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IL-13–Mediated Regulation of Learning and Memory

Tiroyaone M. Brombacher, Justin K. Nono, Keisha S. De Gouveia, Nokuthula Makena, Matthew Darby, Jacqueline Womersley, Ousman Tamgue, Frank Brombacher
2017 Journal of Immunology  
doi:10.4049/jimmunol.1601546 pmid:28202615 fatcat:rtmhjigjdfe5np7cpoh5cxeqge

Targeting Batf2 for infectious diseases and cancer

Reto Guler, Sugata Roy, Harukazu Suzuki, Frank Brombacher
2015 OncoTarget  
Shin JW, Negishi Y, Ozturk M, Hurdayal R, Kubosaki A, Kimura Y, de Hoon MJ, Hayashizaki Y, Brombacher F and Suzuki H.  ...  Schwegmann A and Brombacher F. Host-directed drug targeting of factors hijacked by pathogens. Sci Signal. 2008; 1:re8. 26. Wallis RS and Hafner R. Advancing host-directed therapy for tuberculosis.  ... 
doi:10.18632/oncotarget.5576 pmid:26376615 pmcid:PMC4694937 fatcat:h643zvpnzfcbjnqbq62ny6kveu

C-Type Lectin Receptors in Asthma

Sabelo Hadebe, Frank Brombacher, Gordon D. Brown
2018 Frontiers in Immunology  
Asthma is a heterogeneous disease that affects approximately 300 million people worldwide, largely in developed countries. The etiology of the disease is poorly understood, but is likely to involve specific innate and adaptive responses to inhaled microbial components that are found in allergens. Fungal-derived allergens represent a major contributing factor in the initiation, persistence, exacerbation, and severity of allergic asthma. C-type lectin like receptors, such as dectin-1, dectin-2,
more » ... -specific intercellular adhesion molecule 3-grabbing nonintegrin, and mannose receptor, recognize many fungal-derived allergens and other structurally similar allergens derived from house dust mites (HDM). In some cases, the fungal derived allergens have been structurally and functionally identified alongside their respective receptors in both humans and mice. In this review, we discuss recent understanding on how selected fungal and HDM derived allergens as well as their known or unknown receptors shape allergic airway diseases.
doi:10.3389/fimmu.2018.00733 pmid:29696023 pmcid:PMC5904212 fatcat:jbz4r4ey4rgupci62y2hmweqca

Nippostrongylus-Induced Intestinal Hypercontractility Requires IL-4 Receptor Alpha-Responsiveness by T Cells in Mice

Saskia Schmidt, J. Claire Hoving, William G. C. Horsnell, Helen Mearns, Antony J. Cutler, Tiroyaone M. Brombacher, Frank Brombacher, Maria Leite de Moraes
2012 PLoS ONE  
Gut-dwelling helminthes induce potent IL-4 and IL-13 dominated type 2 T helper cell (T H 2) immune responses, with IL-13 production being essential for Nippostrongylus brasiliensis expulsion. This T H 2 response results in intestinal inflammation associated with local infiltration by T cells and macrophages. The resulting increased IL-4/IL-13 intestinal milieu drives goblet cell hyperplasia, alternative macrophage activation and smooth muscle cell hypercontraction. In this study we investigated
more » ... how IL-4-promoted T cells contributed to the parasite induced effects in the intestine. This was achieved using pan T cell-specific IL-4 receptor alpha-deficient mice (iLck cre IL-4Ra 2/lox ) and IL-4Ra-responsive control mice. Global IL-4Ra 2/ 2 mice showed, as expected, impaired type 2 immunity to N. brasiliensis. Infected T cell-specific IL-4Ra-deficient mice showed comparable worm expulsion, goblet cell hyperplasia and IgE responses to control mice. However, impaired IL-4promoted T H 2 cells in T cell-specific IL-4Ra deficient mice led to strikingly reduced IL-4 production by mesenteric lymph node CD4 + T cells and reduced intestinal IL-4 and IL-13 levels, compared to control mice. This reduced IL-4/IL-13 response was associated with an impaired IL-4/IL-13-mediated smooth muscle cell hypercontractility, similar to that seen in global IL-4Ra 2/2 mice. These results demonstrate that IL-4-promoted T cell responses are not required for the resolution of a primary N. brasiliensis infection. However, they do contribute significantly to an important physiological manifestation of helminth infection; namely intestinal smooth muscle cell-driven hypercontractility.
doi:10.1371/journal.pone.0052211 pmid:23284939 pmcid:PMC3527412 fatcat:dt3g537p5vfefhiejpn2p56wwq

