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1. Kidney resident macrophages have distinct subsets and multifunctional roles

Author

Chew, Christine, Brand, Oliver J, Yamamura, Tomohiko, Lawless, Craig, Morais, Mychel Raony Paiva Teixeira, Zeef, Leo, Lin, I-Hsuan, Howell, Gareth, Lui, Sylvia, Lausecker, Franziska, Jagger, Christopher, Shaw, Tovah N, Krishnan, Siddharth, McClure, Flora A, Bridgeman, Hayley, Wemyss, Kelly, Konkel, Joanne E, Hussell, Tracy, and Lennon, Rachel

Published
2024
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2. Network analysis of genomic regulators of labour using in silico techniques

Author

Lui, Sylvia, Stevens, Frederick, Harris, Lynda, and Jones, Rebecca

Subjects
Network analysis, Systems biology, Microarray, Pathway analysis, Labour/ labour, Myometrium, Decidua, Genes, Transcriptome
Abstract

Preterm birth is a worldwide health issue, with increased incidence of fetal mortality and risk of morbidities. Inhibition of myometrial contractions is the only therapeutic intervention available, but this strategy remains limited in effectiveness as labour is initiated by a network of processes. The regulation of these mechanisms, and the coordination between different uterine tissues, is poorly understood. In order to develop effective therapies, we must first define and understand the processes occurring prior to and during labour. We wished to explore the interactions that occur in the decidua and myometrium, identify the master regulators within the global system of labour and select potential therapeutic candidates for suppression of multiple labouring processes. The detailed investigation of the role of the decidua in labour is critically important, as it is the site of significant inflammatory, progesterone and prostaglandin activity during labour. Using a global approach of detection and analysis, this study used high through-put microarrays, pathway and network analysis, an in silico prediction workflow, and in vitro inhibition of candidate proteins in human and mouse cell lines to identify molecular fingerprint of labour, characterise the changes occurring near the end of pregnancy that lead towards activation of labour, and identify master regulators of these pathways. In human choriodecidua, the most enriched pathways of global gene expression during term labour were inflammatory-associated. Network analysis identified vimentin, TLR4 and TNFSF13B as master regulators of labour in the decidua and identified MT2, TLR2 and RelB in the myometrium. Preliminary in vitro inhibition experiments indicated blockade of individual master regulators could moderately decrease expression of multiple downstream labour-associated genes. The mouse decidua was also characterised by the presence of a significant inflammatory response during active term labour. However, major changes in decidual function and regulators were evident prior to labour; these processes were initiated as early as 60 hours preceding labour. The mouse myometrium was enriched for chemokine pathways, but the majority of gene changes occurred only 12 hours prior to labour in this tissue. In the mouse, in silico predicted master regulators included IRAK4, TIRAP in the decidua and the TLR2/4 complex in the myometrium. In conclusion, this study has shown for the first time that in normal term labour, the human choriodecidua is highly functional with active sterile inflammatory processes occurring. The findings of widespread preparatory events in the murine decidua, that precede changes in the myometrium, suggests integral roles in the initiation of labour. There are highly conserved similarities in the inflammatory receptors, ligands and transcription factors between human and mouse tissues. The master regulators identified govern multiple downstream genes are that not directly associated with contraction, indicating there are multiple important processes occurring during labour as well as the contractile factors. Although some of the regulators have been previously identified as being associated with labour, this study was the first to identify their network regulatory characteristics. Instead of targeting a single and potentially late-stage event such as myometrial contraction, targeting multiple processes with the inclusion of processes in the closely-related and highly functional decidua, may be a more effective strategy in preventing progression of the labour process.

