Publications by authors named "David W Ray"

88 Publications

Sleep, circadian rhythms, and type 2 diabetes mellitus.

Clin Endocrinol (Oxf) 2021 Oct 12. Epub 2021 Oct 12.

Oxford Centre for Diabetes, Endocrinology and Metabolism, University of Oxford, Oxford, UK.

Over the last 60 years we have seen a significant rise in metabolic disease, especially type 2 diabetes. In the same period, the emergence of electricity and artificial lighting has allowed our behavioural cycles to be independent of external patterns of sunlight. This has led to a corresponding increase in sleep deprivation, estimated to be about 1 hour per night, as well as circadian misalignment (living against the clock). Evidence from experimental animals as well as controlled human subjects have shown that sleep deprivation and circadian misalignment can both directly drive metabolic dysfunction, causing diabetes. However, the precise mechanism by which these processes contribute to insulin resistance remains poorly understood. In this article, we will review the new literature in the field and propose a model attempting to reconcile the experimental observations made. We believe our model will serve as a useful point of reference to understand how metabolic dysfunction can emerge from sleep or circadian rhythm disruptions, providing new directions for research and therapy.
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http://dx.doi.org/10.1111/cen.14607DOI Listing
October 2021

Glucocorticoid circadian rhythms in immune function.

Semin Immunopathol 2021 Sep 28. Epub 2021 Sep 28.

NIHR Oxford Biomedical Research Centre, John Radcliffe Hospital, Oxford, OX3 9DU, UK.

Adrenal glucocorticoid (GC) hormones are important regulators of energy metabolism, brain functions, and the immune system. Their release follows robust diurnal rhythms and GCs themselves serve as entrainment signals for circadian clocks in various tissues. In the clinics, synthetic GC analogues are widely used as immunosuppressive drugs. GC inhibitory effects on the immune system are well documented and include suppression of cytokines and increased immune cell death. However, the circadian dynamics of GC action are often neglected. Synthetic GC medications fail to mimic complex GC natural rhythms. Several recent publications have shown that endogenous GCs and their daily concentration rhythms prepare the immune system to face anticipated environmental threats. That includes migration patterns that direct specific cell population to organs and tissues best exemplified by the rhythmic expression of chemoattractants and their receptors. On the other hand, chronotherapeutic approaches may benefit the treatment of immunological diseases such as asthma. In this review, we summarise our current knowledge on the circadian regulation of GCs, their role in innate and adaptive immune functions and the implications for the clinics.
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http://dx.doi.org/10.1007/s00281-021-00889-2DOI Listing
September 2021

The histone methyltransferase Ezh2 restrains macrophage inflammatory responses.

FASEB J 2021 10;35(10):e21843

Faculty of Biology, Medicine and Health, University of Manchester, Manchester Academic Health Sciences Centre, Manchester, UK.

Robust inflammatory responses are critical to survival following respiratory infection, with current attention focused on the clinical consequences of the Coronavirus pandemic. Epigenetic factors are increasingly recognized as important determinants of immune responses, and EZH2 is a prominent target due to the availability of highly specific and efficacious antagonists. However, very little is known about the role of EZH2 in the myeloid lineage. Here, we show EZH2 acts in macrophages to limit inflammatory responses to activation, and in neutrophils for chemotaxis. Selective genetic deletion in macrophages results in a remarkable gain in protection from infection with the prevalent lung pathogen, pneumococcus. In contrast, neutrophils lacking EZH2 showed impaired mobility in response to chemotactic signals, and resulted in increased susceptibility to pneumococcus. In summary, EZH2 shows complex, and divergent roles in different myeloid lineages, likely contributing to the earlier conflicting reports. Compounds targeting EZH2 are likely to impair mucosal immunity; however, they may prove useful for conditions driven by pulmonary neutrophil influx, such as adult respiratory distress syndrome.
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http://dx.doi.org/10.1096/fj.202100044RRRDOI Listing
October 2021

Adipocyte NR1D1 dictates adipose tissue expansion during obesity.

Elife 2021 08 5;10. Epub 2021 Aug 5.

Centre for Biological Timing, Faculty of Biology, Medicine and Health, University of Manchester, Manchester, United Kingdom.

The circadian clock component NR1D1 (REVERBα) is considered a dominant regulator of lipid metabolism, with global deletion driving dysregulation of white adipose tissue (WAT) lipogenesis and obesity. However, a similar phenotype is not observed under adipocyte-selective deletion (), and transcriptional profiling demonstrates that, under basal conditions, direct targets of NR1D1 regulation are limited, and include the circadian clock and collagen dynamics. Under high-fat diet (HFD) feeding, mice do manifest profound obesity, yet without the accompanying WAT inflammation and fibrosis exhibited by controls. Integration of the WAT NR1D1 cistrome with differential gene expression reveals broad control of metabolic processes by NR1D1 which is unmasked in the obese state. Adipocyte NR1D1 does not drive an anticipatory daily rhythm in WAT lipogenesis, but rather modulates WAT activity in response to alterations in metabolic state. Importantly, NR1D1 action in adipocytes is critical to the development of obesity-related WAT pathology and insulin resistance.
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http://dx.doi.org/10.7554/eLife.63324DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8360653PMC
August 2021

Sleep and liver disease: a bidirectional relationship.

Lancet Gastroenterol Hepatol 2021 10 15;6(10):850-863. Epub 2021 Jul 15.

