Macrophage Lab | Katharine Irvine and David Hume

@article{pmid35852018,

title = {Microglia deficiency accelerates prion disease but does not enhance prion accumulation in the brain},

author = {Barry M Bradford and Lynne I McGuire and David A Hume and Clare Pridans and Neil A Mabbott},

doi = {10.1002/glia.24244},

issn = {1098-1136},

year  = {2022},

date = {2022-07-01},

journal = {Glia},

abstract = {Prion diseases are transmissible, neurodegenerative disorders associated with misfolding of the prion protein. Previous studies show that reduction of microglia accelerates central nervous system (CNS) prion disease and increases the accumulation of prions in the brain, suggesting that microglia provide neuroprotection by phagocytosing and destroying prions. In Csf1r mice, the deletion of an enhancer within Csf1r specifically blocks microglia development, however, their brains develop normally and show none of the deficits reported in other microglia-deficient models. Csf1r mice were used as a refined model in which to study the impact of microglia-deficiency on CNS prion disease. Although Csf1r mice succumbed to CNS prion disease much earlier than wild-type mice, the accumulation of prions in their brains was reduced. Instead, astrocytes displayed earlier, non-polarized reactive activation with enhanced phagocytosis of neuronal contents and unfolded protein responses. Our data suggest that rather than simply phagocytosing and destroying prions, the microglia instead provide host-protection during CNS prion disease and restrict the harmful activities of reactive astrocytes.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{pmid35705056,

title = {Absence of microglia promotes diverse pathologies and early lethality in Alzheimer's disease mice},

author = {Sepideh Kiani Shabestari and Samuel Morabito and Emma Pascal Danhash and Amanda McQuade and Jessica Ramirez Sanchez and Emily Miyoshi and Jean Paul Chadarevian and Christel Claes and Morgan Alexandra Coburn and Jonathan Hasselmann and Jorge Hidalgo and Kayla Nhi Tran and Alessandra C Martini and Winston Chang Rothermich and Jesse Pascual and Elizabeth Head and David A Hume and Clare Pridans and Hayk Davtyan and Vivek Swarup and Mathew Blurton-Jones},

doi = {10.1016/j.celrep.2022.110961},

issn = {2211-1247},

year  = {2022},

date = {2022-06-01},

journal = {Cell Rep},

volume = {39},

number = {11},

pages = {110961},

abstract = {Microglia are strongly implicated in the development and progression of Alzheimer's disease (AD), yet their impact on pathology and lifespan remains unclear. Here we utilize a CSF1R hypomorphic mouse to generate a model of AD that genetically lacks microglia. The resulting microglial-deficient mice exhibit a profound shift from parenchymal amyloid plaques to cerebral amyloid angiopathy (CAA), which is accompanied by numerous transcriptional changes, greatly increased brain calcification and hemorrhages, and premature lethality. Remarkably, a single injection of wild-type microglia into adult mice repopulates the microglial niche and prevents each of these pathological changes. Taken together, these results indicate the protective functions of microglia in reducing CAA, blood-brain barrier dysfunction, and brain calcification. To further understand the clinical implications of these findings, human AD tissue and iPSC-microglia were examined, providing evidence that microglia phagocytose calcium crystals, and this process is impaired by loss of the AD risk gene, TREM2.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{pmid35333324,

title = {A kinase-dead Csf1r mutation associated with adult-onset leukoencephalopathy has a dominant inhibitory impact on CSF1R signalling},

author = {Jennifer Stables and Emma K Green and Anuj Sehgal and Omkar L Patkar and Sahar Keshvari and Isis Taylor and Maisie E Ashcroft and Kathleen Grabert and Evi Wollscheid-Lengeling and Stefan Szymkowiak and Barry W McColl and Antony Adamson and Neil E Humphreys and Werner Mueller and Hana Starobova and Irina Vetter and Sepideh Kiani Shabestari and Matthew M Blurton-Jones and Kim M Summers and Katharine M Irvine and Clare Pridans and David A Hume},

doi = {10.1242/dev.200237},

issn = {1477-9129},

year  = {2022},

date = {2022-04-01},

journal = {Development},

volume = {149},

number = {8},

abstract = {Amino acid substitutions in the kinase domain of the human CSF1R gene are associated with autosomal dominant adult-onset leukoencephalopathy with axonal spheroids and pigmented glia (ALSP). To model the human disease, we created a disease-associated mutation (pGlu631Lys; E631K) in the mouse Csf1r locus. Homozygous mutation (Csf1rE631K/E631K) phenocopied the Csf1r knockout, with prenatal mortality or severe postnatal growth retardation and hydrocephalus. Heterozygous mutation delayed the postnatal expansion of tissue macrophage populations in most organs. Bone marrow cells from Csf1rE631K/+mice were resistant to CSF1 stimulation in vitro, and Csf1rE631K/+ mice were unresponsive to administration of a CSF1-Fc fusion protein, which expanded tissue macrophage populations in controls. In the brain, microglial cell numbers and dendritic arborisation were reduced in Csf1rE631K/+ mice, as in patients with ALSP. The microglial phenotype is the opposite of microgliosis observed in Csf1r+/- mice. However, we found no evidence of brain pathology or impacts on motor function in aged Csf1rE631K/+ mice. We conclude that heterozygous disease-associated CSF1R mutations compromise CSF1R signalling. We speculate that leukoencephalopathy associated with dominant human CSF1R mutations requires an environmental trigger and/or epistatic interaction with common neurodegenerative disease-associated alleles.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{pmid35265836,

title = {Generation and network analysis of an RNA-seq transcriptional atlas for the rat},

author = {Kim M Summers and Stephen J Bush and Chunlei Wu and David A Hume},

doi = {10.1093/nargab/lqac017},

issn = {2631-9268},

year  = {2022},

date = {2022-03-01},

journal = {NAR Genom Bioinform},

volume = {4},

number = {1},

pages = {lqac017},

abstract = {The laboratory rat is an important model for biomedical research. To generate a comprehensive rat transcriptomic atlas, we curated and downloaded 7700 rat RNA-seq datasets from public repositories, downsampled them to a common depth and quantified expression. Data from 585 rat tissues and cells, averaged from each BioProject, can be visualized and queried at http://biogps.org/ratatlas. Gene co-expression network (GCN) analysis revealed clusters of transcripts that were tissue or cell type restricted and contained transcription factors implicated in lineage determination. Other clusters were enriched for transcripts associated with biological processes. Many of these clusters overlap with previous data from analysis of other species, while some (e.g. expressed specifically in immune cells, retina/pineal gland, pituitary and germ cells) are unique to these data. GCN analysis on large subsets of the data related specifically to liver, nervous system, kidney, musculoskeletal system and cardiovascular system enabled deconvolution of cell type-specific signatures. The approach is extensible and the dataset can be used as a point of reference from which to analyse the transcriptomes of cell types and tissues that have not yet been sampled. Sets of strictly co-expressed transcripts provide a resource for critical interpretation of single-cell RNA-seq data.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{pmid35169835,

title = {Therapeutic potential of macrophage colony-stimulating factor (CSF1) in chronic liver disease},

author = {Sahar Keshvari and Berit Genz and Ngari Teakle and Melanie Caruso and Michelle F Cestari and Omkar L Patkar and Brian W C Tse and Kamil A Sokolowski and Hilmar Ebersbach and Julia Jascur and Kelli P A MacDonald and Gregory Miller and Grant A Ramm and Allison R Pettit and Andrew D Clouston and Elizabeth E Powell and David A Hume and Katharine M Irvine},

doi = {10.1242/dmm.049387},

issn = {1754-8411},

year  = {2022},

date = {2022-02-01},

journal = {Dis Model Mech},

abstract = {Resident and recruited macrophages control the development and proliferation of the liver. We showed previously in multiple species that treatment with a macrophage colony stimulating factor (CSF1)-Fc fusion protein initiated hepatocyte proliferation and promoted repair in models of acute hepatic injury in mice. Here we investigated the impact of CSF1-Fc on resolution of advanced fibrosis and liver regeneration, utilizing a non-resolving toxin-induced model of chronic liver injury and fibrosis in C57BL/6J mice. Co-administration of CSF1-Fc with exposure to thioacetamide (TAA) exacerbated inflammation consistent with monocyte contributions to initiation of pathology. After removal of TAA, either acute or chronic CSF1-Fc treatment promoted liver growth, prevented progression and promoted resolution of fibrosis. Acute CSF1-Fc treatment was also anti-fibrotic and pro-regenerative in a model of partial hepatectomy in mice with established fibrosis. The beneficial impacts of CSF1-Fc treatment were associated with monocyte-macrophage recruitment and increased expression of remodeling enzymes and growth factors. These studies indicate that CSF1-dependent macrophages contribute to both initiation and resolution of fibrotic injury and that CSF1-Fc has therapeutic potential in human liver disease.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{pmid35613577,

title = {Tumor-associated macrophage heterogeneity is driven by tissue territories in breast cancer},

author = {Marie Laviron and Maxime Petit and Eléonore Weber-Delacroix and Alexis J Combes and Arjun Rao Arkal and Sandrine Barthélémy and Tristan Courau and David A Hume and Christophe Combadière and Matthew F Krummel and Alexandre Boissonnas},

doi = {10.1016/j.celrep.2022.110865},

issn = {2211-1247},

year  = {2022},

date = {2022-01-01},

journal = {Cell Rep},

volume = {39},

number = {8},

pages = {110865},

abstract = {Tissue-resident macrophages adapt to local signals within tissues to acquire specific functions. Neoplasia transforms the tissue, raising the question as to how the environmental perturbations contribute to tumor-associated macrophage (TAM) identity and functions. Combining single-cell RNA sequencing (scRNA-seq) with spatial localization of distinct TAM subsets by imaging, we discover that TAM transcriptomic programs follow two main differentiation paths according to their localization in the stroma or in the neoplastic epithelium of the mammary duct. Furthermore, this diversity is exclusively detected in a spontaneous tumor model and tracks the different tissue territories as well as the type of tumor lesion. These TAM subsets harbor distinct capacity to activate CD8+ T cells and phagocyte tumor cells, supporting that specific tumor regions, rather than defined activation states, are the major drivers of TAM plasticity and heterogeneity. The distinctions created here provide a framework to design cancer treatment targeting specific TAM niches.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{pmid35877685,

title = {Graphia: A platform for the graph-based visualisation and analysis of high dimensional data},

author = {Tom C Freeman and Sebastian Horsewell and Anirudh Patir and Josh Harling-Lee and Tim Regan and Barbara B Shih and James Prendergast and David A Hume and Tim Angus},

doi = {10.1371/journal.pcbi.1010310},

issn = {1553-7358},

year  = {2022},

date = {2022-01-01},

journal = {PLoS Comput Biol},

volume = {18},

number = {7},

pages = {e1010310},

abstract = {Graphia is an open-source platform created for the graph-based analysis of the huge amounts of quantitative and qualitative data currently being generated from the study of genomes, genes, proteins metabolites and cells. Core to Graphia's functionality is support for the calculation of correlation matrices from any tabular matrix of continuous or discrete values, whereupon the software is designed to rapidly visualise the often very large graphs that result in 2D or 3D space. Following graph construction, an extensive range of measurement algorithms, routines for graph transformation, and options for the visualisation of node and edge attributes are available, for graph exploration and analysis. Combined, these provide a powerful solution for the interpretation of high-dimensional data from many sources, or data already in the form of a network or equivalent adjacency matrix. Several use cases of Graphia are described, to showcase its wide range of applications in the analysis biological data. Graphia runs on all major desktop operating systems, is extensible through the deployment of plugins and is freely available to download from https://graphia.app/.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{pmid34767637,

title = {Development of novel reagents to chicken FLT3, XCR1 and CSF2R for the identification and characterization of avian conventional dendritic cells},

author = {Zhiguang Wu and Tuanjun Hu and Cosmin Chintoan-Uta and Joni Macdonald and Mark P Stevens and Helen Sang and David A Hume and Pete Kaiser and Adam Balic},

