated by the common γ chain receptor. Specifically, we observed significant lower induction of p-STAT6 after IL-4 stimulation, p-STAT5 after IL-7 stimulation, and p-STAT3 after IL-21 stimulation (p < 0.001 for FL vs. MCL in all cases). In contrast, receptor-independent signaling was not significantly different as FL tumor infiltrating T cells responded at a level comparable to MCL and DLBCL tumor infiltrating T cells when stimulated with PMA and ionomycin. The lower response to common γ chain family cytokines could be the result of a partial suppression of all tumor infiltrating T cells or a complete suppression of a distinct subset. To distinguish between these possibilities, we analyzed signaling in tumor infiltrating T cell subsets. This single cell approach showed that tumor infiltrating T cells were a heterogeneous mixture of non-responsive cells and highly responsive T cells in response to cytokines. Specifically, the mean percentage of T cells that did not induce p-STAT3 after IL-21 stimulation was 50.3% in FL samples in contrast to only 26.2% in MCL samples. Phenotypic analysis showed that the vast majority of T cells infiltrating FL patient samples were CD4+CD45RO memory cells, and the single cell signaling approach revealed that the FL nonresponsive T cell subset had this phenotype. Furthermore, FL T cells were composed of a significantly larger fraction of T regulatory cells than MCL T cells, on average 17% FoxP3+CD25+ cells compared to only 9% in MCL (p<0.0002). Experiments are ongoing to test whether the prevalence of T regulatory cells influence the signaling capacity of the remaining CD4 conventional T cells. Conclusions: A subpopulation of tumor infiltrating T cells within FL patient samples has reduced responsiveness to the common gamma chain family members IL-4, IL-7 and IL-21, and distinguishes FL from DLBCL and MCL. These results may reflect a more suppressive microenvironment in FL. Disclosures: No relevant conflicts of interest to declare.
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Lite, Christy, Shiek S. S. J. Ahmed, Melita Juliet, and A. J. Freddy. "SARS-CoV-2/human interactome reveals ACE2 locus crosstalk with the immune regulatory network in the host." Pathogens and Disease 79, no. 2 (January 19, 2021). http://dx.doi.org/10.1093/femspd/ftab005.
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ABSTRACT Severe acute respiratory syndrome, coronavirus 2 (SARS-CoV-2), remains to be a threat across the globe. SARS-CoV-2 entry into the host is mediated by binding of viral spike protein to the Human angiotensin-converting enzyme 2 (ACE2) receptor. ACE2 is an essential member of the Renin–Angiotensin system (RAS) involved in maintaining the blood pressure and vascular remodelling. Although ACE2 receptor is the entry point to the host, recent studies show activation of ACE2 to modulate the host to develop a suitable environment for its replication. However, the ACE2 activating the immune signals on SARS-CoV-2 attachment is still under investigation. We have used systems biological approach to construct the host regulatory network upon SARS-CoV-2 attachment to the ACE2 receptor. Since lungs are the primary infection site, we integrate human lung gene expression profile along with the host regulatory network to demonstrate the altered host signalling mechanism in viral infection. Further, the network was functionally enriched to determine immune modulation in the network. We also used the proteomic database to assess the occurrence of similar signalling events in other human tissues that exhibit lineage of infection across different organs. The constructed network contains 133 host proteins with 298 interactions that directly or indirectly connect to the ACE2 receptor. Among 133 proteins, 29 were found to be differentially regulated in the host lungs on SARS-CoV-2 infection. Altered proteins connect multiple proteins in a network that modulates kinase, carboxypeptidase and cytokine activity, leading to changes in the host immune system, cell cycle and signal transduction mechanisms. Further investigation showed the presence of similar signalling events in the kidneys, placenta, pancreas, testis, small intestine and adrenal gland as well. Overall, our results will help in understanding the immune molecular regulatory networks influenced by the ACE2 mediated interaction in other body tissues, which may aid in identifying the secondary health complications associated with SARS-CoV-2 infection.