Liver Unit, Queen Elizabeth Hospital Birmingham, Birmingham, UK.

Sleep is a complex, highly regulated process essential for human health and wellbeing. Increasingly, sleep-wake disturbance has been implicated in the pathogenesis of chronic liver disease, particularly the development and progression of non-alcoholic fatty liver disease and alcohol-related liver disease. Patients with cirrhosis also have a high burden of sleep abnormalities with substantial implications for their quality of life and physical health. This Review summarises the epidemiology and pathophysiology of sleep-wake disturbance in liver disease and discusses the multiple converging pathways leading to abnormal sleeping patterns in patients with cirrhosis. This includes contributions from altered melatonin metabolism, neuromuscular complications, and aberrant thermoregulation. In turn, a vicious cycle is established whereby disrupted sleep can further contribute to liver disease progression. We also begin to unravel the complex, interlinking relationship between sleep-wake disturbance and hepatic encephalopathy, discussing both overlapping and distinct mechanisms and clinical features. Finally, we summarise the current and future therapeutic approaches aiming to improve sleep quality in patients with cirrhosis.
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http://dx.doi.org/10.1016/S2468-1253(21)00169-2DOI Listing
October 2021

Shift work is associated with positive COVID-19 status in hospitalised patients.

Thorax 2021 06 26;76(6):601-606. Epub 2021 Apr 26.

Faculty of Biology, Medicine and Health, University of Manchester, Manchester, UK

Introduction: Shift work is associated with lung disease and infections. We therefore investigated the impact of shift work on significant COVID-19 illness.

Methods: 501 000 UK Biobank participants were linked to secondary care SARS-CoV-2 PCR results from Public Health England. Healthcare worker occupational testing and those without an occupational history were excluded from analysis.

Results: Multivariate logistic regression (age, sex, ethnicity and deprivation index) revealed that irregular shift work (OR 2.42, 95% CI 1.92 to 3.05), permanent shift work (OR 2.5, 95% CI 1.95 to 3.19), day shift work (OR 2.01, 95% CI 1.55 to 2.6), irregular night shift work (OR 3.04, 95% CI 2.37 to 3.9) and permanent night shift work (OR 2.49, 95% CI 1.67 to 3.7) were all associated with positive COVID-19 tests compared with participants that did not perform shift work. This relationship persisted after adding sleep duration, chronotype, premorbid disease, body mass index, alcohol and smoking to the model. The effects of workplace were controlled for in three ways: (1) by adding in work factors (proximity to a colleague combined with estimated disease exposure) to the multivariate model or (2) comparing participants within each job sector (non-essential, essential and healthcare) and (3) comparing shift work and non-shift working colleagues. In all cases, shift work was significantly associated with COVID-19. In 2017, 120 307 UK Biobank participants had their occupational history reprofiled. Using this updated occupational data shift work remained associated with COVID-19 (OR 4.48 (95% CI 1.8 to 11.18).

Conclusions: Shift work is associated with a higher likelihood of in-hospital COVID-19 positivity. This risk could potentially be mitigated via additional workplace precautions or vaccination.
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http://dx.doi.org/10.1136/thoraxjnl-2020-216651DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8098298PMC
June 2021

Circadian control of hepatitis B virus replication.

Nat Commun 2021 03 12;12(1):1658. Epub 2021 Mar 12.

Nuffield Department of Medicine, University of Oxford, Oxford, UK.

Chronic hepatitis B virus (HBV) infection is a major cause of liver disease and cancer worldwide for which there are no curative therapies. The major challenge in curing infection is eradicating or silencing the covalent closed circular DNA (cccDNA) form of the viral genome. The circadian factors BMAL1/CLOCK and REV-ERB are master regulators of the liver transcriptome and yet their role in HBV replication is unknown. We establish a circadian cycling liver cell-model and demonstrate that REV-ERB directly regulates NTCP-dependent hepatitis B and delta virus particle entry. Importantly, we show that pharmacological activation of REV-ERB inhibits HBV infection in vitro and in human liver chimeric mice. We uncover a role for BMAL1 to bind HBV genomes and increase viral promoter activity. Pharmacological inhibition of BMAL1 through REV-ERB ligands reduces pre-genomic RNA and de novo particle secretion. The presence of conserved E-box motifs among members of the Hepadnaviridae family highlight an evolutionarily conserved role for BMAL1 in regulating this family of small DNA viruses.
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http://dx.doi.org/10.1038/s41467-021-21821-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7955118PMC
March 2021

Night shift work is associated with an increased risk of asthma.

Thorax 2021 01 16;76(1):53-60. Epub 2020 Nov 16.

Division of Infection, Immunity and Respiratory Medicine, School of Biological Sciences, Faculty of Biology, Medicine and Health, University of Manchester, Manchester, UK

Introduction: Shift work causes misalignment between internal circadian time and the external light/dark cycle and is associated with metabolic disorders and cancer. Approximately 20% of the working population in industrialised countries work permanent or rotating night shifts, exposing this large population to the risk of circadian misalignment-driven disease. Analysis of the impact of shift work on chronic inflammatory diseases is lacking. We investigated the association between shift work and asthma.

Methods: We describe the cross-sectional relationship between shift work and prevalent asthma in >280000 UK Biobank participants, making adjustments for major confounding factors (smoking history, ethnicity, socioeconomic status, physical activity, body mass index). We also investigated chronotype.