doi = {10.1111/imm.13426},

issn = {1365-2567},

year  = {2022},

date = {2022-01-01},

journal = {Immunology},

volume = {165},

number = {2},

pages = {171--194},

abstract = {Conventional dendritic cells (cDC) are bone marrow-derived immune cells that play a central role in linking innate and adaptive immunity. cDCs efficiently uptake, process and present antigen to naïve T cells, driving clonal expansion of antigen-specific T-cell responses. In chicken, vital reagents are lacking for the efficient and precise identification of cDCs. In this study, we have developed several novel reagents for the identification and characterization of chicken cDCs. Chicken FLT3 cDNA was cloned and a monoclonal antibody to cell surface FLT3 was generated. This antibody identified a distinct FLT3 splenic subset which lack expression of signature markers for B cells, T cells or monocyte/macrophages. By combining anti-FLT3 and CSF1R-eGFP transgenic expression, three major populations within the mononuclear phagocyte system were identified in the spleen. The cDC1 subset of mammalian cDCs express the chemokine receptor XCR1. To characterize chicken cDCs, a synthetic chicken chemokine (C motif) ligand (XCL1) peptide conjugated to Alexa Fluor 647 was developed (XCL1 ). Flow cytometry staining of XCL1 on splenocytes showed that all chicken FLT3 cells exclusively express XCR1, supporting the hypothesis that this population comprises bona fide chicken cDCs. Further analysis revealed that chicken cDCs expressed CSF1R but lacked the expression of CSF2R. Collectively, the cell surface phenotypes of chicken cDCs were partially conserved with mammalian XCR1 cDC1, with distinct differences in CSF1R and CSF2R expression compared with mammalian orthologues. These original reagents allow the efficient identification of chicken cDCs to investigate their important roles in the chicken immunity and diseases.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{kaur_stable_2021b,

title = {Stable colony-stimulating factor 1 fusion protein treatment increases hematopoietic stem cell pool and enhances their mobilisation in mice},

author = {Simranpreet Kaur and Anuj Sehgal and Andy C. Wu and Susan M. Millard and Lena Batoon and Cheyenne J. Sandrock and Michelle Ferrari-Cestari and Jean-Pierre Levesque and David A. Hume and Liza J. Raggatt and Allison R. Pettit},

url = {https://jhoonline.biomedcentral.com/articles/10.1186/s13045-020-00997-w},

doi = {10.1186/s13045-020-00997-w},

issn = {1756-8722},

year  = {2021},

date = {2021-12-01},

urldate = {2021-10-21},

journal = {Journal of Hematology & Oncology},

volume = {14},

number = {1},

pages = {3},

abstract = {Abstract 

 

 Background 

 Prior chemotherapy and/or underlying morbidity commonly leads to poor mobilisation of hematopoietic stem cells (HSC) for transplantation in cancer patients. Increasing the number of available HSC prior to mobilisation is a potential strategy to overcome this deficiency. Resident bone marrow (BM) macrophages are essential for maintenance of niches that support HSC and enable engraftment in transplant recipients. Here we examined potential of donor treatment with modified recombinant colony-stimulating factor 1 (CSF1) to influence the HSC niche and expand the HSC pool for autologous transplantation. 

 

 

 Methods 

 We administered an acute treatment regimen of CSF1 Fc fusion protein (CSF1-Fc, daily injection for 4 consecutive days) to naive C57Bl/6 mice. Treatment impacts on macrophage and HSC number, HSC function and overall hematopoiesis were assessed at both the predicted peak drug action and during post-treatment recovery. A serial treatment strategy using CSF1-Fc followed by granulocyte colony-stimulating factor (G-CSF) was used to interrogate HSC mobilisation impacts. Outcomes were assessed by in situ imaging and ex vivo standard and imaging flow cytometry with functional validation by colony formation and competitive transplantation assay. 

 

 

 Results 

 

 CSF1-Fc treatment caused a transient expansion of monocyte-macrophage cells within BM and spleen at the expense of BM B lymphopoiesis and hematopoietic stem and progenitor cell (HSPC) homeostasis. During the recovery phase after cessation of CSF1-Fc treatment, normalisation of hematopoiesis was accompanied by an increase in the total available HSPC pool. Multiple approaches confirmed that CD48 

 − 

 CD150 

 + 

 HSC do not express the CSF1 receptor, ruling out direct action of CSF1-Fc on these cells. In the spleen, increased HSC was associated with expression of the BM HSC niche macrophage marker CD169 in red pulp macrophages, suggesting elevated spleen engraftment with CD48 

 − 

 CD150 

 + 

 HSC was secondary to CSF1-Fc macrophage impacts. Competitive transplant assays demonstrated that pre-treatment of donors with CSF1-Fc increased the number and reconstitution potential of HSPC in blood following a HSC mobilising regimen of G-CSF treatment. 

 

 

 

 Conclusion 

 These results indicate that CSF1-Fc conditioning could represent a therapeutic strategy to overcome poor HSC mobilisation and subsequently improve HSC transplantation outcomes.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{adams_donor_2021,

title = {Donor bone marrow-derived macrophage MHC II drives neuroinflammation and altered behaviour during chronic GVHD in mice},

author = {Rachael C Adams and Dylan Carter-Cusack and Samreen N Shaikh and Genesis T Llanes and Rebecca L Johnston and Gregory Quaife-Ryan and Glen M Boyle and Lambros T Koufariotis and Andreas Möller and Bruce R. Blazar and Jana Vukovic and Kelli PA MacDonald},

url = {https://ashpublications.org/blood/article/doi/10.1182/blood.2021011671/477054/Donor-bone-marrow-derived-macrophage-MHC-II-drives},

doi = {10.1182/blood.2021011671},

issn = {0006-4971, 1528-0020},

year  = {2021},

date = {2021-09-01},

urldate = {2021-10-21},

journal = {Blood},

pages = {blood.2021011671},

abstract = {Graft-versus-host disease (GVHD) remains the leading cause of non-relapse mortality after allogeneic stem cell transplantation for haematological malignancies. Manifestations of GVHD in the central nervous system (CNS) present as neurocognitive dysfunction in up to 60% of patients, however, the mechanisms driving chronic GVHD in the CNS are yet to be elucidated. Our studies of murine chronic GVHD revealed behavioural deficits associated with broad neuroinflammation and persistent Ifng upregulation. By flow cytometry, we observed a proportional shift in the donor-derived T-cell population in the chronic GVHD brain from early CD8 dominance to later CD4 sequestration. RNA sequencing of the hippocampus identified perturbations to structural and functional synapse-related gene expression, together with the upregulation of genes associated with IFN-γ responses and antigen presentation. Neuroinflammation in the cortex of mice and humans during acute GVHD was recently shown to be mediated by resident microglia-derived TNF. In contrast, infiltration of pro-inflammatory MHC class II+ donor bone marrow-derived macrophages (BMDM) was identified as a distinguishing feature of chronic CNS GVHD. Donor BMDM, which comprised up to 50% of the CNS myeloid population, exhibited a transcriptional signature distinct from resident microglia. Recipients of MHC class II knockout bone marrow grafts exhibited attenuated neuroinflammation and behaviour comparable to controls, suggestive of a critical role of donor BMDM MHC class II expression in CNS chronic GVHD. Our identification of disease mediators distinct from those in the acute phase indicates the necessity to pursue alternative therapeutic targets for late-stage neurological manifestations.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{batoon_treatment_2021b,

title = {Treatment with a long-acting chimeric CSF1 molecule enhances fracture healing of healthy and osteoporotic bones},

author = {Lena Batoon and Susan M. Millard and Liza J. Raggatt and Cheyenne Sandrock and Edmund Pickering and Kyle Williams and Lucas W. H. Sun and Andy C. Wu and Katharine M. Irvine and Peter Pivonka and Vaida Glatt and Martin E. Wullschleger and David A. Hume and Allison R. Pettit},

url = {https://www.sciencedirect.com/science/article/pii/S0142961221002921},

doi = {10.1016/j.biomaterials.2021.120936},

issn = {0142-9612},

year  = {2021},

date = {2021-08-01},

urldate = {2021-08-06},

journal = {Biomaterials},

volume = {275},

pages = {120936},

abstract = {Macrophage-targeted therapies, including macrophage colony-stimulating factor 1 (CSF1), have been shown to have pro-repair impacts post-fracture. Preclinical/clinical applications of CSF1 have been expedited by development of chimeric CSF1-Fc which has extended circulating half-life. Here, we used mouse models to investigate the bone regenerative potential of CSF1-Fc in healthy and osteoporotic fracture. We also explored whether combination of CSF1-Fc with interleukin (IL)-4 provided additional fracture healing benefit in osteopenic bone. Micro-computed tomography, in situ histomorphometry, and bone mechanical parameters were used to assess systemic impacts of CSF1-Fc therapy in naive mice (male and female young, adult and geriatric). An intermittent CSF1-Fc regimen was optimized to mitigate undesirable impacts on bone resorption and hepatosplenomegaly, irrespective of age or gender. The intermittent CSF1-Fc regimen was tested in a mid-diaphyseal femoral fracture model in healthy bones with treatment initiated 1-day post-fracture. Weekly CSF1-Fc did not impact osteoclasts but increased osteal macrophages and improved fracture strength. Importantly, this treatment regimen also improved fracture union and strength in an ovariectomy-model of delayed fracture repair. Combining CSF1-Fc with IL-4 initiated 1-week post-fracture reduced the efficacy of CSF1-Fc. This study describes a novel strategy to specifically achieve bone regenerative actions of CSF1-Fc that has the potential to alleviate fragility fracture morbidity and mortality.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{keshvari_csf1r-dependent_2021b,

title = {CSF1R-dependent macrophages control postnatal somatic growth and organ maturation},

author = {Sahar Keshvari and Melanie Caruso and Ngari Teakle and Lena Batoon and Anuj Sehgal and Omkar L. Patkar and Michelle Ferrari-Cestari and Cameron E. Snell and Chen Chen and Alex Stevenson and Felicity M. Davis and Stephen J. Bush and Clare Pridans and Kim M. Summers and Allison R. Pettit and Katharine M. Irvine and David A. Hume},

editor = {Gregory S. Barsh},

url = {https://dx.plos.org/10.1371/journal.pgen.1009605},

doi = {10.1371/journal.pgen.1009605},

issn = {1553-7404},

year  = {2021},

date = {2021-06-01},

urldate = {2021-10-21},

journal = {PLOS Genetics},

volume = {17},

number = {6},

pages = {e1009605},

abstract = {Homozygous mutation of the 

 Csf1r 

 locus ( 

 Csf1rko 

 ) in mice, rats and humans leads to multiple postnatal developmental abnormalities. To enable analysis of the mechanisms underlying the phenotypic impacts of 

 Csf1r 

 mutation, we bred a rat 

 Csf1rko 

 allele to the inbred dark agouti (DA) genetic background and to a 

 Csf1r 

 -mApple reporter transgene. The 

 Csf1rko 

 led to almost complete loss of embryonic macrophages and ablation of most adult tissue macrophage populations. We extended previous analysis of the 

 Csf1rko 

 phenotype to early postnatal development to reveal impacts on musculoskeletal development and proliferation and morphogenesis in multiple organs. Expression profiling of 3-week old wild-type (WT) and 

 Csf1rko 

 livers identified 2760 differentially expressed genes associated with the loss of macrophages, severe hypoplasia, delayed hepatocyte maturation, disrupted lipid metabolism and the IGF1/IGF binding protein system. Older 

 Csf1rko 

 rats developed severe hepatic steatosis. Consistent with the developmental delay in the liver 

 Csf1rko 

 rats had greatly-reduced circulating IGF1. Transfer of WT bone marrow (BM) cells at weaning without conditioning repopulated resident macrophages in all organs, including microglia in the brain, and reversed the mutant phenotypes enabling long term survival and fertility. WT BM transfer restored osteoclasts, eliminated osteopetrosis, restored bone marrow cellularity and architecture and reversed granulocytosis and B cell deficiency. 