Genome-wide profiling of transcribed enhancers during macrophage activation [article]

Elena Denisenko, Reto Guler, Musa Mhlanga, Harukazu Suzuki, Frank Brombacher, Sebastian Schmeier
2017 bioRxiv   pre-print
Macrophages are sentinel cells essential for tissue homeostasis and host defence. Owing to their plasticity, macrophages acquire a range of functional phenotypes in response to microenvironmental stimuli, of which M(IFN-γ) and M(IL-4/IL-13) are well-known for their opposing pro- and anti-inflammatory roles. Enhancers have emerged as regulatory DNA elements crucial for transcriptional activation of gene expression. Using cap analysis of gene expression and epigenetic data, we identify on
more » ... ale transcribed enhancers in mouse macrophages, their time kinetics and target protein-coding genes. We observe an increase in target gene expression, concomitant with increasing numbers of associated enhancers and find that genes associated to many enhancers show a shift towards stronger enrichment for macrophage-specific biological processes. We infer enhancers that drive transcriptional responses of genes upon M(IFN-γ) and M(IL-4/IL-13) macrophage activation and demonstrate stimuli-specificity of regulatory associations. Finally, we show that enhancer regions are enriched for binding sites of inflammation-related transcription factors, suggesting a link between stimuli response and enhancer transcriptional control. Our study provides new insights into genome-wide enhancer-mediated transcriptional control of macrophage genes, including those implicated in macrophage activation, and offers a detailed genome-wide catalogue to further elucidate enhancer regulation in macrophages.
doi:10.1101/163519 fatcat:gosepzpefngv5edt5gjmckzbye

B Cells That Produce Immunoglobulin E Mediate Colitis in BALB/c Mice

Jennifer C. Hoving, Frank Kirstein, Natalie E. Nieuwenhuizen, Lizette C.E. Fick, Elias Hobeika, Michael Reth, Frank Brombacher
2012 Gastroenterology  
BACKGROUND & AIMS: Induction of colitis in mice by administration of oxazolone is mediated by T-helper (Th) 2 cells and has features of human ulcerative colitis. We investigated whether activation of interleukin (IL)-4R␣ on T and B cells determines their effector functions and mediates oxazolone-induced colitis. METHODS: We studied induction of colitis with oxazolone in wild-type mice and those with CD4 ϩ T cells that did not express IL-4R␣ (Lck cre IL-4R␣ Ϫ/lox ). We also generated mice with B
more » ... cells that did not express IL-4R␣ (mb1 cre IL-4R␣ Ϫ/lox ) and studied induction of colitis. RESULTS: Lck cre IL-4R␣ Ϫ/lox mice did not develop colitis in response to oxazolone, and their levels of IL-4, IL-13, and immunoglobulin (Ig) E were reduced. Adoptive transfer of naïve, wild-type CD4 ϩ Th cells depleted of natural killer T cells to Lck cre IL-4R␣ Ϫ/lox mice restored their susceptibility to colitis. In contrast, Lck cre IL-4R␣ Ϫ/lox mice maintained their protection against colitis when IL-13-deficient CD4 ϩ T cells were transferred. These findings indicate that development of colitis involves not only natural killer T-cell functions, but also requires IL-13 production by CD4 ϩ T helper cells. Mb1 cre IL-4R␣ Ϫ/lox mice, which cannot produce IgE, were also protected against oxazolone-induced colitis. Blocking IgE binding significantly reduced mast cell numbers in colons and protected wild-type BALB/c mice from the onset of colitis. CONCLUSIONS: IL-4 appears to induce CD4 ؉ Th2 cells to produce IL-13 and B cells to produce IgE, which together mediate oxazolone-induced colitis in mice. Colon sections were pooled, snap frozen in liquid nitrogen, and homogenized in phosphate-buffered saline supplemented with protease inhibitors (Sigma, Saint Louis, MO). Homogenates were normalized to 10 mg/mL using a Bicinchoninic Acid Protein Estimation Kit (Pierce, Rockford, IL), and cytokines were detected by enzyme-linked immunosorbent assay (ELISA) from pooled samples measured in triplicate.
doi:10.1053/j.gastro.2011.09.044 pmid:21983080 fatcat:nypuxaxm3bdw7p22sv7tsbreva