Published
2016

6. Alterations in T and B cell function persist in convalescent COVID-19 patients

Author

Ahmed, Rohan, Avery, Miriam, Birchall, Katharine, Charsley, Evelyn, Chenery, Alistair, Chew, Christine, Clark, Richard, Connolly, Emma, Connolly, Karen, Dawson, Simon, Durrans, Laura, Durrington, Hannah, Egan, Jasmine, Filbey, Kara, Fox, Claire, Francis, Helen, Franklin, Miriam, Glasgow, Susannah, Godfrey, Nicola, Gray, Kathryn J., Grundy, Seamus, Guerin, Jacinta, Hackney, Pamela, Hayes, Chantelle, Hardy, Emma, Harris, Jade, John, Anu, Jolly, Bethany, Kästele, Verena, Kerry, Gina, Lui, Sylvia, Lin, Lijing, Mathioudakis, Alex G., Mitchell, Joanne, Moizer, Clare, Moore, Katrina, Moss, Stuart, Baker, Syed Murtuza, Oliver, Rob, Padden, Grace, Parkinson, Christina, Phuycharoen, Michael, Saha, Ananya, Salcman, Barbora, Scott, Nicholas A., Sharma, Seema, Shaw, Jane, Shaw, Joanne, Shepley, Elizabeth, Smith, Lara, Stephan, Simon, Stephens, Ruth, Tavernier, Gael, Tudge, Rhys, Wareing, Louis, Warren, Roanna, Williams, Thomas, Willmore, Lisa, Younas, Mehwish, Shuwa, Halima A., Shaw, Tovah N., Knight, Sean B., Wemyss, Kelly, McClure, Flora A., Pearmain, Laurence, Prise, Ian, Jagger, Christopher, Morgan, David J., Khan, Saba, Brand, Oliver, Mann, Elizabeth R., Ustianowski, Andrew, Bakerly, Nawar Diar, Dark, Paul, Brightling, Christopher E., Brij, Seema, Felton, Timothy, Simpson, Angela, Grainger, John R., Hussell, Tracy, Konkel, Joanne E., and Menon, Madhvi

Published
2021
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10. Alterations in T and B cell function persist in convalescent COVID-19 patients

Author

Shuwa, Halima A., primary, Shaw, Tovah N., additional, Knight, Sean B., additional, Wemyss, Kelly, additional, McClure, Flora A., additional, Pearmain, Laurence, additional, Prise, Ian, additional, Jagger, Christopher, additional, Morgan, David J., additional, Khan, Saba, additional, Brand, Oliver, additional, Mann, Elizabeth R., additional, Ustianowski, Andrew, additional, Bakerly, Nawar Diar, additional, Dark, Paul, additional, Brightling, Christopher E., additional, Brij, Seema, additional, Felton, Timothy, additional, Simpson, Angela, additional, Grainger, John R., additional, Hussell, Tracy, additional, Konkel, Joanne E., additional, Menon, Madhvi, additional, Ahmed, Rohan, additional, Avery, Miriam, additional, Birchall, Katharine, additional, Charsley, Evelyn, additional, Chenery, Alistair, additional, Chew, Christine, additional, Clark, Richard, additional, Connolly, Emma, additional, Connolly, Karen, additional, Dawson, Simon, additional, Durrans, Laura, additional, Durrington, Hannah, additional, Egan, Jasmine, additional, Filbey, Kara, additional, Fox, Claire, additional, Francis, Helen, additional, Franklin, Miriam, additional, Glasgow, Susannah, additional, Godfrey, Nicola, additional, Gray, Kathryn J., additional, Grundy, Seamus, additional, Guerin, Jacinta, additional, Hackney, Pamela, additional, Hayes, Chantelle, additional, Hardy, Emma, additional, Harris, Jade, additional, John, Anu, additional, Jolly, Bethany, additional, Kästele, Verena, additional, Kerry, Gina, additional, Lui, Sylvia, additional, Lin, Lijing, additional, Mathioudakis, Alex G., additional, Mitchell, Joanne, additional, Moizer, Clare, additional, Moore, Katrina, additional, Moss, Stuart, additional, Baker, Syed Murtuza, additional, Oliver, Rob, additional, Padden, Grace, additional, Parkinson, Christina, additional, Phuycharoen, Michael, additional, Saha, Ananya, additional, Salcman, Barbora, additional, Scott, Nicholas A., additional, Sharma, Seema, additional, Shaw, Jane, additional, Shaw, Joanne, additional, Shepley, Elizabeth, additional, Smith, Lara, additional, Stephan, Simon, additional, Stephens, Ruth, additional, Tavernier, Gael, additional, Tudge, Rhys, additional, Wareing, Louis, additional, Warren, Roanna, additional, Williams, Thomas, additional, Willmore, Lisa, additional, and Younas, Mehwish, additional