Results: Compared with day workers, 'permanent' night shift workers had a higher likelihood of moderate-severe asthma (OR 1.36 (95% CI 1.03 to 1.8)) and all asthma (OR 1.23 (95% CI 1.03 to 1.46)). Individuals doing any type of shift work had higher adjusted odds of wheeze/whistling in the chest. Shift workers who never or rarely worked on nights and people working permanent nights had a higher adjusted likelihood of having reduced lung function (FEV <80% predicted). We found an increase in the risk of moderate-severe asthma in morning chronotypes working irregular shifts, including nights (OR 1.55 (95% CI 1.06 to 2.27)).

Conclusions: The public health implications of these findings are far-reaching due to the high prevalence and co-occurrence of both asthma and shift work. Future longitudinal follow-up studies are needed to determine if modifying shift work schedules to take into account chronotype might present a public health measure to reduce the risk of developing inflammatory diseases such as asthma.
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http://dx.doi.org/10.1136/thoraxjnl-2020-215218DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7803886PMC
January 2021

Nuclear receptor REVERBα is a state-dependent regulator of liver energy metabolism.

Proc Natl Acad Sci U S A 2020 10 28;117(41):25869-25879. Epub 2020 Sep 28.

Oxford Centre for Diabetes, Endocrinology and Metabolism, University of Oxford, OX3 7LE Oxford, United Kingdom;

The nuclear receptor REVERBα is a core component of the circadian clock and proposed to be a dominant regulator of hepatic lipid metabolism. Using antibody-independent ChIP-sequencing of REVERBα in mouse liver, we reveal a high-confidence cistrome and define direct target genes. REVERBα-binding sites are highly enriched for consensus RORE or RevDR2 motifs and overlap with corepressor complex binding. We find no evidence for transcription factor tethering and DNA-binding domain-independent action. Moreover, hepatocyte-specific deletion of drives only modest physiological and transcriptional dysregulation, with derepressed target gene enrichment limited to circadian processes. Thus, contrary to previous reports, hepatic REVERBα does not repress lipogenesis under basal conditions. REVERBα control of a more extensive transcriptional program is only revealed under conditions of metabolic perturbation (including mistimed feeding, which is a feature of the global mouse). Repressive action of REVERBα in the liver therefore serves to buffer against metabolic challenge, rather than drive basal rhythmicity in metabolic activity.
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http://dx.doi.org/10.1073/pnas.2005330117DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7568238PMC
October 2020

Circadian asthma airway responses are gated by REV-ERBα.

Eur Respir J 2020 12 17;56(6). Epub 2020 Dec 17.

Division of Diabetes, Endocrinology and Gastroenterology, School of Medical Sciences, Faculty of Biology, Medicine and Health, University of Manchester, Manchester, UK.

Background: The circadian clock powerfully regulates inflammation and the clock protein REV-ERBα is known to play a key role as a repressor of the inflammatory response. Asthma is an inflammatory disease of the airways with a strong time of day rhythm. Airway hyper-responsiveness (AHR) is a dominant feature of asthma; however, it is not known if this is under clock control.

Objectives: To determine if allergy-mediated AHR is gated by the clock protein REV-ERBα.

Methods: After exposure to the intra-nasal house dust mite (HDM) allergen challenge model at either dawn or dusk, AHR to methacholine was measured invasively in mice.

Main Results: Wild-type (WT) mice show markedly different time of day AHR responses (maximal at dusk/start of the active phase), both and , in precision cut lung slices. Time of day effects on AHR were abolished in mice lacking the clock gene α, indicating that such effects on asthma response are likely to be mediated the circadian clock. We suggest that muscarinic receptors one () and three () may play a role in this pathway.

Conclusions: We identify a novel circuit regulating a core process in asthma, potentially involving circadian control of muscarinic receptor expression, in a REV-ERBα dependent fashion.

Clinical Implication: These insights suggest the importance of considering the timing of drug administration in clinic trials and in clinical practice (chronotherapy).
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http://dx.doi.org/10.1183/13993003.02407-2019DOI Listing
December 2020

Glucocorticoids rapidly inhibit cell migration through a novel, non-transcriptional HDAC6 pathway.

J Cell Sci 2020 06 11;133(11). Epub 2020 Jun 11.

Division of Diabetes, Endocrinology, and Gastroenterology, University of Manchester, Manchester, M13 9PT, UK

Glucocorticoids (GCs) act through the glucocorticoid receptor (GR, also known as NR3C1) to regulate immunity, energy metabolism and tissue repair. Upon ligand binding, activated GR mediates cellular effects by regulating gene expression, but some GR effects can occur rapidly without new transcription. Here, we show that GCs rapidly inhibit cell migration, in response to both GR agonist and antagonist ligand binding. The inhibitory effect on migration is prevented by GR knockdown with siRNA, confirming GR specificity, but not by actinomycin D treatment, suggesting a non-transcriptional mechanism. We identified a rapid onset increase in microtubule polymerisation following GC treatment, identifying cytoskeletal stabilisation as the likely mechanism of action. HDAC6 overexpression, but not knockdown of αTAT1, rescued the GC effect, implicating HDAC6 as the GR effector. Consistent with this hypothesis, ligand-dependent cytoplasmic interaction between GR and HDAC6 was demonstrated by quantitative imaging. Taken together, we propose that activated GR inhibits HDAC6 function, and thereby increases the stability of the microtubule network to reduce cell motility. We therefore report a novel, non-transcriptional mechanism whereby GCs impair cell motility through inhibition of HDAC6 and rapid reorganization of the cell architecture.This article has an associated First Person interview with the first author of the paper.
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http://dx.doi.org/10.1242/jcs.242842DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7295589PMC
June 2020

Understanding the pathophysiological mechanisms of cardiometabolic complications in obstructive sleep apnoea: towards personalised treatment approaches.