 Csf1rko 

 rats had an elevated circulating CSF1 concentration which was rapidly reduced to WT levels following BM transfer. However, CD43 

 hi 

 non-classical monocytes, absent in the 

 Csf1rko 

 , were not rescued and bone marrow progenitors remained unresponsive to CSF1. The results demonstrate that the 

 Csf1rko 

 phenotype is autonomous to BM-derived cells and indicate that BM contains a progenitor of tissue macrophages distinct from hematopoietic stem cells. The model provides a unique system in which to define the pathways of development of resident tissue macrophages and their local and systemic roles in growth and organ maturation.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{hume_mononuclear_2021,

title = {The Mononuclear Phagocyte System of the Rat},

author = {David A. Hume and Melanie Caruso and Sahar Keshvari and Omkar L. Patkar and Anuj Sehgal and Stephen J. Bush and Kim M. Summers and Clare Pridans and Katharine M. Irvine},

url = {http://www.jimmunol.org/lookup/doi/10.4049/jimmunol.2100136},

doi = {10.4049/jimmunol.2100136},

issn = {0022-1767, 1550-6606},

year  = {2021},

date = {2021-05-01},

urldate = {2021-10-21},

journal = {The Journal of Immunology},

volume = {206},

number = {10},

pages = {2251--2263},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{pmid34742624,

title = {Functions of macrophage colony-stimulating factor (CSF1) in development, homeostasis, and tissue repair},

author = {Anuj Sehgal and Katharine M Irvine and David A Hume},

doi = {10.1016/j.smim.2021.101509},

issn = {1096-3618},

year  = {2021},

date = {2021-04-01},

journal = {Semin Immunol},

volume = {54},

pages = {101509},

abstract = {Macrophage colony-stimulating factor (CSF1) is the primary growth factor required for the control of monocyte and macrophage differentiation, survival, proliferation and renewal. Although the cDNAs encoding multiple isoforms of human CSF1 were cloned in the 1980s, and recombinant proteins were available for testing in humans, CSF1 has not yet found substantial clinical application. Here we present an overview of CSF1 biology, including evolution, regulation and functions of cell surface and secreted isoforms. CSF1 is widely-expressed, primarily by cells of mesenchymal lineages, in all mouse tissues. Cell-specific deletion of a floxed Csf1 allele in mice indicates that local CSF1 production contributes to the maintenance of tissue-specific macrophage populations but is not saturating. CSF1 in the circulation is controlled primarily by receptor-mediated clearance by macrophages in liver and spleen. Administration of recombinant CSF1 to humans or animals leads to monocytosis and expansion of tissue macrophage populations and growth of the liver and spleen. In a wide variety of tissue injury models, CSF1 administration promotes monocyte infiltration, clearance of damaged cells and repair. We suggest that CSF1 has therapeutic potential in regenerative medicine.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{pmid34818538,

title = {Fragmentation of tissue-resident macrophages during isolation confounds analysis of single-cell preparations from mouse hematopoietic tissues},

author = {Susan M Millard and Ostyn Heng and Khatora S Opperman and Anuj Sehgal and Katharine M Irvine and Simranpreet Kaur and Cheyenne J Sandrock and Andy C Wu and Graham W Magor and Lena Batoon and Andrew C Perkins and Jacqueline E Noll and Andrew C W Zannettino and David P Sester and Jean-Pierre Levesque and David A Hume and Liza J Raggatt and Kim M Summers and Allison R Pettit},

doi = {10.1016/j.celrep.2021.110058},

issn = {2211-1247},

year  = {2021},

date = {2021-01-01},

journal = {Cell Rep},

volume = {37},

number = {8},

pages = {110058},

abstract = {Mouse hematopoietic tissues contain abundant tissue-resident macrophages that support immunity, hematopoiesis, and bone homeostasis. A systematic strategy to characterize macrophage subsets in mouse bone marrow (BM), spleen, and lymph node unexpectedly reveals that macrophage surface marker staining emanates from membrane-bound subcellular remnants associated with unrelated cells. Intact macrophages are not present within these cell preparations. The macrophage remnant binding profile reflects interactions between macrophages and other cell types in vivo. Depletion of CD169 macrophages in vivo eliminates F4/80 remnant attachment. Remnant-restricted macrophage-specific membrane markers, cytoplasmic fluorescent reporters, and mRNA are all detected in non-macrophage cells including isolated stem and progenitor cells. Analysis of RNA sequencing (RNA-seq) data, including publicly available datasets, indicates that macrophage fragmentation is a general phenomenon that confounds bulk and single-cell analysis of disaggregated hematopoietic tissues. Hematopoietic tissue macrophage fragmentation undermines the accuracy of macrophage ex vivo molecular profiling and creates opportunity for misattribution of macrophage-expressed genes to non-macrophage cells.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{lisowski_use_2021,

title = {Use of quantitative real-time PCR to determine the local inflammatory response in the intestinal mucosa and muscularis of horses undergoing small intestinal resection},

author = {Z. M. Lisowski and L. Lefevre and T. S. Mair and E. L. Clark and N. P. H. Hudson and D. A. Hume and R. S. Pirie},

url = {https://www.scopus.com/inward/record.uri?eid=2-s2.0-85102239236&doi=10.1111%2fevj.13429&partnerID=40&md5=9115ede24f37dcb355c70a980474c5bd},

doi = {10.1111/evj.13429},

issn = {04251644},

year  = {2021},

date = {2021-01-01},

journal = {Equine Veterinary Journal},

abstract = {Background: Studies in rodents and humans have demonstrated that intestinal manipulation or surgical trauma initiates an inflammatory response in the intestine which results in leucocyte recruitment to the muscularis externa causing smooth muscle dysfunction. Objectives: To examine the intestinal inflammatory response in horses undergoing colic surgery by measuring relative differential gene expression in intestinal tissues harvested from surgical colic cases and control horses. Study design: Prospective case-control study. Methods: Mucosa and muscularis externa were harvested from healthy margins of resected small intestine from horses undergoing colic surgery (n = 12) and from intestine derived from control horses euthanised for reasons unrelated to the gastrointestinal tract (n = 6). Tissue was analysed for genes encoding proteins involved in the inflammatory response: interleukin (IL) 6 and IL1β, C-C motif chemokine ligand 2 (CCL2), tumour necrosis factor (TNF), prostaglandin-endoperoxide synthase 2 (PTGS2) and indoleamine 2,3-dioxygenase (IDO1). Relative expression of these genes was compared between the two groups. Further analysis was applied to the colic cases to determine whether the magnitude of relative gene expression was associated with the subsequent development of post-operative reflux (POR). Results: Samples obtained from colic cases had increased relative expression of IL1β, IL6, CCL2 and TNF in the mucosa and muscularis externa when compared with the control group. There was no difference in relative gene expression between proximal and distal resection margins and no association between duration of colic, age, resection length, short-term survival and the presence of pre-operative reflux and the relative expression of the genes of interest. Horses that developed POR had significantly greater relative gene expression of TNF in the mucosa compared with horses that did not develop POR. Main limitations: Small sample size per group and variation within the colic cases. Conclusions: These preliminary data support an upregulation of inflammatory genes in the intestine of horses undergoing colic surgery. © 2021 The Authors. Equine Veterinary Journal published by John Wiley & Sons Ltd on behalf of EVJ Ltd.},

note = {Publisher: Equine Veterinary Journal Ltd},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{green_utility_2021,

title = {On the utility of CSF1R inhibitors},

author = {K. N. Green and D. A. Hume},

url = {https://www.scopus.com/inward/record.uri?eid=2-s2.0-85099998259&doi=10.1073%2fpnas.2019695118&partnerID=40&md5=8ceaa389faa37d4c70ad40576e60e5da},

doi = {10.1073/pnas.2019695118},

issn = {00278424},

year  = {2021},

date = {2021-01-01},

journal = {Proceedings of the National Academy of Sciences of the United States of America},

volume = {118},

number = {4},

note = {Publisher: National Academy of Sciences},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{pridans_transcriptomic_2021,

title = {Transcriptomic Analysis of Rat Macrophages},

author = {C. Pridans and K. M. Irvine and G. M. Davis and L. Lefevre and S. J. Bush and D. A. Hume},

url = {https://www.scopus.com/inward/record.uri?eid=2-s2.0-85100832173&doi=10.3389%2ffimmu.2020.594594&partnerID=40&md5=04750fcce24d9c186af9bbb8e2b54e24},

doi = {10.3389/fimmu.2020.594594},

issn = {16643224},

year  = {2021},

date = {2021-01-01},

journal = {Frontiers in Immunology},

volume = {11},

abstract = {The laboratory rat is widely used as a model for human diseases. Many of these diseases involve monocytes and tissue macrophages in different states of activation. Whilst methods for in vitro differentiation of mouse macrophages from embryonic stem cells (ESC) and bone marrow (BM) are well established, these are lacking for the rat. The gene expression profiles of rat macrophages have also not been characterised to the same extent as mouse. We have established the methodology for production of rat ESC-derived macrophages and compared their gene expression profiles to macrophages obtained from the lung and peritoneal cavity and those differentiated from BM and blood monocytes. We determined the gene signature of Kupffer cells in the liver using rats deficient in macrophage colony stimulating factor receptor (CSF1R). We also examined the response of BM-derived macrophages to lipopolysaccharide (LPS). The results indicate that many, but not all, tissue-specific adaptations observed in mice are conserved in the rat. Importantly, we show that unlike mice, rat macrophages express the CSF1R ligand, colony stimulating factor 1 (CSF1). © Copyright © 2021 Pridans, Irvine, Davis, Lefevre, Bush and Hume.},

note = {Publisher: Frontiers Media S.A.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{karagianni_equine_2021,

title = {The equine mononuclear phagocyte system: The relevance of the horse as a model for understanding human innate immunity},

author = {A. E. Karagianni and Z. M. Lisowski and D. A. Hume and R. Scott Pirie},

url = {https://www.scopus.com/inward/record.uri?eid=2-s2.0-85091603719&doi=10.1111%2fevj.13341&partnerID=40&md5=bb80aa4e612df49b6b60168b52d961ed},

doi = {10.1111/evj.13341},

issn = {04251644},

year  = {2021},

date = {2021-01-01},

journal = {Equine Veterinary Journal},

volume = {53},

number = {2},

pages = {231--249},

abstract = {The mononuclear phagocyte system (MPS) is a family of cells of related function that includes bone marrow progenitors, blood monocytes and resident tissue macrophages. Macrophages are effector cells in both innate and acquired immunity. They are a major resident cell population in every organ and their numbers increase in response to proinflammatory stimuli. Their function is highly regulated by a wide range of agonists, including lymphokines, cytokines and products of microorganisms. Macrophage biology has been studied most extensively in mice, yet direct comparisons of rodent and human macrophages have revealed many functional differences. In this review, we provide an overview of the equine MPS, describing the variation in the function and phenotype of macrophages depending on their location and the similarities and differences between the rodent, human and equine immune response. We discuss the use of the horse as a large animal model in which to study macrophage biology and pathological processes shared with humans. Finally, following the recent update to the horse genome, facilitating further comparative analysis of regulated gene expression between the species, we highlight the importance of future transcriptomic macrophage studies in the horse, the findings of which may also be applicable to human as well as veterinary research. © 2021 The Authors. Equine Veterinary Journal published by John Wiley & Sons Ltd on behalf of EVJ Ltd},

note = {Publisher: Equine Veterinary Journal Ltd},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{wiener_whole-genome_2021,

title = {Whole-Genome Sequence Data Suggest Environmental Adaptation of Ethiopian Sheep Populations},

author = {P. Wiener and C. Robert and A. Ahbara and M. Salavati and A. Abebe and A. Kebede and D. Wragg and J. Friedrich and D. Vasoya and D. A. Hume and A. Djikeng and M. Watson and J. G. D. Prendergast and O. Hanotte and J. M. Mwacharo and E. L. Clark},

url = {https://www.scopus.com/inward/record.uri?eid=2-s2.0-85102965415&doi=10.1093%2fgbe%2fevab014&partnerID=40&md5=cccda84cd1d01e51c73fb8ee8a1f080a},