IRNdb: The database of immunologically relevant non-coding RNAs [article]

Elena Denisenko, Daniel Ho, Ousman Tamgue, Mumin Ozturk, Harukazu Suzuki, Frank Brombacher, Reto Guler, Sebastian Schmeier
2016 bioRxiv   pre-print
MicroRNAs (miRNAs), long non-coding RNAs (lncRNAs) and other functional non-coding RNAs (ncRNAs) have emerged as pivotal regulators involved in multiple biological processes. Recently, ncRNA control of gene expression has been identified as a critical regulatory mechanism in the immune system. Despite the great efforts made to discover and characterize ncRNAs, the functional role for most remains unknown. To facilitate discoveries in ncRNA regulation of immune system-related processes we
more » ... ed the database of immunologically relevant ncRNAs and target genes (IRNdb). We integrated mouse data on predicted and experimentally supported ncRNA-target interactions, ncRNA and gene annotations, biological pathways and processes, and experimental data in a uniform format with a user-friendly web interface. The current version of IRNdb documents 12,930 experimentally supported miRNA-target interactions between 724 miRNAs and 2,427 immune-related murine targets. In addition, we recorded 22,453 lncRNA-immune target and 377 PIWI-interacting RNA-immune target interactions. IRNdb is a comprehensive searchable data repository which will be of help in studying the role of ncRNAs in the immune system. Database URL: http://irndb.org
doi:10.1101/037911 fatcat:euk7kipbwfahrhwdymwppoflsm

Host Regulators of Liver Fibrosis During Human Schistosomiasis

Severin Donald Kamdem, Roger Moyou-Somo, Frank Brombacher, Justin Komguep Nono
2018 Frontiers in Immunology  
doi:10.3389/fimmu.2018.02781 fatcat:bmeu7y6blvcr3czqf7tlmu7m5e

Transcribed enhancers in the macrophage immune response to Mycobacterium tuberculosis infection [article]

Elena Denisenko, Reto Guler, Musa M Mhlanga, Harukazu Suzuki, Frank Brombacher, Sebastian Schmeier
2018 bioRxiv   pre-print
Tuberculosis (TB) remains a major public health threat and cause of death worldwide. Macrophages are immune cells that compose the first line of an organism's defence against Mycobacterium tuberculosis (M.tb), the causative agent of TB. Interactions between macrophages and M.tb define the infection outcome. Enhancers are cis-regulatory DNA elements that activate transcription of target genes and mediate various responses in macrophages. To what extent the host's genetic response to infection is
more » ... controlled by enhancers remains unexplored. We analysed the regulation by transcribed enhancers in M.tb-infected mouse bone marrow-derived macrophages. We found that transcribed enhancers have a strong influence in the M.tb infection response and mediate up-regulation of many important immune genes. We characterise highly transcriptionally induced enhancers and show that many genes acquire de novo transcribed enhancers upon M.tb infection. We report enhancers targeting known immune genes crucial for the host's genetic response to M.tb, such as Tnf, Tnfrsf1b, Irg1, Hilpda, Ccl3, and Ccl4, and highlight transcription factors that are likely regulating these enhancers including AP-1, NF-kB, Irf1, and Rbpj. Finally, we highlight particular chromosomal domains carrying groups of highly transcriptionally induced enhancers and genes with previously unappreciated roles in M.tb infection, such as Fbxl3, Tapt1, Edn1, and Hivep1. Our study links M.tb-responsive transcription factors to activation of transcribed enhancers, which, in turn, target protein-coding immune genes upon infection. We find that many genes who respond with increased expression to M.tb are under the control of transcribed enhancers. Our findings extend current knowledge of M.tb-response regulation in macrophages and provide a basis for future functional studies on enhancer-gene interactions in this process.
doi:10.1101/303552 fatcat:jujlvfubp5htteletgkki53b6u

MOESM3 of Genome-wide profiling of transcribed enhancers during macrophage activation