Eur Respir J 2020 08 6;56(2). Epub 2020 Aug 6.

Unitat de Biofísica i Bioenginyeria, Facultat de Medicina i Ciències de la Salut, Universitat de Barcelona-IDIBAPS, and CIBER Enfermedades Respiratorias, Barcelona, Spain.

In January 2019, a European Respiratory Society research seminar entitled "Targeting the detrimental effects of sleep disturbances and disorders" was held in Dublin, Ireland. It provided the opportunity to critically review the current evidence of pathophysiological responses of sleep disturbances, such as sleep deprivation, sleep fragmentation or circadian misalignment and of abnormalities in physiological gases such as oxygen and carbon dioxide, which occur frequently in respiratory conditions during sleep. A specific emphasis of the seminar was placed on the evaluation of the current state of knowledge of the pathophysiology of cardiovascular and metabolic diseases in obstructive sleep apnoea (OSA). Identification of the detailed mechanisms of these processes is of major importance to the field and this seminar offered an ideal platform to exchange knowledge, and to discuss pitfalls of current models and the design of future collaborative studies. In addition, we debated the limitations of current treatment strategies for cardiometabolic complications in OSA and discussed potentially valuable alternative approaches.
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http://dx.doi.org/10.1183/13993003.02295-2019DOI Listing
August 2020

The clock gene inhibits macrophage motility, phagocytosis, and impairs defense against pneumonia.

Proc Natl Acad Sci U S A 2020 01 3;117(3):1543-1551. Epub 2020 Jan 3.

National Institute for Health Research, John Radcliffe Hospital, Oxford Biomedical Research Centre, OX3 9DU Oxford, United Kingdom;

The circadian clock regulates many aspects of immunity. Bacterial infections are affected by time of day, but the mechanisms involved remain undefined. Here we show that loss of the core clock protein BMAL1 in macrophages confers protection against pneumococcal pneumonia. Infected mice show both reduced weight loss and lower bacterial burden in circulating blood. In vivo studies of macrophage phagocytosis reveal increased bacterial ingestion following deletion, which was also seen in vitro. BMAL1 macrophages exhibited marked differences in actin cytoskeletal organization, a phosphoproteome enriched for cytoskeletal changes, with reduced phosphocofilin and increased active RhoA. Further analysis of the BMAL1 macrophages identified altered cell morphology and increased motility. Mechanistically, BMAL1 regulated a network of cell movement genes, 148 of which were within 100 kb of high-confidence BMAL1 binding sites. Links to RhoA function were identified, with 29 genes impacting RhoA expression or activation. RhoA inhibition restored the phagocytic phenotype to that seen in control macrophages. In summary, we identify a surprising gain of antibacterial function due to loss of BMAL1 in macrophages, associated with a RhoA-dependent cytoskeletal change, an increase in cell motility, and gain of phagocytic function.
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http://dx.doi.org/10.1073/pnas.1915932117DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6983378PMC
January 2020

The circadian clock protein REVERBα inhibits pulmonary fibrosis development.

Proc Natl Acad Sci U S A 2020 01 26;117(2):1139-1147. Epub 2019 Dec 26.

Faculty of Biology, Medicine and Health, The University of Manchester, Manchester M13 9PL, United Kingdom;

Pulmonary inflammatory responses lie under circadian control; however, the importance of circadian mechanisms in the underlying fibrotic phenotype is not understood. Here, we identify a striking change to these mechanisms resulting in a gain of amplitude and lack of synchrony within pulmonary fibrotic tissue. These changes result from an infiltration of mesenchymal cells, an important cell type in the pathogenesis of pulmonary fibrosis. Mutation of the core clock protein REVERBα in these cells exacerbated the development of bleomycin-induced fibrosis, whereas mutation of REVERBα in club or myeloid cells had no effect on the bleomycin phenotype. Knockdown of REVERBα revealed regulation of the little-understood transcription factor TBPL1. Both REVERBα and TBPL1 altered integrinβ1 focal-adhesion formation, resulting in increased myofibroblast activation. The translational importance of our findings was established through analysis of 2 human cohorts. In the UK Biobank, circadian strain markers (sleep length, chronotype, and shift work) are associated with pulmonary fibrosis, making them risk factors. In a separate cohort, REVERBα expression was increased in human idiopathic pulmonary fibrosis (IPF) lung tissue. Pharmacological targeting of REVERBα inhibited myofibroblast activation in IPF fibroblasts and collagen secretion in organotypic cultures from IPF patients, thus suggesting that targeting of REVERBα could be a viable therapeutic approach.
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http://dx.doi.org/10.1073/pnas.1912109117DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6969503PMC
January 2020

Circadian rhythms in innate immunity and stress responses.

Immunology 2020 12 3;161(4):261-267. Epub 2020 Jan 3.

Oxford Centre for Diabetes, Endocrinology and Metabolism, University of Oxford, Oxford, UK.