Published
2021
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12. Longitudinal immune profiling reveals distinct features of COVID-19 pathogenesis

Author

Mann, Elizabeth R., Menon, Madhvi, Knight, Sean Blandin, Konkel, Joanne E., Jagger, Christopher, Shaw, Tovah N., Krishnan, Siddharth, Rattray, Magnus, Ustianowski, Andrew, Bakerly, Nawar Diar, Dark, Paul, Lord, Graham, Simpson, Angela, Felton, Timothy, Ho, Ling Pei, Feldmann, Marc, Grainger, John R., Hussell, Tracy, Ahmed, Rohan, Shuwa, Halima Ali, Avery, Miriam, Birchall, Katharine, Brand, Oliver, Charsley, Evelyn, Chenery, Alistair, Chew, Christine, Clark, Richard, Connolly, Emma, Connolly, Karen, Dawson, Simon, Durrans, Laura, Durrington, Hannah, Egan, Jasmine, Fox, Claire, Francis, Helen, Franklin, Miriam, Glasgow, Susannah, Godfrey, Nicola, Gray, Kathryn J., Grundy, Seamus, Guerin, Jacinta, Hackney, Pamela, Iqbal, Mudassar, Hayes, Chantelle, Hardy, Emma, Harris, Jade, John, Anu, Jolly, Bethany, Kästele, Verena, Khan, Saba, Lindergard, Gabriella, Lui, Sylvia, Lowe, Lesley, Mathioudakis, Alex G., McClure, Flora A., Mitchell, Joanne, Moizer, Clare, Moore, Katrina, Morgan, David, Moss, Stuart, Baker, Syed Murtuza, Oliver, Rob, Padden, Grace, Parkinson, Christina, Pearmain, Laurence, Phuychareon, Mike, Saha, Ananya, Salcman, Barbora, Scott, Nicholas A., Sharma, Seema, Shaw, Jane, Shaw, Joanne, Shepley, Elizabeth, Smith, Lara, Stephan, Simon, Stephens, Ruth, Tavernier, Gael, Tudge, Rhys, Wareing, Louis, Warren, Roanna, Williams, Thomas, Willmore, Lisa, Younas, Mehwish, Horsley, Alex, Harrison, Tim, Porter, Joanna, Djukanovic, Ratko, Marciniak, Stefan, Brightling, Chris, McGarvey, Lorcan, and Davies, Jane

Subjects
business.industry, T cell, Inflammation, Context (language use), Disease, Clinical trial, Pathogenesis, Immune system, medicine.anatomical_structure, Intensive care, Immunology, medicine, medicine.symptom, business
Abstract