Elena Denisenko, Reto Guler, Musa Mhlanga, Harukazu Suzuki, Frank Brombacher, Sebastian Schmeier
2017 Figshare  
Additional file 3: Figure S1. Comparison of 222,870 TAD-based E–P pairs to a subset of 64,891 correlation-based E–P pairs. Figure S2. 1844 macrophage-specific and 8923 non-macrophage-specific genes. Figure S3. Expression of macrophage-specific and non-macrophage-specific genes associated with different number of enhancers. Figure S4. KEGG pathway maps significantly enriched for G1 and G2 genes. Figure S5. Overlaps of M(IFN-γ)- and M(IL-4/IL-13)-responsive and macrophage-specific genes and
more » ... ers. Figure S6. M(IFN-γ) marker enhancer associated with Cxcl9, Cxcl10, and Cxcl11 M(IFN-γ) marker genes. Figure S7. Time-course expression of Arg1 and associated M(IL-4/IL-13)-specific enhancer. Figure S8. Igf1 marker gene. Figure S9. M(IL-4/IL-13) marker enhancer associated with Igf1 M(IL-4/IL-13) marker gene. Figure S10. Macrophage-specific enhancer, associated with Spi1 gene.
doi:10.6084/m9.figshare.c.3911671_d3.v1 fatcat:5eoi2lxaj5frhd44eonhwtkxom

House dust mite induced allergic airway disease is attenuated in CD11ccreIL-4Rα−/l°x mice

Natalie Eva Nieuwenhuizen, Frank Kirstein, Jennifer Claire Hoving, Frank Brombacher
2018 Scientific Reports  
The precise mechanisms leading to development of T helper type (Th)2-driven allergic responses are unknown. We aimed to determine how IL-4 receptor alpha (IL-4Rα) signaling on CD11c + cells influences allergen-induced Th2 responses in mice. CD11c cre IL-4Rα −/l°x mice, deficient in IL-4Rα on dendritic cells and alveolar macrophages, were compared to IL-4Rα −/l°x littermate controls in models of allergic airway disease induced by OVA/alum, OVA alone or house dust mite. Cytokine responses,
more » ... hil and neutrophil infiltration into the lungs, airway hyperreactivity and mucus hypersecretion were evaluated after allergen challenge. In the OVA/alum model, CD11c cre IL-4Rα −/lox mice had similar airway hyperreactivity, eosinophil infiltration, Th2-type cytokine production and mucus hypersecretion to littermate controls. When alum was omitted during sensitization, CD11c cre IL-4Rα −/lox mice had similar airway hyperreactivity and mucus secretion but reduced Th2-type cytokine production and eosinophils, suggesting alum overrides the requirement for IL-4Rα signaling on CD11c + cells in enhancing Th2-type responses. In the house dust mite model, CD11c cre IL-4Rα −/lox mice showed similar mucus secretion, but reduced Th2 responses, eosinophils, neutrophils and airway hyperreactivity, unlike previously tested LysM cre IL-4Rα −/lox mice, which lack IL-4Rα on alveolar macrophages but not on dendritic cells. Therefore, our results indicate that IL-4Rα signaling on dendritic cells promotes allergen-induced Th2 responses and eosinophil infiltration into the lung. Adaptive cellular immune responses, including T cell responses, are driven by professional antigen presenting cells. Dendritic cells (DCs), the sentinels of the immune system, can present antigen in an immunogenic or a tolerogenic manner in order to elicit the appropriate adaptive response. While the signals that drive DC driven induction of Th1 and Th17 responses are well understood, the mechanisms leading to the Th2 differentiation observed in allergic disease and helminth infection are still unclear 1 . However it is well-established that IL-4 plays an important role 1,2 , and in the absence of DCs, Th2 responses are dramatically reduced 3 . Recently it was shown that IL-4 treatment of DCs results in upregulation of markers typically associated with alternatively activated macrophages, including RELM-α, which appeared to be important in promoting optimal Th2 responses 4 . While IL-4 is the primary inducer of Th2 responses 5 , paradoxically it has also been shown that IL-4 promotes IL-12 production by bone marrow derived dendritic cells (BMDCs) stimulated with CpG or LPS by inhibiting production of regulatory IL-10 6-9 . In a recent publication, we demonstrated that IL-4Rα signaling on DCs was required for optimal Th1 responses in an in vivo model of Leishmania major infection by generating CD11c cre IL-4Rα −/lox mice, which lack IL-4Rα signaling on DCs 10 . Furthermore, IL-4Rα signaling was required to avoid tissue damage after Leishmania infection following DC-mediated vaccination of BALB/c mice 11 . IL-4Rα can associate with either the common gamma chain to form IL-4 receptor 1, through which only IL-4 is able to signal, or with IL-13Rα1, forming IL-4 receptor 2 through which both IL-4 and IL-13 can signal. CD11c cre IL-4Rα −/lox mice demonstrated hypersusceptbility to infection, associated with decreased IL-12 and Th1 responses and reduced killing effector functions of myeloid DCs.
doi:10.1038/s41598-017-19060-9 pmid:29343807 pmcid:PMC5772663 fatcat:qm5zrqqupfhrfkvgebba3cpzre