Circadian clocks are a common feature of life on our planet, allowing physiology and behaviour to be adapted to recurrent environmental fluctuation. There is now compelling evidence that disturbance of circadian coherence can severely undermine mental and physical health, as well as exacerbate pre-existing pathology. Common molecular design principles underpin the generation of cellular circadian rhythms across the kingdoms, and in animals, the genetic components are extremely well conserved. In mammals, the circadian timing mechanism is present in most cell types and establishes local cycles of gene expression and metabolic activity. These distributed tissue clocks are normally synchronized by a central pacemaker, the suprachiasmatic nuclei (SCN), located in the hypothalamus. Nevertheless, most clocks of the body remain responsive to non-SCN-derived hormonal and metabolic cues (for example, re-alignment of liver clocks to altered meal patterning). It has been demonstrated that the clock is an influential regulator of energy metabolism, allowing key pathways to be tuned across the 24-hr cycle as metabolic requirements fluctuate. Furthermore, clock components, including Cryptochrome and Rev-Erb proteins, have been identified as essential modulators of the innate immune system and inflammatory responses. Studies have also revealed that these proteins regulate glucocorticoid receptor function, a major drug target and crucial regulator of inflammation and metabolism.
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http://dx.doi.org/10.1111/imm.13166DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7692257PMC
December 2020

Circadian Clock Regulation of Hepatic Energy Metabolism Regulatory Circuits.

Biology (Basel) 2019 Oct 19;8(4). Epub 2019 Oct 19.

NIHR Oxford Biomedical Research Centre, John Radcliffe Hospital, Oxford, UK and Oxford Centre for Diabetes, Endocrinology and Metabolism, University of Oxford, Oxford OX3 9DU, UK.

The liver is a critical organ of energy metabolism. At least 10% of the liver transcriptome demonstrates rhythmic expression, implying that the circadian clock regulates large programmes of hepatic genes. Here, we review the mechanisms by which this rhythmic regulation is conferred, with a particular focus on the transcription factors whose actions combine to impart liver- and time-specificity to metabolic gene expression.
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http://dx.doi.org/10.3390/biology8040079DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6956161PMC
October 2019

Monthly variance in UK renal transplantation activity: a national retrospective cohort study.

BMJ Open 2019 09 17;9(9):e028786. Epub 2019 Sep 17.

Faculty of Biology, Medicine and Health, University of Manchester, Manchester, UK

Objective: To identify whether renal transplant activity varies in a reproducible manner across the year.

Design: Retrospective cohort study using NHS Blood and Transplant data.

Setting: All renal transplant centres in the UK.

Participants: A total of 24 270 patients who underwent renal transplantation between 2005 and 2014.

Primary Outcome: Monthly transplant activity was analysed to see if transplant activity showed variation during the year.

Secondary Outcome: The number of organs rejected due to healthcare capacity was analysed to see if this affected transplantation rates.

Results: Analysis of national transplant data revealed a reproducible yearly variance in transplant activity. This activity increased in late autumn and early winter (p=0.05) and could be attributed to increased rates of living (October and November) and deceased organ donation (November and December). An increase in deceased donation was attributed to a rise in donors following cerebrovascular accidents and hypoxic brain injury. Other causes of death (infections and road traffic accidents) were more seasonal in nature peaking in the winter or summer, respectively. Only 1.4% of transplants to intended recipients were redirected due to a lack of healthcare capacity, suggesting that capacity pressures in the National Health Service did not significantly affect transplant activity.

Conclusion: UK renal transplant activity peaks in late autumn/winter in contrast to other countries. Currently, healthcare capacity, though under strain, does not affect transplant activity; however, this may change if transplantation activity increases in line with national strategies as the spike in transplant activity coincides with peak activity in the national healthcare system.
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http://dx.doi.org/10.1136/bmjopen-2018-028786DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6756352PMC
September 2019

Circadian rhythm of exhaled biomarkers in health and asthma.

Eur Respir J 2019 10 17;54(4). Epub 2019 Oct 17.

Division of Infection, Immunity and Respiratory Medicine, School of Biological Sciences, Faculty of Biology, Medicine and Health, University of Manchester, Manchester, UK

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http://dx.doi.org/10.1183/13993003.01068-2019DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6796150PMC
October 2019

An improved method for quantitative ChIP studies of nuclear receptor function.

J Mol Endocrinol 2019 05;62(4):169-177

Faculty of Biology, Medicine and Health, University of Manchester, Manchester, UK.

Chromatin immunoprecipitation (ChIP) is a valuable tool for the endocrine researcher, providing a means to measure the recruitment of hormone-activated nuclear receptors, for example. However, the technique can be challenging to perform and has multiple experimental steps, risking introduction of error at each. The data produced can be challenging to interpret; several different methods are commonly used for normalising data and thus comparing between conditions. Absolute, sensitive quantification of protein-bound DNA is important for correct interpretation of the data. In addition, such quantification can help the investigator in troubleshooting experiments. Here, we outline a ChIP strategy combining droplet digital PCR for accurate quantification with an internal spike-in control for normalisation. This combination strengthens the reliability of ChIP data and allows the operator to optimise their protocol with greater confidence.
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http://dx.doi.org/10.1530/JME-18-0243DOI Listing
May 2019

How Do Glucocorticoids Used in Rheumatic Disease Affect Body Weight? A Narrative Review of the Evidence.