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Byun, Hyewon, Poulami Das, Houqing Yu, Alejandro Aleman, Mary M. Lozano, Andreas Matouschek, and Jaquelin P. Dudley. "Mouse Mammary Tumor Virus Signal Peptide Uses a Novel p97-Dependent and Derlin-Independent Retrotranslocation Mechanism To Escape Proteasomal Degradation." mBio 8, no. 2 (March 28, 2017). http://dx.doi.org/10.1128/mbio.00328-17.
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ABSTRACT Multiple pathogens, including viruses and bacteria, manipulate endoplasmic reticulum-associated degradation (ERAD) to avoid the host immune response and promote their replication. The betaretrovirus mouse mammary tumor virus (MMTV) encodes Rem, which is a precursor protein that is cleaved into a 98-amino-acid signal peptide (SP) and a C-terminal protein (Rem-CT). SP uses retrotranslocation for ER membrane extraction and yet avoids ERAD by an unknown mechanism to enter the nucleus and function as a Rev-like protein. To determine how SP escapes ERAD, we used a ubiquitin-activated interaction trap (UBAIT) screen to trap and identify transient protein interactions with SP, including the ERAD-associated p97 ATPase, but not E3 ligases or Derlin proteins linked to retrotranslocation, polyubiquitylation, and proteasomal degradation of extracted proteins. A dominant negative p97 ATPase inhibited both Rem and SP function. Immunoprecipitation experiments indicated that Rem, but not SP, is polyubiquitylated. Using both yeast and mammalian expression systems, linkage of a ubiquitin-like domain (UbL) to SP or Rem induced degradation by the proteasome, whereas SP was stable in the absence of the UbL. ERAD-associated Derlin proteins were not required for SP activity. Together, these results suggested that Rem uses a novel p97-dependent, Derlin-independent retrotranslocation mechanism distinct from other pathogens to avoid SP ubiquitylation and proteasomal degradation. IMPORTANCE Bacterial and viral infections produce pathogen-specific proteins that interfere with host functions, including the immune response. Mouse mammary tumor virus (MMTV) is a model system for studies of human complex retroviruses, such as HIV-1, as well as cancer induction. We have shown that MMTV encodes a regulatory protein, Rem, which is cleaved into an N-terminal signal peptide (SP) and a C-terminal protein (Rem-CT) within the endoplasmic reticulum (ER) membrane. SP function requires ER membrane extraction by retrotranslocation, which is part of a protein quality control system known as ER-associated degradation (ERAD) that is essential to cellular health. Through poorly understood mechanisms, certain pathogen-derived proteins are retrotranslocated but not degraded. We demonstrate here that MMTV SP retrotranslocation from the ER membrane avoids degradation through a unique process involving interaction with cellular p97 ATPase and failure to acquire cellular proteasome-targeting sequences.
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Cai, Yaoyao, Haipeng Yao, Zhen Sun, Ying Wang, Yunyun Zhao, Zhongqun Wang, and Lihua Li. "Role of NFAT in the Progression of Diabetic Atherosclerosis." Frontiers in Cardiovascular Medicine 8 (March 11, 2021). http://dx.doi.org/10.3389/fcvm.2021.635172.
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Nuclear factor of activated T cells (NFAT) is a transcription factor with a multidirectional regulatory function, that is widely expressed in immune cells, including cells in the cardiovascular system, and non-immune cells. A large number of studies have confirmed that calcineurin/NFAT signal transduction is very important in the development of vascular system and cardiovascular system during embryonic development, and plays some role in the occurrence of vascular diseases such as atherosclerosis, vascular calcification, and hypertension. Recent in vitro and in vivo studies have shown that NFAT proteins and their activation in the nucleus and binding to DNA-related sites can easily ɨnduce the expression of downstream target genes that participate in the proliferation, migration, angiogenesis, and vascular inflammation of vascular wall related cells in various pathophysiological states. NFAT expression is regulated by various signaling pathways, including CD137-CD137L, and OX40-OX40L pathways. As a functionally diverse transcription factor, NFAT interacts with a large number of signaling molecules to modulate intracellular and extracellular signaling pathways. These NFAT-centered signaling pathways play important regulatory roles in the progression of atherosclerosis, such as in vascular smooth muscle cell phenotypic transition and migration, endothelial cell injury, macrophage-derived foam cell formation, and plaque calcification. NFAT and related signaling pathways provide new therapeutic targets for vascular diseases such as atherosclerosis. Hence, further studies of the mechanism of NFAT in the occurrence and evolution of atherosclerosis remain crucial.