β-Glucan exacerbates allergic airway responses to house dust mite allergen

Sabelo Hadebe, Frank Kirstein, Kaat Fierens, Pierre Redelinghuys, Graeme I. Murray, David L. Williams, Bart N. Lambrecht, Frank Brombacher, Gordon D. Brown
2016 Respiratory Research  
β-(1,3)-Glucan is present in mould cell walls and frequently detected in house dust mite (HDM) faeces. β-Glucan exposure is thought to be associated with pulmonary allergic inflammation in mouse and man, although the published data are inconsistent. Here, we show that highly purified β-glucan exacerbates HDM-induced eosinophilic, T helper 2 type airway responses by acting as an adjuvant, promoting activation, proliferation and polarisation of HDM-specific T cells (1-Derβ T cells). We therefore
more » ... rovide definitive evidence that β-glucan can influence allergic pulmonary inflammation.
doi:10.1186/s12931-016-0352-5 pmid:27039089 pmcid:PMC4818888 fatcat:gtti43plyjhrpcdbg44vxqpbim

Genome-wide profiling of transcribed enhancers during macrophage activation

Elena Denisenko, Reto Guler, Musa M. Mhlanga, Harukazu Suzuki, Frank Brombacher, Sebastian Schmeier
2017 Epigenetics & Chromatin  
Macrophages are sentinel cells essential for tissue homeostasis and host defence. Owing to their plasticity, macrophages acquire a range of functional phenotypes in response to microenvironmental stimuli, of which M(IFN-γ) and M(IL-4/IL-13) are well-known for their opposing pro-and anti-inflammatory roles. Enhancers have emerged as regulatory DNA elements crucial for transcriptional activation of gene expression. Using cap analysis of gene expression and epigenetic data, we identify on
more » ... le transcribed enhancers in mouse macrophages, their time kinetics and target protein-coding genes. We observe an increase in target gene expression, concomitant with increasing numbers of associated enhancers and find that genes associated to many enhancers show a shift towards stronger enrichment for macrophage-specific biological processes. We infer enhancers that drive transcriptional responses of genes upon M(IFN-γ) and M(IL-4/IL-13) macrophage activation and demonstrate stimuli-specificity of regulatory associations. Finally, we show that enhancer regions are enriched for binding sites of inflammation-related transcription factors, suggesting a link between stimuli response and enhancer transcriptional control. Our study provides new insights into genome-wide enhancer-mediated transcriptional control of macrophage genes, including those implicated in macrophage activation, and offers a detailed genome-wide catalogue to further elucidate enhancer regulation in macrophages. Imbalance in populations of macrophages with opposing pro-and anti-inflammatory roles has been implicated in disease progression 1 . Intracellular pathogen Mycobacterium tuberculosis, the causative agent of tuberculosis, interferes with classical activation of macrophages to avoid its anti-bacterial action, and promotes alternative activation state 11,12 . Tumour microenvironments promote phenotypic switches from pro-to anti-inflammatory macrophages, which might contribute to the tumour progression by inhibiting immune responses to tumour antigens 1,2 . Conversely, the phenotypic switch from anti-to proinflammatory population of macrophages might contribute to obesity and metabolic syndrome 1,2,13 . Therefore, the development of techniques for manipulation and specific targeting of macrophage populations could ultimately improve diagnosis and treatment of inflammatory diseases 2 . To advance this area of research, the cellular mechanisms responsible for macrophage activation need to be further deciphered. Gene expression in eukaryotic cells is a complex process guided by a multitude of mechanisms 14 . Precise regulation is required to ensure dynamic control of tissue-specific gene expression and to fine tune the responses to external stimuli 15 . One such level of control is facilitated via regulation of RNA transcription. This process is mediated by a complex transcriptional machinery with its components recognising specific regulatory regions of DNA. Promoters represent a better-characterized class of such regions from which