Arthritis Care Res (Hoboken) 2020 04;72(4):489-497

Manchester Academic Health Science Centre and The University of Manchester, Manchester, UK.

Glucocorticoids (GCs) are widely used to effectively treat inflammatory disease, but GCs have a number of recognized side effects. Patients and clinicians view these side effects differently, with clinicians most concerned with serious side effects such as osteoporosis and diabetes mellitus. Consequently, these side effects are well researched with clinical guidelines and recommendations. A side effect of particular concern to patients is weight gain, but this topic has not been well researched, and consequently clinicians find it difficult to provide patients with accurate information about the potential of weight gain. The aim of this review is to provide an overview of GC use specifically in rheumatic disease, patient views on GC therapy, and GC-induced weight gain. We will discuss the evidence, including the extent and the impact of weight gain on the patient, and highlight areas that warrant further investigation.
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http://dx.doi.org/10.1002/acr.23879DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7155058PMC
April 2020

Genome-wide association study identifies genetic loci for self-reported habitual sleep duration supported by accelerometer-derived estimates.

Nat Commun 2019 03 7;10(1):1100. Epub 2019 Mar 7.

Division of Endocrinology, Diabetes & Gastroenterology, School of Medical Sciences, Faculty of Biology, Medicine and Health, University of Manchester, Manchester, M13 9PL, UK.

Sleep is an essential state of decreased activity and alertness but molecular factors regulating sleep duration remain unknown. Through genome-wide association analysis in 446,118 adults of European ancestry from the UK Biobank, we identify 78 loci for self-reported habitual sleep duration (p < 5 × 10; 43 loci at p < 6 × 10). Replication is observed for PAX8, VRK2, and FBXL12/UBL5/PIN1 loci in the CHARGE study (n = 47,180; p < 6.3 × 10), and 55 signals show sign-concordant effects. The 78 loci further associate with accelerometer-derived sleep duration, daytime inactivity, sleep efficiency and number of sleep bouts in secondary analysis (n = 85,499). Loci are enriched for pathways including striatum and subpallium development, mechanosensory response, dopamine binding, synaptic neurotransmission and plasticity, among others. Genetic correlation indicates shared links with anthropometric, cognitive, metabolic, and psychiatric traits and two-sample Mendelian randomization highlights a bidirectional causal link with schizophrenia. This work provides insights into the genetic basis for inter-individual variation in sleep duration implicating multiple biological pathways.
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http://dx.doi.org/10.1038/s41467-019-08917-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6405943PMC
March 2019

Biological and clinical insights from genetics of insomnia symptoms.

Nat Genet 2019 03 25;51(3):387-393. Epub 2019 Feb 25.

K.G. Jebsen Centre for Genetic Epidemiology, Department of Public Health and Nursing, NTNU, Norwegian University of Science and Technology, Trondheim, Norway.

Insomnia is a common disorder linked with adverse long-term medical and psychiatric outcomes. The underlying pathophysiological processes and causal relationships of insomnia with disease are poorly understood. Here we identified 57 loci for self-reported insomnia symptoms in the UK Biobank (n = 453,379) and confirmed their effects on self-reported insomnia symptoms in the HUNT Study (n = 14,923 cases and 47,610 controls), physician-diagnosed insomnia in the Partners Biobank (n = 2,217 cases and 14,240 controls), and accelerometer-derived measures of sleep efficiency and sleep duration in the UK Biobank (n = 83,726). Our results suggest enrichment of genes involved in ubiquitin-mediated proteolysis and of genes expressed in multiple brain regions, skeletal muscle, and adrenal glands. Evidence of shared genetic factors was found between frequent insomnia symptoms and restless legs syndrome, aging, and cardiometabolic, behavioral, psychiatric, and reproductive traits. Evidence was found for a possible causal link between insomnia symptoms and coronary artery disease, depressive symptoms, and subjective well-being.
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http://dx.doi.org/10.1038/s41588-019-0361-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6415688PMC
March 2019

Genome-wide effect of pulmonary airway epithelial cell-specific deletion.

FASEB J 2019 05 22;33(5):6226-6238. Epub 2019 Feb 22.

Centre for Biological Timing, Faculty of Biology, Health, and Medicine, University of Manchester, Manchester, United Kingdom.

Pulmonary airway epithelial cells (AECs) form a critical interface between host and environment. We investigated the role of the circadian clock using mice bearing targeted deletion of the circadian gene brain and muscle ARNT-like 1 () in AECs. Pulmonary neutrophil infiltration, biomechanical function, and responses to influenza infection were all disrupted. A circadian time-series RNA sequencing study of laser-captured AECs revealed widespread disruption in genes of the core circadian clock and output pathways regulating cell metabolism (lipids and xenobiotics), extracellular matrix, and chemokine signaling, but strikingly also the gain of a novel rhythmic transcriptome in -targeted cells. Many of the rhythmic components were replicated in primary AECs cultured in air-liquid interface, indicating significant cell autonomy for control of pulmonary circadian physiology. Finally, we found that metabolic cues dictate phasing of the pulmonary clock and circadian responses to immunologic challenges. Thus, the local circadian clock in AECs is vital in lung health by coordinating major cell processes such as metabolism and immunity.-Zhang, Z. Hunter, L., Wu, G., Maidstone, R., Mizoro, Y., Vonslow, R., Fife, M., Hopwood, T., Begley, N., Saer, B., Wang, P., Cunningham, P., Baxter, M., Durrington, H., Blaikley, J. F., Hussell, T., Rattray, M., Hogenesch, J. B., Gibbs, J., Ray, D. W., Loudon, A. S. I. Genome-wide effect of pulmonary airway epithelial cell-specific deletion.
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http://dx.doi.org/10.1096/fj.201801682RDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6463917PMC
May 2019

Rheumatoid arthritis reprograms circadian output pathways.