doi = {10.1093/gbe/evab014},

issn = {17596653},

year  = {2021},

date = {2021-01-01},

journal = {Genome biology and evolution},

volume = {13},

number = {3},

abstract = {Great progress has been made over recent years in the identification of selection signatures in the genomes of livestock species. This work has primarily been carried out in commercial breeds for which the dominant selection pressures are associated with artificial selection. As agriculture and food security are likely to be strongly affected by climate change, a better understanding of environment-imposed selection on agricultural species is warranted. Ethiopia is an ideal setting to investigate environmental adaptation in livestock due to its wide variation in geo-climatic characteristics and the extensive genetic and phenotypic variation of its livestock. Here, we identified over three million single nucleotide variants across 12 Ethiopian sheep populations and applied landscape genomics approaches to investigate the association between these variants and environmental variables. Our results suggest that environmental adaptation for precipitation-related variables is stronger than that related to altitude or temperature, consistent with large-scale meta-analyses of selection pressure across species. The set of genes showing association with environmental variables was enriched for genes highly expressed in human blood and nerve tissues. There was also evidence of enrichment for genes associated with high-altitude adaptation although no strong association was identified with hypoxia-inducible-factor (HIF) genes. One of the strongest altitude-related signals was for a collagen gene, consistent with previous studies of high-altitude adaptation. Several altitude-associated genes also showed evidence of adaptation with temperature, suggesting a relationship between responses to these environmental factors. These results provide a foundation to investigate further the effects of climatic variables on small ruminant populations. © The Author(s) 2021. Published by Oxford University Press on behalf of the Society for Molecular Biology and Evolution.},

note = {Publisher: NLM (Medline)},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{patkar_analysis_2021,

title = {Analysis of homozygous and heterozygous Csf1r knockout in the rat as a model for understanding microglial function in brain development and the impacts of human CSF1R mutations},

author = {O. L. Patkar and M. Caruso and N. Teakle and S. Keshvari and S. J. Bush and C. Pridans and A. Belmer and K. M. Summers and K. M. Irvine and D. A. Hume},

url = {https://www.scopus.com/inward/record.uri?eid=2-s2.0-85099616799&doi=10.1016%2fj.nbd.2021.105268&partnerID=40&md5=b1a09a2930f62a2ec0fc08fd98da6279},

doi = {10.1016/j.nbd.2021.105268},

issn = {09699961},

year  = {2021},

date = {2021-01-01},

journal = {Neurobiology of Disease},

volume = {151},

abstract = {Mutations in the human CSF1R gene have been associated with dominant and recessive forms of neurodegenerative disease. Here we describe the impacts of Csf1r mutation in the rat on development of the brain. Diffusion imaging indicated small reductions in major fiber tracts that may be associated in part with ventricular enlargement. RNA-seq profiling revealed a set of 105 microglial markers depleted in all brain regions of the Csf1rko rats. There was no evidence of region or sex-specific expression of microglia-associated transcripts. Other than the microglial signature, Csf1rko had no effect on any neuronal or region-specific transcript cluster. Expression of markers of oligodendrocytes, astrocytes, dopaminergic neurons and Purkinje cells was minimally affected. However, there were defects in dendritic arborization of doublecortin-positive neurogenic precursors and expression of poly-sialylated neural cell adhesion molecule (PS-NCAM) in the dentate gyrus of the hippocampus. Heterozygous Csf1rko rats had no detectable brain phenotype. We conclude that most brain developmental processes occur normally in the absence of microglia and that CSF1R haploinsufficiency is unlikely to cause leukoencephalopathy. © 2021 The Authors},

note = {Publisher: Academic Press Inc.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{gazova_crispr-cas9_2021,

title = {CRISPR-Cas9 Editing of Human Histone Deubiquitinase Gene USP16 in Human Monocytic Leukemia Cell Line THP-1},

author = {I. Gažová and L. Lefevre and S. J. Bush and R. Rojo and D. A. Hume and A. Lengeling and K. M. Summers},

url = {https://www.scopus.com/inward/record.uri?eid=2-s2.0-85107882201&doi=10.3389%2ffcell.2021.679544&partnerID=40&md5=7ceb37180729d682d95b35e55a3e4f9c},

doi = {10.3389/fcell.2021.679544},

issn = {2296634X},

year  = {2021},

date = {2021-01-01},

journal = {Frontiers in Cell and Developmental Biology},

volume = {9},

abstract = {USP16 is a histone deubiquitinase which facilitates G2/M transition during the cell cycle, regulates DNA damage repair and contributes to inducible gene expression. We mutated the USP16 gene in a high differentiation clone of the acute monocytic leukemia cell line THP-1 using the CRISPR-Cas9 system and generated four homozygous knockout clones. All were able to proliferate and to differentiate in response to phorbol ester (PMA) treatment. One line was highly proliferative prior to PMA treatment and shut down proliferation upon differentiation, like wild type. Three clones showed sustained expression of the progenitor cell marker MYB, indicating that differentiation had not completely blocked proliferation in these clones. Network analysis of transcriptomic differences among wild type, heterozygotes and homozygotes showed clusters of genes that were up- or down-regulated after differentiation in all cell lines. Prior to PMA treatment, the homozygous clones had lower levels than wild type of genes relating to metabolism and mitochondria, including SRPRB, encoding an interaction partner of USP16. There was also apparent loss of interferon signaling. In contrast, a number of genes were up-regulated in the homozygous cells compared to wild type at baseline, including other deubiquitinases (USP12, BAP1, and MYSM1). However, three homozygotes failed to fully induce USP3 during differentiation. Other network clusters showed effects prior to or after differentiation in the homozygous clones. Thus the removal of USP16 affected the transcriptome of the cells, although all these lines were able to survive, which suggests that the functions attributed to USP16 may be redundant. Our analysis indicates that the leukemic line can adapt to the extreme selection pressure applied by the loss of USP16, and the harsh conditions of the gene editing and selection protocol, through different compensatory pathways. Similar selection pressures occur during the evolution of a cancer in vivo, and our results can be seen as a case study in leukemic cell adaptation. USP16 has been considered a target for cancer chemotherapy, but our results suggest that treatment would select for escape mutants that are resistant to USP16 inhibitors. © Copyright © 2021 Gažová, Lefevre, Bush, Rojo, Hume, Lengeling and Summers.},

note = {Publisher: Frontiers Media S.A.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{psifidi_quantitative_2021,

title = {Quantitative trait loci and transcriptome signatures associated with avian heritable resistance to Campylobacter},

author = {A. Psifidi and A. Kranis and L. M. Rothwell and A. Bremner and K. Russell and D. Robledo and S. J. Bush and M. Fife and P. M. Hocking and G. Banos and D. A. Hume and J. Kaufman and R. A. Bailey and S. Avendano and K. A. Watson and P. Kaiser and M. P. Stevens},

url = {https://www.scopus.com/inward/record.uri?eid=2-s2.0-85099217911&doi=10.1038%2fs41598-020-79005-7&partnerID=40&md5=d9562b8abe8f8bba2af250aeb7308966},

doi = {10.1038/s41598-020-79005-7},

issn = {20452322},

year  = {2021},

date = {2021-01-01},

journal = {Scientific Reports},

volume = {11},

number = {1},

abstract = {Campylobacter is the leading cause of bacterial foodborne gastroenteritis worldwide. Handling or consumption of contaminated poultry meat is a key risk factor for human campylobacteriosis. One potential control strategy is to select poultry with increased resistance to Campylobacter. We associated high-density genome-wide genotypes (600K single nucleotide polymorphisms) of 3000 commercial broilers with Campylobacter load in their caeca. Trait heritability was modest but significant (h2 = 0.11 ± 0.03). Results confirmed quantitative trait loci (QTL) on chromosomes 14 and 16 previously identified in inbred chicken lines, and detected two additional QTLs on chromosomes 19 and 26. RNA-Seq analysis of broilers at the extremes of colonisation phenotype identified differentially transcribed genes within the QTL on chromosome 16 and proximal to the major histocompatibility complex (MHC) locus. We identified strong cis-QTLs located within MHC suggesting the presence of cis-acting variation in MHC class I and II and BG genes. Pathway and network analyses implicated cooperative functional pathways and networks in colonisation, including those related to antigen presentation, innate and adaptive immune responses, calcium, and renin–angiotensin signalling. While co-selection for enhanced resistance and other breeding goals is feasible, the frequency of resistance-associated alleles was high in the population studied and non-genetic factors significantly influenced Campylobacter colonisation. © 2021, The Author(s).},

note = {Publisher: Nature Research},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{batoon_treatment_2021,

title = {Treatment with a long-acting chimeric CSF1 molecule enhances fracture healing of healthy and osteoporotic bones},

author = {Lena Batoon and Susan M Millard and Liza J Raggatt and Cheyenne Sandrock and Edmund Pickering and Kyle Williams and Lucas W H Sun and Andy C Wu and Katharine M Irvine and Peter Pivonka and Vaida Glatt and Martin E Wullschleger and David A Hume and Allison R Pettit},

url = {https://www.sciencedirect.com/science/article/pii/S0142961221002921},

doi = {10.1016/j.biomaterials.2021.120936},

issn = {0142-9612},

year  = {2021},

date = {2021-01-01},

urldate = {2021-08-06},

journal = {Biomaterials},

volume = {275},

pages = {120936},

abstract = {Macrophage-targeted therapies, including macrophage colony-stimulating factor 1 (CSF1), have been shown to have pro-repair impacts post-fracture. Preclinical/clinical applications of CSF1 have been expedited by development of chimeric CSF1-Fc which has extended circulating half-life. Here, we used mouse models to investigate the bone regenerative potential of CSF1-Fc in healthy and osteoporotic fracture. We also explored whether combination of CSF1-Fc with interleukin (IL)-4 provided additional fracture healing benefit in osteopenic bone. Micro-computed tomography, in situ histomorphometry, and bone mechanical parameters were used to assess systemic impacts of CSF1-Fc therapy in naive mice (male and female young, adult and geriatric). An intermittent CSF1-Fc regimen was optimized to mitigate undesirable impacts on bone resorption and hepatosplenomegaly, irrespective of age or gender. The intermittent CSF1-Fc regimen was tested in a mid-diaphyseal femoral fracture model in healthy bones with treatment initiated 1-day post-fracture. Weekly CSF1-Fc did not impact osteoclasts but increased osteal macrophages and improved fracture strength. Importantly, this treatment regimen also improved fracture union and strength in an ovariectomy-model of delayed fracture repair. Combining CSF1-Fc with IL-4 initiated 1-week post-fracture reduced the efficacy of CSF1-Fc. This study describes a novel strategy to specifically achieve bone regenerative actions of CSF1-Fc that has the potential to alleviate fragility fracture morbidity and mortality.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{keshvari_csf1r-dependent_2021,

title = {CSF1R-dependent macrophages control postnatal somatic growth and organ maturation},

author = {Sahar Keshvari and Melanie Caruso and Ngari Teakle and Lena Batoon and Anuj Sehgal and Omkar L Patkar and Michelle Ferrari-Cestari and Cameron E Snell and Chen Chen and Alex Stevenson and Felicity M Davis and Stephen J Bush and Clare Pridans and Kim M Summers and Allison R Pettit and Katharine M Irvine and David A Hume},

url = {https://journals.plos.org/plosgenetics/article?id=10.1371/journal.pgen.1009605},