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Sikorski, Patricia M., Alessandra G. Commodaro, and Michael E. Grigg. "A Protective and Pathogenic Role for Complement During Acute Toxoplasma gondii Infection." Frontiers in Cellular and Infection Microbiology 11 (February 22, 2021). http://dx.doi.org/10.3389/fcimb.2021.634610.
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The infection competence of the protozoan pathogen Toxoplasma gondii is critically dependent on the parasite’s ability to inactivate the host complement system. Toxoplasma actively resists complement-mediated killing in non-immune serum by recruiting host-derived complement regulatory proteins C4BP and Factor H (FH) to the parasite surface to inactivate surface-bound C3 and limit formation of the C5b-9 membrane attack complex (MAC). While decreased complement activation on the parasite surface certainly protects Toxoplasma from immediate lysis, the biological effector functions of C3 split products C3b and C3a are maintained, which includes opsonization of the parasite for phagocytosis and potent immunomodulatory effects that promote pro-inflammatory responses and alters mucosal defenses during infection, respectively. In this review, we discuss how complement regulation by Toxoplasma controls parasite burden systemically but drives exacerbated immune responses locally in the gut of genetically susceptible C57BL/6J mice. In effect, Toxoplasma has evolved to strike a balance with the complement system, by inactivating complement to protect the parasite from immediate serum killing, it generates sufficient C3 catabolites that signal through their cognate receptors to stimulate protective immunity. This regulation ultimately controls tachyzoite proliferation and promotes host survival, parasite persistence, and transmissibility to new hosts.
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Fishman, Maxwell R., Johnson Zhang, Philip A. Bronstein, Paul Stodghill, and Melanie J. Filiatrault. "Ca 2+ -Induced Two-Component System CvsSR Regulates the Type III Secretion System and the Extracytoplasmic Function Sigma Factor AlgU in Pseudomonas syringae pv. tomato DC3000." Journal of Bacteriology 200, no. 5 (December 20, 2017). http://dx.doi.org/10.1128/jb.00538-17.
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ABSTRACT Two-component systems (TCSs) of bacteria regulate many different aspects of the bacterial life cycle, including pathogenesis. Most TCSs remain uncharacterized, with no information about the signal(s) or regulatory targets and/or role in bacterial pathogenesis. Here, we characterized a TCS in the plant-pathogenic bacterium Pseudomonas syringae pv. tomato DC3000 composed of the histidine kinase CvsS and the response regulator CvsR. CvsSR is necessary for virulence of P. syringae pv. tomato DC3000, since Δ cvsS and Δ cvsR strains produced fewer symptoms than the wild type (WT) and demonstrated reduced growth on multiple hosts. We discovered that expression of cvsSR is induced by Ca 2+ concentrations found in leaf apoplastic fluid. Thus, Ca 2+ can be added to the list of signals that promote pathogenesis of P. syringae pv. tomato DC3000 during host colonization. Through chromatin immunoprecipitation followed by next-generation sequencing (ChIP-seq) and global transcriptome analysis (RNA-seq), we discerned the CvsR regulon. CvsR directly activated expression of the type III secretion system regulators, hrpR and hrpS , that regulate P. syringae pv. tomato DC3000 virulence in a type III secretion system-dependent manner. CvsR also indirectly repressed transcription of the extracytoplasmic sigma factor algU and production of alginate. Phenotypic analysis determined that CvsSR inversely regulated biofilm formation, swarming motility, and cellulose production in a Ca 2+ -dependent manner. Overall, our results show that CvsSR is a key regulatory hub critical for interaction with host plants. IMPORTANCE Pathogenic bacteria must be able to react and respond to the surrounding environment, make use of available resources, and avert or counter host immune responses. Often, these abilities rely on two-component systems (TCSs) composed of interacting proteins that modulate gene expression. We identified a TCS in the plant-pathogenic bacterium Pseudomonas syringae that responds to the presence of calcium, which is an important signal during the plant defense response. We showed that when P. syringae is grown in the presence of calcium, this TCS regulates expression of factors contributing to disease. Overall, our results provide a better understanding of how bacterial pathogens respond to plant signals and control systems necessary for eliciting disease.