Arthritis Res Ther 2019 02 6;21(1):47. Epub 2019 Feb 6.

Division of Digestion, Endocrinology and Metabolism, The University of Manchester, Manchester, M13 9PT, UK.

Objective: We applied systems biology approaches to investigate circadian rhythmicity in rheumatoid arthritis (RA).

Methods: We recruited adults (age 16-80 years old) with a clinical diagnosis of RA (active disease [DAS28 > 3.2]). Sleep profiles were determined before inpatient measurements of saliva, serum, and peripheral blood mononuclear leukocytes (PBML). Transcriptome and proteome analyses were carried out by RNA-SEQ and LC-MS/MS. Serum samples were analysed by targeted lipidomics, along with serum from mouse collagen induced-arthritis (CIA). Bioinformatic analysis identified RA-specific gene networks and rhythmic processes differing between healthy and RA.

Results: RA caused greater time-of-day variation in PBML gene expression, and ex vivo stimulation identified a time-of-day-specific RA transcriptome. We found increased phospho-STAT3 in RA patients, and some targets, including phospho-ATF2, acquired time-of-day variation in RA. Serum ceramides also gained circadian rhythmicity in RA, which was also seen in mouse experimental arthritis, resulting from gain in circadian rhythmicity of hepatic ceramide synthases.

Conclusion: RA drives a gain in circadian rhythmicity, both in immune cells, and systemically. The coupling of distant timing information to ceramide synthesis and joint inflammation points to a systemic re-wiring of the circadian repertoire. Circadian reprogramming in response to chronic inflammation has implications for inflammatory co-morbidities and time-of-day therapeutics.
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http://dx.doi.org/10.1186/s13075-019-1825-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6366099PMC
February 2019

Genome-wide association analyses of chronotype in 697,828 individuals provides insights into circadian rhythms.

Nat Commun 2019 01 29;10(1):343. Epub 2019 Jan 29.

23andMe Inc., 899W. Evelyn Avenue, Mountain View, CA, 94041, USA.

Being a morning person is a behavioural indicator of a person's underlying circadian rhythm. Using genome-wide data from 697,828 UK Biobank and 23andMe participants we increase the number of genetic loci associated with being a morning person from 24 to 351. Using data from 85,760 individuals with activity-monitor derived measures of sleep timing we find that the chronotype loci associate with sleep timing: the mean sleep timing of the 5% of individuals carrying the most morningness alleles is 25 min earlier than the 5% carrying the fewest. The loci are enriched for genes involved in circadian regulation, cAMP, glutamate and insulin signalling pathways, and those expressed in the retina, hindbrain, hypothalamus, and pituitary. Using Mendelian Randomisation, we show that being a morning person is causally associated with better mental health but does not affect BMI or risk of Type 2 diabetes. This study offers insights into circadian biology and its links to disease in humans.
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http://dx.doi.org/10.1038/s41467-018-08259-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6351539PMC
January 2019

Cardiomyocyte transcription is controlled by combined MR and circadian clock signalling.

J Endocrinol 2019 01 1. Epub 2019 Jan 1.

M Young, Cardiovascular Endocrinology, Hudson Institute of Medical Research, Clayton, 3166, Australia.

We previously identified a critical pathogenic role for MR activation in cardiomyocytes that included a potential interaction between the MR and the molecular circadian clock. While glucocorticoid regulation of the circadian clock is undisputed, MR interactions with circadian clock signalling are limited. We hypothesised that the MR influences cardiac circadian clock signalling, and vice versa. 10nM aldosterone or corticosterone regulated CRY 1, PER1, PER2 and ReverbA (NR1D1) gene expression patterns in H9c2 cells over 24hr. MR-dependent regulation of circadian gene promoters containing GREs and E-box sequences was established for CLOCK, Bmal, CRY 1 and CRY2, PER1 and PER2 and transcriptional activators CLOCK and Bmal modulated MR-dependent transcription of a subset of these promoters. We also demonstrated differential regulation of MR target gene expression in hearts of mice 4hr after administration of aldosterone at 8AM versus 8PM. Our data support combined MR regulation of a subset of circadian genes and that endogenous circadian transcription factors CLOCK and Bmal modulate this response. This unsuspected relationship links MR in the heart to circadian rhythmicity at the molecular level and has important implications for the biology of MR signalling in response to aldosterone as well as cortisol. These data are consistent with MR signalling in the brain where, like the heart, it preferentially responds to cortisol. Given the undisputed requirement for diurnal cortisol release in the entrainment of peripheral clocks, the present study highlights the MR as an important mechanism for transducing the circadian actions of cortisol in addition to the GR in the heart.
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http://dx.doi.org/10.1530/JOE-18-0584DOI Listing
January 2019

The circadian regulator Bmal1 in joint mesenchymal cells regulates both joint development and inflammatory arthritis.