doi = {10.1371/journal.pgen.1009605},

issn = {1553-7404},

year  = {2021},

date = {2021-01-01},

urldate = {2021-08-06},

journal = {PLOS Genetics},

volume = {17},

number = {6},

pages = {e1009605},

abstract = {Homozygous mutation of the Csf1r locus (Csf1rko) in mice, rats and humans leads to multiple postnatal developmental abnormalities. To enable analysis of the mechanisms underlying the phenotypic impacts of Csf1r mutation, we bred a rat Csf1rko allele to the inbred dark agouti (DA) genetic background and to a Csf1r-mApple reporter transgene. The Csf1rko led to almost complete loss of embryonic macrophages and ablation of most adult tissue macrophage populations. We extended previous analysis of the Csf1rko phenotype to early postnatal development to reveal impacts on musculoskeletal development and proliferation and morphogenesis in multiple organs. Expression profiling of 3-week old wild-type (WT) and Csf1rko livers identified 2760 differentially expressed genes associated with the loss of macrophages, severe hypoplasia, delayed hepatocyte maturation, disrupted lipid metabolism and the IGF1/IGF binding protein system. Older Csf1rko rats developed severe hepatic steatosis. Consistent with the developmental delay in the liver Csf1rko rats had greatly-reduced circulating IGF1. Transfer of WT bone marrow (BM) cells at weaning without conditioning repopulated resident macrophages in all organs, including microglia in the brain, and reversed the mutant phenotypes enabling long term survival and fertility. WT BM transfer restored osteoclasts, eliminated osteopetrosis, restored bone marrow cellularity and architecture and reversed granulocytosis and B cell deficiency. Csf1rko rats had an elevated circulating CSF1 concentration which was rapidly reduced to WT levels following BM transfer. However, CD43hi non-classical monocytes, absent in the Csf1rko, were not rescued and bone marrow progenitors remained unresponsive to CSF1. The results demonstrate that the Csf1rko phenotype is autonomous to BM-derived cells and indicate that BM contains a progenitor of tissue macrophages distinct from hematopoietic stem cells. The model provides a unique system in which to define the pathways of development of resident tissue macrophages and their local and systemic roles in growth and organ maturation.},

note = {Publisher: Public Library of Science},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{kaur_stable_2021,

title = {Stable colony-stimulating factor 1 fusion protein treatment increases hematopoietic stem cell pool and enhances their mobilisation in mice},

author = {Simranpreet Kaur and Anuj Sehgal and Andy C Wu and Susan M Millard and Lena Batoon and Cheyenne J Sandrock and Michelle Ferrari-Cestari and Jean-Pierre Levesque and David A Hume and Liza J Raggatt and Allison R Pettit},

url = {https://doi.org/10.1186/s13045-020-00997-w},

doi = {10.1186/s13045-020-00997-w},

issn = {1756-8722},

year  = {2021},

date = {2021-01-01},

urldate = {2021-08-06},

journal = {Journal of Hematology & Oncology},

volume = {14},

number = {1},

pages = {3},

abstract = {Prior chemotherapy and/or underlying morbidity commonly leads to poor mobilisation of hematopoietic stem cells (HSC) for transplantation in cancer patients. Increasing the number of available HSC prior to mobilisation is a potential strategy to overcome this deficiency. Resident bone marrow (BM) macrophages are essential for maintenance of niches that support HSC and enable engraftment in transplant recipients. Here we examined potential of donor treatment with modified recombinant colony-stimulating factor 1 (CSF1) to influence the HSC niche and expand the HSC pool for autologous transplantation.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{grabert_transgenic_2020,

title = {A Transgenic Line That Reports CSF1R Protein Expression Provides a Definitive Marker for the Mouse Mononuclear Phagocyte System},

author = {Kathleen Grabert and Anuj Sehgal and Katharine M. Irvine and Evi Wollscheid-Lengeling and Derya D. Ozdemir and Jennifer Stables and Garry A. Luke and Martin D. Ryan and Antony Adamson and Neil E. Humphreys and Cheyenne J. Sandrock and Rocio Rojo and Veera A. Verkasalo and Werner Mueller and Peter Hohenstein and Allison R. Pettit and Clare Pridans and David A. Hume},

url = {http://www.jimmunol.org/lookup/doi/10.4049/jimmunol.2000835},

doi = {10.4049/jimmunol.2000835},

issn = {0022-1767, 1550-6606},

year  = {2020},

date = {2020-12-01},

urldate = {2021-10-21},

journal = {The Journal of Immunology},

volume = {205},

number = {11},

pages = {3154--3166},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{irvine_analysis_2020,

title = {Analysis of the impact of CSF‐1 administration in adult rats using a novel textitCsf1r ‐mApple reporter gene},

author = {Katharine M. Irvine and Melanie Caruso and Michelle Ferrari Cestari and Gemma M. Davis and Sahar Keshvari and Anuj Sehgal and Clare Pridans and David A. Hume},

url = {https://onlinelibrary.wiley.com/doi/10.1002/JLB.MA0519-149R},

doi = {10.1002/JLB.MA0519-149R},

issn = {0741-5400, 1938-3673},

year  = {2020},

date = {2020-02-01},

urldate = {2021-10-21},

journal = {Journal of Leukocyte Biology},

volume = {107},

number = {2},

pages = {221--235},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{warr_improved_2020,

title = {An improved pig reference genome sequence to enable pig genetics and genomics research},

author = {A. Warr and N. Affara and B. Aken and H. Beiki and D. M. Bickhart and K. Billis and W. Chow and L. Eory and H. A. Finlayson and P. Flicek and C. G. Girón and D. K. Griffin and R. Hall and G. Hannum and T. Hourlier and K. Howe and D. A. Hume and O. Izuogu and K. Kim and S. Koren and H. Liu and N. Manchanda and F. J. Martin and D. J. Nonneman and R. E. O'Connor and A. M. Phillippy and G. A. Rohrer and B. D. Rosen and L. A. Rund and C. A. Sargent and L. B. Schook and S. G. Schroeder and A. S. Schwartz and B. M. Skinner and R. Talbot and E. Tseng and C. K. Tuggle and M. Watson and T. P. L. Smith and A. L. Archibald},

url = {https://www.scopus.com/inward/record.uri?eid=2-s2.0-85086624247&doi=10.1093%2fGIGASCIENCE%2fGIAA051&partnerID=40&md5=df7b31183e91943382f5a7f20e4c33fa},

doi = {10.1093/GIGASCIENCE/GIAA051},

issn = {2047217X},

year  = {2020},

date = {2020-01-01},

journal = {GigaScience},

volume = {9},

number = {6},

abstract = {Background: The domestic pig (Sus scrofa) is important both as a food source and as a biomedical model given its similarity in size, anatomy, physiology, metabolism, pathology, and pharmacology to humans. The draft reference genome (Sscrofa10.2) of a purebred Duroc female pig established using older clone-based sequencing methods was incomplete, and unresolved redundancies, short-range order and orientation errors, and associated misassembled genes limited its utility. Results: We present 2 annotated highly contiguous chromosome-level genome assemblies created with more recent long-read technologies and a whole-genome shotgun strategy, 1 for the same Duroc female (Sscrofa11.1) and 1 for an outbred, composite-breed male (USMARCv1.0). Both assemblies are of substantially higher (textgreater90-fold) continuity and accuracy than Sscrofa10.2. Conclusions: These highly contiguous assemblies plus annotation of a further 11 short-read assemblies provide an unprecedented view of the genetic make-up of this important agricultural and biomedical model species. We propose that the improved Duroc assembly (Sscrofa11.1) become the reference genome for genomic research in pigs. © The Author(s) 2020. Published by Oxford University Press. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted reuse, distribution, and reproduction in any medium, provided the original work is properly cited.},

note = {Publisher: Oxford University Press},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{abbott_geometry_2020,

title = {The geometry of generalized loxodromic elements},

author = {C. R. Abbott and D. Hume},

url = {https://www.scopus.com/inward/record.uri?eid=2-s2.0-85107724618&doi=10.5802%2fAIF.3379&partnerID=40&md5=9a7af472208daea85fd6dcf3a0b568e9},

doi = {10.5802/AIF.3379},

issn = {03730956},

year  = {2020},

date = {2020-01-01},

journal = {Annales de l'Institut Fourier},

volume = {70},

number = {4},

pages = {1689--1713},

abstract = {We explore geometric conditions which ensure that a given element of a finitely generated group is, or fails to be, generalized loxodromic; as part of this we prove a generalization of Sisto’s result that every generalized loxodromic element is Morse. We provide a sufficient geometric condition for an element of a small cancellation group to be generalized loxodromic in terms of the defining relations and provide a number of constructions which prove that this condition is sharp. © 2020 Association des Annales de l'Institut Fourier. All rights reserved.},

note = {Publisher: Association des Annales de l'Institut Fourier},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{hume_functional_2020,

title = {Functional evolution of the colony-stimulating factor 1 receptor (CSF1R) and its ligands in birds},

author = {D. A. Hume and M. W. Gutowska-Ding and C. Garcia-Morales and A. Kebede and O. Bamidele and A. V. Trujillo and A. A. Gheyas and J. Smith},

url = {https://www.scopus.com/inward/record.uri?eid=2-s2.0-85071752943&doi=10.1002%2fJLB.6MA0519-172R&partnerID=40&md5=4f1d858e6f843c7a6b4a7590dbfb1301},

doi = {10.1002/JLB.6MA0519-172R},

issn = {07415400},

year  = {2020},

date = {2020-01-01},

journal = {Journal of Leukocyte Biology},

volume = {107},

number = {2},

pages = {237--250},

abstract = {Macrophage colony-stimulating factor (CSF1 or M-CSF) and interleukin 34 (IL34) are secreted cytokines that control macrophage survival and differentiation. Both act through the CSF1 receptor (CSF1R), a type III transmembrane receptor tyrosine kinase. The functions of CSF1R and both ligands are conserved in birds. We have analyzed protein-coding sequence divergence among avian species. The intracellular tyrosine kinase domain of CSF1R was highly conserved in bird species as in mammals but the extracellular domain of avian CSF1R was more divergent in birds with multiple positively selected amino acids. Based upon crystal structures of the mammalian CSF1/IL34 receptor-ligand interfaces and structure-based alignments, we identified amino acids involved in avian receptor-ligand interactions. The contact amino acids in both CSF1 and CSF1R diverged among avian species. Ligand-binding domain swaps between chicken and zebra finch CSF1 confirmed the function of variants that confer species specificity on the interaction of CSF1 with CSF1R. Based upon genomic sequence analysis, we identified prevalent amino acid changes in the extracellular domain of CSF1R even within the chicken species that distinguished commercial broilers and layers and tropically adapted breeds. The rapid evolution in the extracellular domain of avian CSF1R suggests that at least in birds this ligand-receptor interaction is subjected to pathogen selection. We discuss this finding in the context of expression of CSF1R in antigen-sampling and antigen-presenting cells. © 2019 The Authors. Journal of Leukocyte Biology published by Wiley Periodicals, Inc. on behalf of Society for Leukocyte Biology},

note = {Publisher: John Wiley and Sons Inc.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{hume_phenotypic_2020,

title = {Phenotypic impacts of CSF1R deficiencies in humans and model organisms},

author = {D. A. Hume and M. Caruso and M. Ferrari-Cestari and K. M. Summers and C. Pridans and K. M. Irvine},

url = {https://www.scopus.com/inward/record.uri?eid=2-s2.0-85075575069&doi=10.1002%2fJLB.MR0519-143R&partnerID=40&md5=4140a7666153d4ddbdafb8e7987f8c2f},

doi = {10.1002/JLB.MR0519-143R},

issn = {07415400},

year  = {2020},

date = {2020-01-01},

journal = {Journal of Leukocyte Biology},

volume = {107},

number = {2},

pages = {205--219},

abstract = {Mϕ proliferation, differentiation, and survival are controlled by signals from the Mϕ CSF receptor (CSF1R). Mono-allelic gain-of-function mutations in CSF1R in humans are associated with an autosomal-dominant leukodystrophy and bi-allelic loss-of-function mutations with recessive skeletal dysplasia, brain disorders, and developmental anomalies. Most of the phenotypes observed in these human disease states are also observed in mice and rats with loss-of-function mutations in Csf1r or in Csf1 encoding one of its two ligands. Studies in rodent models also highlight the importance of genetic background and likely epistatic interactions between Csf1r and other loci. The impacts of Csf1r mutations on the brain are usually attributed solely to direct impacts on microglial number and function. However, analysis of hypomorphic Csf1r mutants in mice and several other lines of evidence suggest that primary hydrocephalus and loss of the physiological functions of Mϕs in the periphery contribute to the development of brain pathology. In this review, we outline the evidence that CSF1R is expressed exclusively in mononuclear phagocytes and explore the mechanisms linking CSF1R mutations to pleiotropic impacts on postnatal growth and development. © 2019 The Authors. Journal of Leukocyte Biology published by Wiley Periodicals, Inc. on behalf of Society for Leukocyte Biology},

note = {Publisher: John Wiley and Sons Inc.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{summers_functional_2020,