BackgroundThe pathogenesis of COVID-19, caused by a novel strain of coronavirus (SARS-CoV-2), involves a complex host-virus interaction and is characterised by an exaggerated immune response, the specific components of which are poorly understood. Here we report the outcome of a longitudinal immune profiling study in hospitalised patients during the peak of the COVID-19 pandemic in the UK and show the relationship between immune responses and severity of the clinical presentation.MethodsThe Coronavirus Immune Response and Clinical Outcomes (CIRCO) study was conducted at four hospitals in Greater Manchester. Patients with SARS-CoV-2 infection, recruited as close to admission as possible, provided peripheral blood samples at enrolment and sequentially thereafter. Fresh samples were assessed for immune cells and proteins in whole blood and serum. Some samples were also stimulated for 3 hours with LPS and analysed for intracellular proteins. Results were stratified based on patient-level data including severity of symptoms and date of reported symptom onset.FindingsLongitudinal analysis showed a very high neutrophil to T cell ratio and abnormal activation of monocytes in the blood, which displayed high levels of the cell cycle marker, Ki67 and low COX-2. These properties all reverted in patient with good outcome. Unexpectedly, multiple aspects of inflammation were diminished as patients progressed in severity and time, even in ITU patients not recovering.InterpretationThis is the first detailed longitudinal analysis of COVID-19 patients of varying severity and outcome, revealing common features and aspects that track with severity. Patients destined for a severe outcome can be identified at admission when still displaying mild-moderate symptoms. We provide clues concerning pathogenesis that should influence clinical trials and therapeutics. Targeting pathways involved in neutrophil and monocyte release from the bone marrow should be tested in patients with COVID-19.FundingThe Kennedy Trust for Rheumatology Research, The Wellcome Trust, The Royal Society, The BBSRC, National Institute for Health Research (NIHR) Biomedical Research Centres (BRC).Research in contextEvidence before this studyAnalysis of the literature before the study via pubmed and bioRxiv searches using the terms COVID-19, SARS-CoV2, immune and inflammation (with the last search performed on 27th April 2020) showed evidence of an overactive immune response in a handful of studies in cross-sectional analyses all done at a single time point.Added value of this studyTo determine the role of the immune response in a disease process, it is necessary to correlate immune activity with clinical parameters dynamically. In this study patients presented to hospital at different stages of disease so we took samples at different time-points to provide an accurate picture of the relevant pathobiology. In order to avoid loss of large components of the immune system due to the processes of storage, longitudinal samples were interrogated in real time to reveal the full immune alterations in COVID-19.Implications of all the available evidenceRespiratory viruses continue to cause devastating global disease. The finding of altered myelopoiesis, with excess neutrophils and altered monocyte function, as dominant features in our study provides an incentive for clinical testing of therapeutics that specifically target this pathobiology. Given that inflammation is greatest prior to admission to intensive care, trials of specific immune-modulating therapies should be considered earlier in admission. Future studies of COVID-19 mechanisms should place more emphasis on longitudinal analyses since disease changes dramatically over time.

Published
2020

18. Tumor-homing peptides as tools for targeted delivery of payloads to the placenta

Author

King, Anna, primary, Ndifon, Cornelia, additional, Lui, Sylvia, additional, Widdows, Kate, additional, Kotamraju, Venkata R., additional, Agemy, Lilach, additional, Teesalu, Tambet, additional, Glazier, Jocelyn D., additional, Cellesi, Francesco, additional, Tirelli, Nicola, additional, Aplin, John D., additional, Ruoslahti, Erkki, additional, and Harris, Lynda K., additional

Published
2016
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27. Distribution and Function of Prostaglandin E 2 Receptors in Mouse Uterus: Translational Value for Human Reproduction.

Author

Fischer DP, Griffiths AL, Lui S, Sabar UJ, Farrar D, O'Donovan PJ, Woodward DF, and Marshall KM

Subjects
Adult, Animals, Cesarean Section methods, Dinoprostone analogs & derivatives, Dinoprostone pharmacology, Female, Humans, Mice, Muscle Contraction drug effects, Muscle Contraction physiology, Pregnancy, Reproduction drug effects, Uterine Contraction drug effects, Uterine Contraction metabolism, Uterus drug effects, Young Adult, Receptors, Prostaglandin E, EP2 Subtype metabolism, Reproduction physiology, Uterus metabolism
Abstract