Arthritis Res Ther 2019 01 6;21(1). Epub 2019 Jan 6.

Division of Diabetes, Endocrinology and Gastroenterology, School of Medical Sciences, Faculty of Biology, Medicine and Health, University of Manchester, AV Hill Building, Oxford Road, Manchester, UK.

Background: The circadian clock plays a crucial role in regulating physiology and is important for maintaining immune homeostasis and responses to inflammatory stimuli. Inflammatory arthritis often shows diurnal variation in disease symptoms and disease markers, and it is now established that cellular clocks regulate joint inflammation. The clock gene Bmal1 is critical for maintenance of 24-h rhythms and plays a key role in regulating immune responses, as well as in aging-related processes. Fibroblast-like synoviocytes (FLS) are circadian rhythmic joint mesenchymal cells which are important for maintenance of joint health and play a crucial role in the development of inflammatory arthritis. The aim of this study was to investigate the importance of the joint mesenchymal cell circadian clock in health and disease.

Methods: Mice were generated which lack Bmal1 in Col6a1-expressing cells, targeting mesenchymal cells in the ankle joints. Joints of these animals were assessed by X-ray imaging, whole-mount staining and histology, and the composition of the synovium was assessed by flow cytometry. Arthritis was induced using collagen antibodies.

Results: Bmal1 deletion in joint mesenchymal cells rendered the FLS and articular cartilage cells arrhythmic. Targeted mice exhibited significant changes in the architecture of the joints, including chondroid metaplasia (suggesting a switch of connective tissue stem cells towards a chondroid phenotype), reductions in resident synovial macrophages and changes in the basal pro-inflammatory activity of FLS. Loss of Bmal1 in FLS rendered these resident immune cells more pro-inflammatory in response to challenge, leading to increased paw swelling, localised infiltration of mononuclear cells and enhanced cytokine production in a model of arthritis.

Conclusions: This study demonstrates the importance of Bmal1 in joint mesenchymal cells in regulating FLS and chondrocyte development. Additionally, we have identified a role for this core clock component for restraining local responses to inflammation and highlight a role for the circadian clock in regulating inflammatory arthritis.
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http://dx.doi.org/10.1186/s13075-018-1770-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6322248PMC
January 2019

Reply to Moitra et al.: Individual Chronotype May Confound Asthma Symptoms and Therapy.

Am J Respir Crit Care Med 2019 02;199(3):392-394

1 University of Manchester Manchester, United Kingdom and.

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http://dx.doi.org/10.1164/rccm.201809-1712LEDOI Listing
February 2019

Low salivary cortisol levels in patients with rheumatoid arthritis exposed to oral glucocorticoids: a cross-sectional study set within UK electronic health records.

RMD Open 2018 1;4(2):e000700. Epub 2018 Oct 1.

Arthritis Research UK Centre for Epidemiology, Centre for Musculoskeletal Research, School of Biological Sciences, Manchester Academic Health Science Centre, The University of Manchester, Manchester, UK.

Background: Glucocorticoids (GCs) suppress endogenous cortisol levels which can lead to adrenal insufficiency (AI). The frequency of GC-induced AI remains unclear. In this cross-sectional study, low morning salivary cortisol (MSC) levels were used as a measure of adrenal function. The study aim was to investigate the prevalence of low MSC in patients with rheumatoid arthritis (RA) currently and formerly exposed to oral GCs, and the association with potential risk factors.

Methods: Sample collection was nested within UK primary care electronic health records (from the Clinical Practice Research Datalink). Participants were patients with RA with at least one prescription for oral GCs in the past 2 years. Self-reported oral GC use was used to define current use and current dose; prescription data were used to define exposure duration. MSC was determined from saliva samples; 5 nmol/L was the cut-off for low MSC. The prevalence of low MSC was estimated, and logistic regression was used to assess the association with potential risk factors.

Results: 66% of 38 current and 11 % of 38 former GC users had low MSC. Among former users with low MSC, the longest time since GC withdrawal was 6 months. Current GC dose, age and RA duration were significantly associated with increased risk of low MSC.

Conclusion: The prevalence of low MSC among current GC users is high, and MSC levels may remain suppressed for several months after GC withdrawal. Clinicians should therefore consider the risk of suppressed cortisol and remain vigilant for symptoms of AI following GC withdrawal.
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http://dx.doi.org/10.1136/rmdopen-2018-000700DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6173262PMC
October 2018

Incidence of primary graft dysfunction after lung transplantation is altered by timing of allograft implantation.

Thorax 2019 04 9;74(4):413-416. Epub 2018 Oct 9.

Faculty of Biology, Medicine and Health, Manchester Academic Health Sciences Centre, The University of Manchester, Manchester, UK.

The importance of circadian factors in managing patients is poorly understood. We present two retrospective cohort studies showing that lungs reperfused between 4 and 8 AM have a higher incidence (OR 1.12; 95% CI 1.03 to 1.21; p=0.01) of primary graft dysfunction (PGD) in the first 72 hours after transplantation. Cooling of the donor lung, occurring during organ preservation, shifts the donor circadian clock causing desynchrony with the recipient. The clock protein REV-ERBα directly regulates PGD biomarkers explaining this circadian regulation while also allowing them to be manipulated with synthetic REV-ERB ligands.
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http://dx.doi.org/10.1136/thoraxjnl-2018-212021DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6484691PMC
April 2019
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