title = {Functional Annotation of the Transcriptome of the Pig, Sus scrofa, Based Upon Network Analysis of an RNAseq Transcriptional Atlas},

author = {K. M. Summers and S. J. Bush and C. Wu and A. I. Su and C. Muriuki and E. L. Clark and H. A. Finlayson and L. Eory and L. A. Waddell and R. Talbot and A. L. Archibald and D. A. Hume},

url = {https://www.scopus.com/inward/record.uri?eid=2-s2.0-85080059352&doi=10.3389%2ffgene.2019.01355&partnerID=40&md5=0d2a49ca8e839a3f0834df22b422bbb1},

doi = {10.3389/fgene.2019.01355},

issn = {16648021},

year  = {2020},

date = {2020-01-01},

journal = {Frontiers in Genetics},

volume = {10},

abstract = {The domestic pig (Sus scrofa) is both an economically important livestock species and a model for biomedical research. Two highly contiguous pig reference genomes have recently been released. To support functional annotation of the pig genomes and comparative analysis with large human transcriptomic data sets, we aimed to create a pig gene expression atlas. To achieve this objective, we extended a previous approach developed for the chicken. We downloaded RNAseq data sets from public repositories, down-sampled to a common depth, and quantified expression against a reference transcriptome using the mRNA quantitation tool, Kallisto. We then used the network analysis tool Graphia to identify clusters of transcripts that were coexpressed across the merged data set. Consistent with the principle of guilt-by-association, we identified coexpression clusters that were highly tissue or cell-type restricted and contained transcription factors that have previously been implicated in lineage determination. Other clusters were enriched for transcripts associated with biological processes, such as the cell cycle and oxidative phosphorylation. The same approach was used to identify coexpression clusters within RNAseq data from multiple individual liver and brain samples, highlighting cell type, process, and region-specific gene expression. Evidence of conserved expression can add confidence to assignment of orthology between pig and human genes. Many transcripts currently identified as novel genes with ENSSSCG or LOC IDs were found to be coexpressed with annotated neighbouring transcripts in the same orientation, indicating they may be products of the same transcriptional unit. The meta-analytic approach to utilising public RNAseq data is extendable to include new data sets and new species and provides a framework to support the Functional Annotation of Animals Genomes (FAANG) initiative. © Copyright © 2020 Summers, Bush, Wu, Su, Muriuki, Clark, Finlayson, Eory, Waddell, Talbot, Archibald and Hume.},

note = {Publisher: Frontiers Media S.A.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{wu_regulation_2020,

title = {Regulation and function of macrophage colony-stimulating factor (CSF1) in the chicken immune system},

author = {Z. Wu and R. Harne and C. Chintoan-Uta and T. -J. Hu and R. Wallace and A. MacCallum and M. P. Stevens and P. Kaiser and A. Balic and D. A. Hume},

url = {https://www.scopus.com/inward/record.uri?eid=2-s2.0-85076698109&doi=10.1016%2fj.dci.2019.103586&partnerID=40&md5=18b2956f0b64e9854c228fb3b6d31ec1},

doi = {10.1016/j.dci.2019.103586},

issn = {0145305X},

year  = {2020},

date = {2020-01-01},

journal = {Developmental and Comparative Immunology},

volume = {105},

abstract = {Macrophage colony-stimulating factor (CSF1) is an essential growth factor to control the proliferation, differentiation and survival of cells of the macrophage lineage in vertebrates. We have previously produced a recombinant chicken CSF1-Fc fusion protein and administrated it to birds which produced a substantial expansion of tissue macrophage populations. To further study the biology of CSF1 in the chicken, here we generated anti-chicken CSF1 antibodies (ROS-AV181 and 183) using CSF1-Fc as an immunogen. The specific binding of each monoclonal antibody was confirmed by ELISA, Western blotting and immunohistochemistry on tissue sections. Using the anti-CSF1 antibodies, we show that chicken bone marrow derived macrophages (BMDM) express CSF1 on their surface, and that the level appears to be regulated further by exogenous CSF1. By capture ELISA circulating CSF1 levels increased transiently in both layer and broiler embryos around the day of hatch. The levels of CSF1 in broilers was higher than in layers during the first week after hatch. Antibody ROS-AV183 was able to block CSF1 biological activity in vitro and treatment of hatchlings using this neutralising antibody in vivo impacted on some tissue macrophage populations, but not blood monocytes. After anti-CSF1 treatment, CSF1R-transgene reporter expressing cells were reduced in the bursa of Fabricius and cecal tonsil and TIM4+ Kupffer cells in the liver were almost completely ablated. Anti-CSF1 treatment also produced a reduction in overall bone density, trabecular volume and TRAP+ osteoclasts. Our novel neutralising antibody provides a new tool to study the roles of CSF1 in birds. © 2019},

note = {Publisher: Elsevier Ltd},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{clohisey_comprehensive_2020,

title = {Comprehensive characterization of transcriptional activity during influenza a virus infection reveals biases in cap-snatching of host rna sequences},

author = {S. Clohisey and N. Parkinson and B. Wang and N. Bertin and H. Wise and A. Tomoiu and K. M. Summers and R. W. Hendry and P. Carninci and A. P. R. Forrest and Y. Hayashizaki and P. Digard and D. A. Hume and J. K. Baillie},

url = {https://www.scopus.com/inward/record.uri?eid=2-s2.0-85084271888&doi=10.1128%2fJVI.01720-19&partnerID=40&md5=1210251fda1a4b28d8b96a50eeeed553},

doi = {10.1128/JVI.01720-19},

issn = {0022538X},

year  = {2020},

date = {2020-01-01},

journal = {Journal of Virology},

volume = {94},

number = {10},

abstract = {Macrophages in the lung detect and respond to influenza A virus (IAV), determining the nature of the immune response. Using terminal-depth cap analysis of gene expression (CAGE), we quantified transcriptional activity of both host and pathogen over a 24-h time course of IAV infection in primary human monocytederived macrophages (MDMs). This method allowed us to observe heterogenous host sequences incorporated into IAV mRNA, "snatched" 5= RNA caps, and corresponding RNA sequences from host RNAs. In order to determine whether capsnatching is random or exhibits a bias, we systematically compared host sequences incorporated into viral mRNA ("snatched") against a complete survey of all background host RNA in the same cells, at the same time. Using a computational strategy designed to eliminate sources of bias due to read length, sequencing depth, and multimapping, we were able to quantify overrepresentation of host RNA features among the sequences that were snatched by IAV. We demonstrate biased snatching of numerous host RNAs, particularly small nuclear RNAs (snRNAs), and avoidance of host transcripts encoding host ribosomal proteins, which are required by IAV for replication. We then used a systems approach to describe the transcriptional landscape of the host response to IAV, observing many new features, including a failure of IAV-Treated MDMs to induce feedback inhibitors of inflammation, seen in response to other treatments. © 2020 Clohisey et al. This is an open-Access article distributed under the terms of the Creative Commons Attribution 4.0 International license.},

note = {Publisher: American Society for Microbiology},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{wittenberg_effects_2020,

title = {Effects of immunomodulatory drugs on depressive symptoms: A mega-analysis of randomized, placebo-controlled clinical trials in inflammatory disorders},

author = {G. M. Wittenberg and A. Stylianou and Y. Zhang and Y. Sun and A. Gupta and P. S. Jagannatha and D. Wang and B. Hsu and M. E. Curran and S. Khan and P. E. Vértes and R. Cardinal and S. Richardson and G. Leday and T. Freeman and D. Hume and T. Regan and Z. Wu and C. Pariante and A. Cattaneo and P. Zunszain and A. Borsini and R. Stewart and D. Chandran and L. Carvalho and J. Bell and L. H. Souza-Teodoro and H. Perry and N. Harrison and D. Jones and R. B. Henderson and G. Chen and E. T. Bullmore and W. C. Drevets and MRC ImmunoPsychiatry Consortium},

url = {https://www.scopus.com/inward/record.uri?eid=2-s2.0-85070810380&doi=10.1038%2fs41380-019-0471-8&partnerID=40&md5=8191ee3588ff3f729e38455d4572f251},

doi = {10.1038/s41380-019-0471-8},

issn = {13594184},

year  = {2020},

date = {2020-01-01},

journal = {Molecular Psychiatry},

volume = {25},

number = {6},

pages = {1275--1285},

abstract = {Activation of the innate immune system is commonly associated with depression. Immunomodulatory drugs may have efficacy for depressive symptoms that are co-morbidly associated with inflammatory disorders. We report a large-scale re-analysis by standardized procedures (mega-analysis) of patient-level data combined from 18 randomized clinical trials conducted by Janssen or GlaxoSmithKline for one of nine disorders (N = 10,743 participants). Core depressive symptoms (low mood, anhedonia) were measured by the Short Form Survey (SF-36) or the Hospital Anxiety and Depression Scale (HADS), and participants were stratified into high (N = 1921) versus low-depressive strata based on baseline ratings. Placebo-controlled change from baseline after 4–16 weeks of treatment was estimated by the standardized mean difference (SMD) over all trials and for each subgroup of trials targeting one of 7 mechanisms (IL-6, TNF-α, IL-12/23, CD20, COX2, BLγS, p38/MAPK14). Patients in the high depressive stratum showed modest but significant effects on core depressive symptoms (SMD = 0.29, 95% CI [0.12–0.45]) and related SF-36 measures of mental health and vitality. Anti-IL-6 antibodies (SMD = 0.8, 95% CI [0.20–1.41]) and an anti-IL-12/23 antibody (SMD = 0.48, 95% CI [0.26–0.70]) had larger effects on depressive symptoms than other drug classes. Adjustments for physical health outcome marginally attenuated the average treatment effect on depressive symptoms (SMD = 0.20, 95% CI: 0.06–0.35), but more strongly attenuated effects on mental health and vitality. Effects of anti-IL-12/23 remained significant and anti-IL-6 antibodies became a trend after controlling for physical response to treatment. Novel immune-therapeutics can produce antidepressant effects in depressed patients with primary inflammatory disorders that are not entirely explained by treatment-related changes in physical health. © 2019, The Author(s).},

note = {Publisher: Springer Nature},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{gazova_transcriptional_2020,

title = {The Transcriptional Network That Controls Growth Arrest and Macrophage Differentiation in the Human Myeloid Leukemia Cell Line THP-1},

author = {I. Gažová and L. Lefevre and S. J. Bush and S. Clohisey and E. Arner and M. Hoon and J. Severin and L. Duin and R. Andersson and A. Lengeling and D. A. Hume and K. M. Summers},

url = {https://www.scopus.com/inward/record.uri?eid=2-s2.0-85088440705&doi=10.3389%2ffcell.2020.00498&partnerID=40&md5=300d463734b5396ed4bfbbe29d461035},

doi = {10.3389/fcell.2020.00498},

issn = {2296634X},

year  = {2020},

date = {2020-01-01},

journal = {Frontiers in Cell and Developmental Biology},

volume = {8},

abstract = {The response of the human acute myeloid leukemia cell line THP-1 to phorbol esters has been widely studied to test candidate leukemia therapies and as a model of cell cycle arrest and monocyte-macrophage differentiation. Here we have employed Cap Analysis of Gene Expression (CAGE) to analyze a dense time course of transcriptional regulation in THP-1 cells treated with phorbol myristate acetate (PMA) over 96 h. PMA treatment greatly reduced the numbers of cells entering S phase and also blocked cells exiting G2/M. The PMA-treated cells became adherent and expression of mature macrophage-specific genes increased progressively over the duration of the time course. Within 1–2 h PMA induced known targets of tumor protein p53 (TP53), notably CDKN1A, followed by gradual down-regulation of cell-cycle associated genes. Also within the first 2 h, PMA induced immediate early genes including transcription factor genes encoding proteins implicated in macrophage differentiation (EGR2, JUN, MAFB) and down-regulated genes for transcription factors involved in immature myeloid cell proliferation (MYB, IRF8, GFI1). The dense time course revealed that the response to PMA was not linear and progressive. Rather, network-based clustering of the time course data highlighted a sequential cascade of transient up- and down-regulated expression of genes encoding feedback regulators, as well as transcription factors associated with macrophage differentiation and their inferred target genes. CAGE also identified known and candidate novel enhancers expressed in THP-1 cells and many novel inducible genes that currently lack functional annotation and/or had no previously known function in macrophages. The time course is available on the ZENBU platform allowing comparison to FANTOM4 and FANTOM5 data. © Copyright © 2020 Gažová, Lefevre, Bush, Clohisey, Arner, de Hoon, Severin, van Duin, Andersson, Lengeling, Hume and Summers.},