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Vandchali, Noushin Rezaei, Fatemeh Moadab, Eskandar Taghizadeh, Amir Tajbakhsh, and Seyed Mohammad Gheibi-hayat. "CD47 Functionalization of Nanoparticles as a Poly(ethylene glycol) Alternative: A Novel Approach to Improve Drug Delivery." Current Drug Targets 22 (February 4, 2021). http://dx.doi.org/10.2174/1389450122666210204203514.
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Abstract: Bio-degradable nanoparticles (NPs) have several utilizations as the drug delivery vehicles due to their acceptable bio-availability, lower toxicity, potency for encapsulation and controlled release. Moreover, interaction of the NPs with the macrophages of reticuloendothelial system (RES) may decrease NPs efficacy for medical purposes. The surface of NPs is conventionally neutralized with the molecules such as poly(ethylene glycol) (PEG), as one of the most widely applied stealth polymers, in order to restrict the NPs clearance through the RES system. In fact, these molecules exhibit resistance to the RES clearance and proteins adsorption. It is unfortunate that modifying the PEG has some shortcomings like problems in the synthesis as well as correlation to the immune reaction. The CD47 receptor has been well known as a ‘don’t-eat-me’ molecule on the self-cells' surface. Therefore, the receptor will inhibit phagocytosis via binding to its ligand that is known as the signal regulatory protein α (SIRP-α). Moreover, the CD47 receptor, as one of the biomimetic substances, or its derivative peptides have been used recently on the surface of nanoparticles to inhibit phagocytosis and increase the NPs retention time in the blood circulation. Therefore, this review study examined the CD47 receptor and its role in the immune system as well as the use of the CD47 receptor in coating NPs to increase their retention time in the blood circulation.
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Golonka, Rachel M., Johnathan Kawika Cooper, Rochell Issa, Pratyush Pavan Devarasetty, Veda Gokula, Joshua Busken, Jasenka Zubcevic, et al. "Impact of Nutritional Epigenetics in Essential Hypertension: Targeting microRNAs in the Gut-Liver Axis." Current Hypertension Reports 23, no. 5 (May 2021). http://dx.doi.org/10.1007/s11906-021-01142-9.
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Abstract Purpose of Review To review the current knowledge on interactions between dietary factors and microRNAs (miRNAs) in essential hypertension (EH) pathogenesis. Recent Findings There exists an integration of maintenance signals generated by genetic, epigenetic, immune, and environmental (e.g., dietary) factors that work to sustain balance in the gut-liver axis. It is well established that an imbalance in this complex, intertwined system substantially increases the risk for EH. As such, pertinent research has been taken to decipher how each signal operates in isolation and together in EH progression. Recent literature indicates that both macro- and micronutrients interrupt regulatory miRNA expressions and thus, alter multiple cellular processes that contribute to EH and its comorbidities. We highlight how carbohydrates, lipids, proteins, salt, and potassium modify miRNA signatures during EH. The disruption in miRNA expression can negatively impact communication systems such as over activating the renin-angiotensin-aldosterone system, modulating the vascular smooth muscle cell phenotype, and promoting angiogenesis to favor EH. We also delineate the prognostic value of miRNAs in EH and discuss the pros and cons of surgical vs dietary prophylactic approaches in EH prevention. Summary We propose that dietary-dependent perturbation of the miRNA profile is one mechanism within the gut-liver axis that dictates EH development.