Prostaglandin (PG) E analogs are used clinically to ripen the cervix and induce labor. However, selective receptor agonists may have potential to improve induction response rates or manage unwanted uterine hypercontractility in conditions such as dysmenorrhea and preterm labor. To characterize their therapeutic value, PGE 2 analogs were used to investigate the functional E-type prostanoid (EP) receptor population in isolated human uterus. Responsiveness in mouse tissues was also examined to validate its use as a preclinical model. Uterine samples were obtained from mice at dioestrus ( n = 12), term gestation ( n = 14), and labor ( n = 12) and from the lower uterus of women undergoing hysterectomy ( n = 12) or Caesarean section ( n = 18). Vehicle and agonist effects were assessed using superfusion and immersion techniques. PGE 2 evoked predominant excitatory responses in mouse and relaxation in human tissues. Selective EP 4 agonists inhibited tissue activity in both nonpregnant species, while the EP 2 mimetic CP533536 also attenuated uterine contractions throughout gestation. The uterotonic effects of the EP 3/1 agonist sulprostone were more pronounced than the EP 1 agonist ONO-D1-004, corresponding to abundant EP 3 receptor expression in all samples. The contractile phenotype in mouse compared with human uteri may relate to regional differences as well as high expression of EP 3 receptor transcripts. Similarities in nonpregnant and gestational tissues across species suggest that EP 3 may represent a valuable translational drug target for preventing uterine hypercontractility by employing a selective antagonist. SIGNIFICANCE STATEMENT: This research validates the use of nonpregnant mice for preclinical drug discovery of uterine EP receptor targets. To determine the utility of novel drugs and delivery systems at term pregnancy and labor, pharmacological agents interacting with EP 3 receptors have clear translational value., (Copyright © 2020 by The Author(s).)

Published
2020
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28. Uterine epithelial changes during placentation in the viviparous skink Eulamprus tympanum.

Author

Adams SM, Lui S, Jones SM, Thompson MB, and Murphy CR

Subjects
Animals, Cell Differentiation, Chorioallantoic Membrane ultrastructure, Embryonic Development, Female, Placenta cytology, Placenta ultrastructure, Progesterone blood, Vitellogenesis, Yolk Sac ultrastructure, Epithelium ultrastructure, Lizards embryology, Placentation physiology, Uterus ultrastructure, Viviparity, Nonmammalian physiology
Abstract

We used scanning electron microscopy (SEM) and transmission electron microscopy (TEM) to describe the complete ontogeny of simple placentation and the development of both the yolk sac placentae and chorioallantoic placentae from nonreproductive through postparturition phases in the maternal uterine epithelium of the Australian skink, Eulamprus tympanum. We chose E. tympanum, a species with a simple, noninvasive placenta, and which we know, has little net nutrient uptake during gestation to develop hypotheses about placental function and to identify any difference between the oviparous and viviparous conditions. Placental differentiation into the chorioallantoic placenta and yolk sac placenta occurs from embryonic Stage 29; both placentae are simple structures without specialized features for materno/fetal connection. The uterine epithelial cells are not squamous as previously described by Claire Weekes, but are columnar, becoming increasingly attenuated because of the pressure of the impinging underlying capillaries as gestation progresses. When the females are nonreproductive, the luminal uterine surface is flat and the microvillous cells that contain electron-dense vesicles partly obscure the ciliated cells. As vitellogenesis progresses, the microvillous cells are less hypertrophied than in nonreproductive females. After ovulation and fertilization, there is no regional differentiation of the uterine epithelium around the circumference of the egg. The first differentiation, associated with the chorioallantoic placentae and yolk sac placentae, occurs at embryonic Stage 29 and continues through to Stage 39. As gestation proceeds, the uterine chorioallantoic placenta forms ridges, the microvillous cells become less hypertrophied, ciliated cells are less abundant, the underlying blood vessels increase in size, and the gland openings at the uterine surface are more apparent. In contrast, the yolk sac placenta has no particular folding with cells having a random orientation and where the microvillous cells remain hypertrophied throughout gestation. However, the ciliated cells become less abundant as gestation proceeds, as also seen in the chorioallantoic placenta. Secretory vesicles are visible in the uterine lumen. All placental differentiation and cell detail is lost at Stage 40, and the uterine structure has returned to the nonreproductive condition within 2 weeks. Circulating progesterone concentrations begin to rise during late vitellogenesis, peak at embryonic Stages 28-30, and decline after Stage 35 in the later stages of gestation. The coincidence between the time of oviposition and placental differentiation demonstrates a similarity during gestation in the uterus between oviparous and simple placental viviparous squamates., ((c) 2007 Wiley-Liss, Inc.)

Published
2007
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