note = {Publisher: Frontiers Media S.A.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{bush_species-specificity_2020,

title = {Species-Specificity of Transcriptional Regulation and the Response to Lipopolysaccharide in Mammalian Macrophages},

author = {S. J. Bush and M. E. B. McCulloch and Z. M. Lisowski and C. Muriuki and E. L. Clark and R. Young and C. Pridans and J. G. D. Prendergast and K. M. Summers and D. A. Hume},

url = {https://www.scopus.com/inward/record.uri?eid=2-s2.0-85089065673&doi=10.3389%2ffcell.2020.00661&partnerID=40&md5=d0df874320cc014c3a1d0ef8436cddf4},

doi = {10.3389/fcell.2020.00661},

issn = {2296634X},

year  = {2020},

date = {2020-01-01},

journal = {Frontiers in Cell and Developmental Biology},

volume = {8},

abstract = {Mammalian macrophages differ in their basal gene expression profiles and response to the toll-like receptor 4 (TLR4) agonist, lipopolysaccharide (LPS). In human macrophages, LPS elicits a temporal cascade of transient gene expression including feed forward activators and feedback regulators that limit the response. Here we present a transcriptional network analysis of the response of sheep bone marrow-derived macrophages (BMDM) to LPS based upon RNA-seq at 0, 2, 4, 7, and 24 h post-stimulation. The analysis reveals a conserved transcription factor network with humans, and rapid induction of feedback regulators that constrain the response at every level. The gene expression profiles of sheep BMDM at 0 and 7 h post LPS addition were compared to similar data obtained from goat, cow, water buffalo, horse, pig, mouse and rat BMDM. This comparison was based upon identification of 8,200 genes annotated in all species and detected at textgreater10TPM in at least one sample. Analysis of expression of transcription factors revealed a conserved transcriptional millieu associated with macrophage differentiation and LPS response. The largest co-expression clusters, including genes encoding cell surface receptors, endosome–lysosome components and secretory activity, were also expressed in all species and the combined dataset defines a macrophage functional transcriptome. All of the large animals differed from rodents in lacking inducible expression of genes involved in arginine metabolism and nitric oxide production. Instead, they expressed inducible transporters and enzymes of tryptophan and kynurenine metabolism. BMDM from all species expressed high levels of transcripts encoding transporters and enzymes involved in glutamine metabolism suggesting that glutamine is a major metabolic fuel. We identify and discuss transcripts that were uniquely expressed or regulated in rodents compared to large animals including ACOD1, CXC and CC chemokines, CD163, CLEC4E, CPM, CSF1, CSF2, CTSK, MARCO, MMP9, SLC2A3, SLC7A7, and SUCNR1. Conversely, the data confirm the conserved regulation of multiple transcripts for which there is limited functional data from mouse models and knockouts. The data provide a resource for functional annotation and interpretation of loci involved in susceptibility to infectious and inflammatory disease in humans and large animal species. © Copyright © 2020 Bush, McCulloch, Lisowski, Muriuki, Clark, Young, Pridans, Prendergast, Summers and Hume.},

note = {Publisher: Frontiers Media S.A.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{lisowski_immunohistochemical_2020,

title = {Immunohistochemical study of morphology and distribution of CD163+ve macrophages in the normal adult equine gastrointestinal tract},

author = {Z. M. Lisowski and K. A. Sauter and L. A. Waddell and D. A. Hume and R. S. Pirie and N. P. H. Hudson},

url = {https://www.scopus.com/inward/record.uri?eid=2-s2.0-85086443822&doi=10.1016%2fj.vetimm.2020.110073&partnerID=40&md5=5da4a4e5d6cf6d1fa0c17de469d003a1},

doi = {10.1016/j.vetimm.2020.110073},

issn = {01652427},

year  = {2020},

date = {2020-01-01},

journal = {Veterinary Immunology and Immunopathology},

volume = {226},

abstract = {Intestinal macrophages are the largest group of mononuclear phagocytes in the body and play a role in intestinal innate immunity, neuroimmune interactions and maintaining intestinal homeostasis. Conversely, they also are implicated in numerous pathologies of the gastrointestinal tract, such as postoperative ileus and inflammatory bowel disease. As a result, macrophages could be potential therapeutic targets. To date, there are limited studies on the morphology and distribution of macrophages in the equine gastrointestinal tract (GIT). The aim of this study was to identify the location and abundance of resident macrophages in the equine GIT using CD163 as an immunohistochemical marker. Tissue samples were obtained post-mortem from 14 sites along the gastrointestinal tracts of 10 horses free from gastrointestinal disease; sample sites extended from the stomach to the small colon. CD163+ve cells were present in all regions of the equine GIT from stomach to small colon. CD163+ve cells were also identified in all tissue layers of the intestinal wall, namely, mucosa, submucosa, muscularis externa (ME), myenteric plexus and serosa. Consistent with a proposed function in regulation of intestinal motility, CD163+ve cells were regularly distributed within the ME, with accumulations closely associated with the myenteric plexus and effector cells such as neurons and the interstitial cells of Cajal (ICC). © 2020 Elsevier B.V.},

note = {Publisher: Elsevier B.V.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{tsang_expression_2020,

title = {Expression of Calcification and Extracellular Matrix Genes in the Cardiovascular System of the Healthy Domestic Sheep (Ovis aries)},

author = {H. -G. Tsang and E. L. Clark and G. R. Markby and S. J. Bush and D. A. Hume and B. M. Corcoran and V. E. MacRae and K. M. Summers},

url = {https://www.scopus.com/inward/record.uri?eid=2-s2.0-85091456550&doi=10.3389%2ffgene.2020.00919&partnerID=40&md5=7dbe1220983578fdf98385dee306378c},

doi = {10.3389/fgene.2020.00919},

issn = {16648021},

year  = {2020},

date = {2020-01-01},

journal = {Frontiers in Genetics},

volume = {11},

abstract = {The maintenance of a healthy cardiovascular system requires expression of genes that contribute to essential biological activities and repression of those that are associated with functions likely to be detrimental to cardiovascular homeostasis. Vascular calcification is a major disruption to cardiovascular homeostasis, where tissues of the cardiovascular system undergo ectopic calcification and consequent dysfunction, but little is known about the expression of calcification genes in the healthy cardiovascular system. Large animal models are of increasing importance in cardiovascular disease research as they demonstrate more similar cardiovascular features (in terms of anatomy, physiology and size) to humans than do rodent species. We used RNA sequencing results from the sheep, which has been utilized extensively to examine calcification of prosthetic cardiac valves, to explore the transcriptome of the heart and cardiac valves in this large animal, in particular looking at expression of calcification and extracellular matrix genes. We then examined genes implicated in the process of vascular calcification in a wide array of cardiovascular tissues and across multiple developmental stages, using RT-qPCR. Our results demonstrate that there is a balance between genes that promote and those that suppress mineralization during development and across cardiovascular tissues. We show extensive expression of genes encoding proteins involved in formation and maintenance of the extracellular matrix in cardiovascular tissues, and high expression of hematopoietic genes in the cardiac valves. Our analysis will support future research into the functions of implicated genes in the development of valve calcification, and increase the utility of the sheep as a large animal model for understanding ectopic calcification in cardiovascular disease. This study provides a foundation to explore the transcriptome of the developing cardiovascular system and is a valuable resource for the fields of mammalian genomics and cardiovascular research. © Copyright © 2020 Tsang, Clark, Markby, Bush, Hume, Corcoran, MacRae and Summers.},

note = {Publisher: Frontiers Media S.A.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{gow_measurement_2020,

title = {Measurement of serum Interleukin 34 (IL-34) and correlation with severity and pruritus scores in client-owned dogs with atopic dermatitis},

author = {D. J. Gow and H. Jackson and P. Forsythe and T. Nuttall and A. G. Gow and R. J. Mellanby and D. A. Hume},

url = {https://www.scopus.com/inward/record.uri?eid=2-s2.0-85089369057&doi=10.1111%2fvde.12873&partnerID=40&md5=9ee098d532a8282cbccf22af743092ea},

doi = {10.1111/vde.12873},

issn = {09594493},

year  = {2020},

date = {2020-01-01},

journal = {Veterinary Dermatology},

volume = {31},

number = {5},

pages = {359--e94},

abstract = {Background: Atopic dermatitis (AD) is a common inflammatory skin disease of dogs. Interleukin (IL)-34 is a monocyte/macrophage growth factor, produced mainly by keratinocytes, that has been implicated in several human inflammatory conditions including human AD. Hypothesis: Canine serum IL-34 concentrations are increased in dogs with AD and correlate with clinical lesion and pruritus scores. Animals: Forty seven client-owned dogs diagnosed with AD and 25 healthy, unaffected control dogs. Methods and materials: A commercially available IL-34 ELISA was optimized for the measurement of IL-34 in canine serum samples. Information regarding treatment, clinical lesion scores [Canine Atopic Dermatitis Extent and Severity Index, 4th iteration (CADESI-04)] and pruritus Visual Analog Score (pVAS) were recorded for each dog at the time of serum collection. Results: Dogs with AD had significantly increased serum IL-34 concentrations compared to controls. There was a significant positive correlation between IL-34 concentrations and CADESI-04 and pVAS scores. Concentrations of IL-34 remained increased in dogs with AD receiving steroids or the JAK1 inhibitor, oclacitinib, compared to unaffected control dogs. Conclusions and clinical importance: Serum IL-34 concentrations are increased in dogs with AD and are correlated with clinical severity and pruritus. IL-34 may be a suitable candidate therapeutic target for canine AD. © 2020 ESVD and ACVD, throughout article},

note = {Publisher: Blackwell Publishing Ltd},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{summers_network_2020,

title = {Network analysis of transcriptomic diversity amongst resident tissue macrophages and dendritic cells in the mouse mononuclear phagocyte system},

author = {K. M. Summers and S. J. Bush and D. A. Hume},

url = {https://www.scopus.com/inward/record.uri?eid=2-s2.0-85094206266&doi=10.1371%2fJOURNAL.PBIO.3000859&partnerID=40&md5=39acc0391bd08f3a1f30c5fa66be6fbb},

doi = {10.1371/JOURNAL.PBIO.3000859},

issn = {15449173},

year  = {2020},

date = {2020-01-01},

journal = {PLoS Biology},

volume = {18},

number = {10},

abstract = {The mononuclear phagocyte system (MPS) is a family of cells including progenitors, circulating blood monocytes, resident tissue macrophages, and dendritic cells (DCs) present in every tissue in the body. To test the relationships between markers and transcriptomic diversity in the MPS, we collected from National Center for Biotechnology Information Gene Expression Omnibus (NCBI-GEO) a total of 466 quality RNA sequencing (RNA-seq) data sets generated from mouse MPS cells isolated from bone marrow, blood, and multiple tissues. The primary data were randomly downsized to a depth of 10 million reads and requantified. The resulting data set was clustered using the network analysis tool BioLayout. A sample-to-sample matrix revealed that MPS populations could be separated based upon tissue of origin. Cells identified as classical DC subsets, cDC1s and cDC2s, and lacking Fcgr1 (encoding the protein CD64) were contained within the MPS cluster, no more distinct than other MPS cells. A gene-to-gene correlation matrix identified large generic coexpression clusters associated with MPS maturation and innate immune function. Smaller coexpression gene clusters, including the transcription factors that drive them, showed higher expression within defined isolated cells, including monocytes, macrophages, and DCs isolated from specific tissues. They include a cluster containing Lyve1 that implies a function in endothelial cell (EC) homeostasis, a cluster of transcripts enriched in intestinal macrophages, and a generic lymphoid tissue cDC cluster associated with Ccr7. However, transcripts encoding Adgre1, Itgax, Itgam, Clec9a, Cd163, Mertk, Mrc1, Retnla, and H2-a/e (encoding class II major histocompatibility complex [MHC] proteins) and many other proposed macrophage subset and DC lineage markers each had idiosyncratic expression profiles. Coexpression of immediate early genes (for example, Egr1, Fos, Dusp1) and inflammatory cytokines and chemokines (tumour necrosis factor [Tnf], Il1b, Ccl3/4) indicated that all tissue disaggregation and separation protocols activate MPS cells. Tissue-specific expression clusters indicated that all cell isolation procedures also co-purify other unrelated cell types that may interact with MPS cells in vivo. Comparative analysis of RNA-seq and single-cell RNA-seq (scRNA-seq) data from the same lung cell populations indicated that MPS heterogeneity implied by global cluster analysis may be even greater at a single-cell level. This analysis highlights the power of large data sets to identify the diversity of MPS cellular phenotypes and the limited predictive value of surface markers to define lineages, functions, or subpopulations. © 2020 Summers et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.},