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Bhatia, Garima, Santosh K. Upadhyay, Anuradha Upadhyay, and Kashmir Singh. "Investigation of long non-coding RNAs as regulatory players of grapevine response to powdery and downy mildew infection." BMC Plant Biology 21, no. 1 (June 8, 2021). http://dx.doi.org/10.1186/s12870-021-03059-6.
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Abstract Background Long non-coding RNAs (lncRNAs) are regulatory transcripts of length > 200 nt. Owing to the rapidly progressing RNA-sequencing technologies, lncRNAs are emerging as considerable nodes in the plant antifungal defense networks. Therefore, we investigated their role in Vitis vinifera (grapevine) in response to obligate biotrophic fungal phytopathogens, Erysiphe necator (powdery mildew, PM) and Plasmopara viticola (downy mildew, DM), which impose huge agro-economic burden on grape-growers worldwide. Results Using computational approach based on RNA-seq data, 71 PM- and 83 DM-responsive V. vinifera lncRNAs were identified and comprehensively examined for their putative functional roles in plant defense response. V. vinifera protein coding sequences (CDS) were also profiled based on expression levels, and 1037 PM-responsive and 670 DM-responsive CDS were identified. Next, co-expression analysis-based functional annotation revealed their association with gene ontology (GO) terms for ‘response to stress’, ‘response to biotic stimulus’, ‘immune system process’, etc. Further investigation based on analysis of domains, enzyme classification, pathways enrichment, transcription factors (TFs), interactions with microRNAs (miRNAs), and real-time quantitative PCR of lncRNAs and co-expressing CDS pairs suggested their involvement in modulation of basal and specific defense responses such as: Ca2+-dependent signaling, cell wall reinforcement, reactive oxygen species metabolism, pathogenesis related proteins accumulation, phytohormonal signal transduction, and secondary metabolism. Conclusions Overall, the identified lncRNAs provide insights into the underlying intricacy of grapevine transcriptional reprogramming/post-transcriptional regulation to delay or seize the living cell-dependent pathogen growth. Therefore, in addition to defense-responsive genes such as TFs, the identified lncRNAs can be further examined and leveraged to candidates for biotechnological improvement/breeding to enhance fungal stress resistance in this susceptible fruit crop of economic and nutritional importance.
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Abu-Humaidan, Anas H. A., Lars Ekblad, Johan Wennerberg, and Ole E. Sørensen. "EGFR modulates complement activation in head and neck squamous cell carcinoma." BMC Cancer 20, no. 1 (February 13, 2020). http://dx.doi.org/10.1186/s12885-020-6615-z.
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Abstract Background The epidermal growth factor receptor (EGFR) is pivotal for growth of epithelial cells and is overexpressed in several epithelial cancers like head and neck squamous cell carcinoma (HNSCC). EGFR signalling is also involved in diverse innate immune functions in epithelia. We previously found a role for EGFR in modulating the complement system in skin, this prompted an investigation into EGFR role in complement modulation in HNSCC. Methods We used patient derived HNSCC cell lines with varying sensitivities to EGFR inhibitors, and generated EGFR inhibition resistant cell lines to study the role of EGFR in modulating complement in HNSCC. Results We found that HNSCC cell lines activate the complement system when incubated with human serum. This complement activation was increased in cell lines sensitive to EGFR inhibition following the use of the tyrosine kinase inhibitor Iressa. Sensitive cell line made resistant to EGFR-inhibitors displayed complement activation and a decrease in complement regulatory proteins even in the absence of EGFR-inhibitors. Complement activation did not cause lysis of HNSCC cells, and rather led to increased extracellular signal-regulated kinase (ERK) phosphorylation in one cell line. Conclusion These data indicate that EGFR has a complement modulatory role in HNSCC, and that a prolonged EGFR-inhibition treatment in sensitive cancer cells increases complement activation. This has implications in understanding the response to EGFR inhibitors, in which resistance and inflammatory skin lesions are two major causes for treatment cessation.