RNA transcription is initiated 16, 17 . They act in concert with other cis-regulatory DNA elements, including enhancers, which are believed to play key roles in transcriptional regulation 18 . Enhancers are defined as regulatory DNA regions that activate transcription of target genes in a distance-and orientation-independent manner 18 . According to the dominant model, transcriptional regulation by enhancers is exerted via direct physical interaction between enhancer and target gene promoter mediated by DNA looping 18, 19 . Recent identification of distinct properties of enhancer regions enabled novel approaches to enhancer profiling 18 . Enhancer regions are often distinguished by a specific combination of chromatin marks present at these locations, such as H3K4me1 and H3K27ac 20,21 . Enhancer sequences contain transcription factor binding sites (TFBS) that recruit transcription factors (TFs) to regulate target genes 22,23 . In addition, enhancers are frequently bound by proteins such as histone acetyltransferase p300 and insulator-binding protein CTCF 21,24-26 . Large-scale profiling of these enhancerassociated signatures by chromatin immunoprecipitation followed by sequencing (ChIP-seq) 26,27 has greatly advanced enhancer identification and enabled systematic and genome-wide enhancer mapping 28,29 . Another group of methods such as chromosome conformation capture (3C) 30 and its variant Hi-C 31 has been employed to profile physical DNA contacts, including those between promoters and enhancers 32,33 . However, none of these methods has become a gold standard of enhancer detection, and the field is still actively developing. Recent studies have led to the unexpected finding that most active enhancers recruit RNA polymerase II and are bi-directionally and divergently transcribed to produce RNA transcripts, referred to as eRNAs 34, 35 . While the functionality of eRNA remains controversial, a recent study by Hon et al. showed that many enhancers are transcribed into potentially functional long-noncoding RNAs (lncRNAs) playing a role in inflammation and immunity 36, 37 . Recently, quantification of eRNA transcription laid the foundation peer-reviewed)
doi:10.1186/s13072-017-0158-9 pmid:29061167 pmcid:PMC5654053 fatcat:4fladwer3ferteqmwekcvibhgm

Can We Harness Immune Responses to Improve Drug Treatment in Leishmaniasis?

Raphael Taiwo Aruleba, Katharine C. Carter, Frank Brombacher, Ramona Hurdayal
2020 Microorganisms  
Leishmaniasis is a vector-borne parasitic disease that has been neglected in priority for control and eradication of malaria, tuberculosis, and HIV/AIDS. Collectively, over one seventh of the world's population is at risk of being infected with 0.7–1.2 million new infections reported annually. Clinical manifestations range from self-healing cutaneous lesions to fatal visceral disease. The first anti-leishmanial drugs were introduced in the 1950′s and, despite several shortcomings, remain the
more » ... nstay for treatment. Regardless of this and the steady increase in infections over the years, particularly among populations of low economic status, research on leishmaniasis remains under funded. This review looks at the drugs currently in clinical use and how they interact with the host immune response. Employing chemoimmunotherapeutic approaches may be one viable alternative to improve the efficacy of novel/existing drugs and extend their lifespan in clinical use.
doi:10.3390/microorganisms8071069 pmid:32709117 fatcat:zgp35ulpenczxdtetnxe7atdri

Key Roles for Specific and Nonspecific Antibody in Intestinal Nematode Expulsion

William G.C. Horsnell, Frank Brombacher
2008 Cell Host and Microbe  
Any future development of effective vaccines against intestinal parasitic nematodes requires in-depth understanding of host-parasite interactions. In this issue, McCoy et al. (2008) demonstrate important protective roles for host antibody against parasitic nematodes. These findings are not only of great practical importance, but also highlight how little we understand these important pathogens.
doi:10.1016/j.chom.2008.08.015 pmid:18854231 fatcat:62qpx4uepves7c6lgsltajpvp4
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