note = {Publisher: Public Library of Science},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{hume_poorly_2020,

title = {Poorly connected groups},

author = {D. Hume and J. M. Mackay},

url = {https://www.scopus.com/inward/record.uri?eid=2-s2.0-85092788878&doi=10.1090%2fproc%2f15128&partnerID=40&md5=1100e1f7f6a9162720851c42f98a1899},

doi = {10.1090/proc/15128},

issn = {00029939},

year  = {2020},

date = {2020-01-01},

journal = {Proceedings of the American Mathematical Society},

volume = {148},

number = {11},

pages = {4653--4664},

abstract = {We investigate groups whose Cayley graphs have poorly connected subgraphs. We prove that a finitely generated group has bounded separation in the sense of Benjamini-Schramm-Timár if and only if it is virtually free. We then prove a gap theorem for connectivity of finitely presented groups, and prove that there is no comparable theorem for all finitely generated groups. Finally, we formulate a connectivity version of the conjecture that every group of type F with no Baumslag-Solitar subgroup is hyperbolic, and prove it for groups with at most quadratic Dehn function. © 2020 Copyright by the authors},

note = {Publisher: American Mathematical Society},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{wragg_using_2020,

title = {Using regulatory variants to detect gene–gene interactions identifies networks of genes linked to cell immortalisation},

author = {D. Wragg and Q. Liu and Z. Lin and V. Riggio and C. A. Pugh and A. J. Beveridge and H. Brown and D. A. Hume and S. E. Harris and I. J. Deary and A. Tenesa and J. G. D. Prendergast},

url = {https://www.scopus.com/inward/record.uri?eid=2-s2.0-85078069693&doi=10.1038%2fs41467-019-13762-6&partnerID=40&md5=7042e46e5299da0a6ed2a166d5dc230e},

doi = {10.1038/s41467-019-13762-6},

issn = {20411723},

year  = {2020},

date = {2020-01-01},

journal = {Nature Communications},

volume = {11},

number = {1},

abstract = {The extent to which the impact of regulatory genetic variants may depend on other factors, such as the expression levels of upstream transcription factors, remains poorly understood. Here we report a framework in which regulatory variants are first aggregated into sets, and using these as estimates of the total cis-genetic effects on a gene we model their non-additive interactions with the expression of other genes in the genome. Using 1220 lymphoblastoid cell lines across platforms and independent datasets we identify 74 genes where the impact of their regulatory variant-set is linked to the expression levels of networks of distal genes. We show that these networks are predominantly associated with tumourigenesis pathways, through which immortalised cells are able to rapidly proliferate. We consequently present an approach to define gene interaction networks underlying important cellular pathways such as cell immortalisation. © 2020, The Author(s).},

note = {Publisher: Nature Research},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{dutta_whole_2020,

title = {Whole genome analysis of water buffalo and global cattle breeds highlights convergent signatures of domestication},

author = {P. Dutta and A. Talenti and R. Young and S. Jayaraman and R. Callaby and S. K. Jadhav and V. Dhanikachalam and M. Manikandan and B. B. Biswa and W. Y. Low and J. L. Williams and E. Cook and P. Toye and E. Wall and A. Djikeng and K. Marshall and A. L. Archibald and S. Gokhale and S. Kumar and D. A. Hume and J. G. D. Prendergast},

url = {https://www.scopus.com/inward/record.uri?eid=2-s2.0-85091279142&doi=10.1038%2fs41467-020-18550-1&partnerID=40&md5=619c64eb0de91cb01bd9ed1fb7840521},

doi = {10.1038/s41467-020-18550-1},

issn = {20411723},

year  = {2020},

date = {2020-01-01},

journal = {Nature Communications},

volume = {11},

number = {1},

abstract = {More people globally depend on the water buffalo than any other domesticated species, and as the most closely related domesticated species to cattle they can provide important insights into the shared evolutionary basis of domestication. Here, we sequence the genomes of 79 water buffalo across seven breeds and compare patterns of between breed selective sweeps with those seen for 294 cattle genomes representing 13 global breeds. The genomic regions under selection between cattle breeds significantly overlap regions linked to stature in human genetic studies, with a disproportionate number of these loci also shown to be under selection between water buffalo breeds. Investigation of potential functional variants in the water buffalo genome identifies a rare example of convergent domestication down to the same mutation having independently occurred and been selected for across domesticated species. Cross-species comparisons of recent selective sweeps can consequently help identify and refine important loci linked to domestication. © 2020, Crown.},

note = {Publisher: Nature Research},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{munro_cns_2020,

title = {CNS macrophages differentially rely on an intronic Csf1r enhancer for their development},

author = {D. A. D. Munro and B. M. Bradford and S. A. Mariani and D. W. Hampton and C. S. Vink and S. Chandran and D. A. Hume and C. Pridans and J. Priller},

url = {https://www.scopus.com/inward/record.uri?eid=2-s2.0-85098533941&doi=10.1242%2fdev.194449&partnerID=40&md5=bf5f3ec9853de59b6604b9ad47105349},

doi = {10.1242/dev.194449},

issn = {09501991},

year  = {2020},

date = {2020-01-01},

journal = {Development (Cambridge)},

volume = {147},

number = {23},

abstract = {The central nervous system hosts parenchymal macrophages, known as microglia, and non-parenchymal macrophages, collectively termed border-associated macrophages (BAMs). Microglia, but not BAMs, were reported to be absent in mice lacking a conserved Csf1r enhancer: the fms-intronic regulatory element (FIRE). However, it is unknown whether FIRE deficiency also impacts BAM arrival and/or maintenance. Here, we show that macrophages in the ventricular system of the brain, including Kolmer's epiplexus macrophages, are absent in Csf1rΔFIRE/ΔFIRE mice. Stromal choroid plexus BAMs are also considerably reduced. During normal development, we demonstrate that intracerebroventricular macrophages arrive from embryonic day 10.5, and can traverse ventricular walls in embryonic slice cultures. In Csf1rΔFIRE/ΔFIRE embryos, the arrival of both primitive microglia and intracerebroventricular macrophages was eliminated, whereas the arrival of cephalic mesenchyme and stromal choroid plexus BAMs was only partially restricted. Our results provide new insights into the development and regulation of different CNS macrophage populations. © 2020. Published by The Company of Biologists Ltd},

note = {Publisher: Company of Biologists Ltd},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{irvine_casuses_2019,

title = {Casuses and consequences of innate immune dysfucntion in cirrhosis},

author = {K. M. Irvine and I. Ratnasekera and E. E. Powell and D. A. Hume},

url = {https://www.scopus.com/inward/record.uri?eid=2-s2.0-85062959223&doi=10.3389%2ffimmu.2019.00293&partnerID=40&md5=5d5b49a795347ded8d993e874cb9a1cf},

doi = {10.3389/fimmu.2019.00293},

issn = {16643224},

year  = {2019},

date = {2019-01-01},

journal = {Frontiers in Immunology},

volume = {10},

number = {FEB},

abstract = {Liver cirrhosis is an increasing health burden and public health concern. Regardless of etiology, patients with cirrhosis are at risk of a range of life-threatening complications, including the development of infections, which are associated with high morbidity and mortality and frequent hospital admissions. The term Cirrhosis-Associated Immune Dysfunction (CAID) refers to a dynamic spectrum of immunological perturbations that develop in patients with cirrhosis, which are intimately linked to the underlying liver disease, and negatively correlated with prognosis. At the two extremes of the CAID spectrum are systemic inflammation, which can exacerbate clinical manifestations of cirrhosis such as hemodynamic derangement and kidney injury; and immunodeficiency, which contributes to the high rate of infection in patients with decompensated cirrhosis. Innate immune cells, in particular monocytes/macrophages and neutrophils, are pivotal effector and target cells in CAID. This review focuses on the pathophysiological mechanisms leading to impaired innate immune function in cirrhosis. Knowledge of the phenotypic manifestation and pathophysiological mechanisms of cirrhosis associated immunosuppression may lead to immune targeted therapies to reduce susceptibility to infection in patients with cirrhosis, and better biomarkers for risk stratification, and assessment of efficacy of novel immunotherapies. © 2019 Frew.},

note = {Publisher: Frontiers Media S.A.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{irvine_corrigendum_2019,

title = {Corrigendum: Causes and consequences of innate immune dysfunction in cirrhosis (Frontiers in Immunology (2019) 10 (293) DOI: 10.3389/fimmu.2019.00293)},

author = {K. M. Irvine and I. Ratnasekera and E. E. Powell and D. A. Hume},

url = {https://www.scopus.com/inward/record.uri?eid=2-s2.0-85065394406&doi=10.3389%2ffimmu.2019.00818&partnerID=40&md5=3c8593ea05366e4515e7f3c1fc25acdf},

doi = {10.3389/fimmu.2019.00818},

issn = {16643224},

year  = {2019},

date = {2019-01-01},

journal = {Frontiers in Immunology},

volume = {10},

number = {APR},

abstract = {In the original article, we neglected to include the funder "Equity Trustees." The funding statement has therefore been revised as follows: "KI, IR, and DH are grateful for research funding support from the Mater Research Foundation and Equity Trustees, Australia." The authors apologize for this error and state that this does not change the scientific conclusions of the article in any way. The original article has been updated. Copyright © 2019 Irvine, Ratnasekera, Powell and Hume.},

note = {Publisher: Frontiers Media S.A.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{arzhantseva_negative_2019,

title = {Negative curvature in graphical small cancellation groups},

author = {G. N. Arzhantseva and C. H. Cashen and D. Gruber and D. Hume},

url = {https://www.scopus.com/inward/record.uri?eid=2-s2.0-85065735338&doi=10.4171%2fGGD%2f498&partnerID=40&md5=4fa92c6a1621dc1de609d9de016616e0},

doi = {10.4171/GGD/498},

issn = {16617207},

year  = {2019},

date = {2019-01-01},

journal = {Groups, Geometry, and Dynamics},

volume = {13},

number = {2},

pages = {579--632},

abstract = {We use the interplay between combinatorial and coarse geometric versions of negative curvature to investigate the geometry of infinitely presented graphical Gr0 1=6/ small cancellation groups. In particular, we characterize their ‘contracting geodesics,’ which should be thought of as the geodesics that behave hyperbolically. We show that every degree of contraction can be achieved by a geodesic in a finitely generated group. We construct the first example of a finitely generated group G containing an element g that is strongly contracting with respect to one finite generating set of G and not strongly contracting with respect to another. In the case of classical C 0 1=6/ small cancellation groups we give complete characterizations of geodesics that are Morse and that are strongly contracting. We show that many graphical Gr0 1=6/ small cancellation groups contain strongly contracting elements and, in particular, are growth tight. We construct uncountably many quasi-isometry classes of finitely generated, torsion-free groups in which every maximal cyclic subgroup is hyperbolically embedded. These are the first examples of this kind that are not subgroups of hyperbolic groups. In the course of our analysis we show that if the defining graph of a graphical Gr0 1=6/ small cancellation group has finite components, then the elements of the group have translation lengths that are rational and bounded away from zero. © European Mathematical Society.},

note = {Publisher: European Mathematical Society Publishing House},

keywords = {},

pubstate = {published},

tppubtype = {article}

}