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Rong, Jiping, Lu Xu, Yinying Hu, Fan Liu, Yanrong Yu, Hongyan Guo, Xudong Ni, Yanqin Huang, Lin Zhao, and Zhigang Wang. "Inhibition of let-7b-5p contributes to an anti-tumorigenic macrophage phenotype through the SOCS1/STAT pathway in prostate cancer." Cancer Cell International 20, no. 1 (September 29, 2020). http://dx.doi.org/10.1186/s12935-020-01563-7.
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Abstract Background Dysfunction of microRNAs (miRNAs) is a major cause of aberrant expression of inflammatory cytokines and contributes to macrophage polarization. Proinflammatory M1 macrophages promote T helper (Th) 1 responses and show tumoricidal activity, whereas M2 macrophages display regulatory functions in tissue repair and remodeling and promote Th2 immune responses. Previous studies have shown that miRNA let-7 is associated with cellular differentiation and that the expression of let-7b-5p is significantly augmented in M2 macrophages. However, the mechanism by which let-7b-5p regulates macrophage differentiation in prostate cancer (PCa) remains largely unknown. Methods Human macrophages were induced by blood monocytes from healthy male donors, and M1 macrophages were polarized by stimulating them overnight with 100 ng/ml of lipopolysaccharides and 100 ng/ml of IFN-γ. Conditioned medium from PC-3 cells was used to induce prostatic macrophages (M-CMs) in vitro, and we then transfected let-7b-5p mimics or inhibitors into M1 and M-CMs for 72 h. The expression of cluster of differentiation 206 (CD206) in each group was detected with the High-Throughput Connotation of Imaging System. We used quantitative real-time polymerase chain reaction (qRT-PCR) to examine the expression of the inflammatory cytokines IL-10, IL-12, IL-13, TNF-alpha, and let-7b in macrophages. SOCS1 protein levels were evaluated by ELISA, and the phosphorylation difference in STAT family member proteins was analyzed using CST signal-pathway chip. Phagocytosis by macrophages and the effect of macrophages on the proliferation of prostate cancer PC-3 cells were evaluated with phagocytosis assay or the Cell Counting Kit-8 (CCK-8) and colony formation assay. The relationship between SOCS1 and let-7b-5p was confirmed with a dual-luciferase reporter. Results The expression of cluster of differentiation 206 (CD206, a M2-like macrophage surface molecule) was significantly increased in M1 macrophages treated with let-7b-5p mimics, while CD206 expression was decreased in M-CMs treated with let-7b-5p inhibitors. Overexpression or knockdown of let-7b-5p significantly affected the expression of inflammatory factors in macrophages—including interleukin 10 (IL-10), IL-12, IL-13, and tumor necrosis factor alpha. Let-7b-5p downregulated the expression of suppressor of cytokine signaling 1 (SOCS1) and increased the phosphorylation of signal transducer and activator of transcription 1 (STAT1), STAT3, and STAT5a proteins in M-CMs and M1 macrophages with let-7b-5p mimics relative to the other groups. In addition, with the elevated expression of let-7b-5p, the phagocytosis by macrophages showed a commensurate and significant decrease. As a result, M-CMs treated with let-7b-5p inhibitors reduced the proliferation of PC-3 PCa cells. Conclusions Collectively, these data indicated that let-7b-5p may regulate M2 polarization through the SOCS1/STAT pathway and that reversal of M2 differentiation by let-7b-5p inhibitors enhanced macrophage phagocytosis, ultimately inhibiting the proliferation of PCa cells.