• 3D DESI-MS lipid imaging in a xenograft model of glioblastoma: a proof of principle

      Henderson, Fiona; Jones, Emrys; Denbigh, Joanna; Christie, Lidan; Chapman, Richard; Hoyes, Emmy; Claude, Emmanuelle; Williams, Kaye J.; Roncaroli, Federico; McMahon, Adam; email: adam.mcmahon@manchester.ac.uk (Nature Publishing Group UK, 2020-10-05)
      Abstract: Desorption electrospray ionisation mass spectrometry (DESI-MS) can image hundreds of molecules in a 2D tissue section, making it an ideal tool for mapping tumour heterogeneity. Tumour lipid metabolism has gained increasing attention over the past decade; and here, lipid heterogeneity has been visualised in a glioblastoma xenograft tumour using 3D DESI-MS imaging. The use of an automatic slide loader automates 3D imaging for high sample-throughput. Glioblastomas are highly aggressive primary brain tumours, which display heterogeneous characteristics and are resistant to chemotherapy and radiotherapy. It is therefore important to understand biochemical contributions to their heterogeneity, which may be contributing to treatment resistance. Adjacent sections to those used for DESI-MS imaging were used for H&E staining and immunofluorescence to identify different histological regions, and areas of hypoxia. Comparing DESI-MS imaging with biological staining allowed association of different lipid species with hypoxic and viable tissue within the tumour, and hence mapping of molecularly different tumour regions in 3D space. This work highlights that lipids are playing an important role in the heterogeneity of this xenograft tumour model, and DESI-MS imaging can be used for lipid 3D imaging in an automated fashion to reveal heterogeneity, which is not apparent in H&E stains alone.
    • A miRNA signature predicts benefit from addition of hypoxia-modifying therapy to radiation treatment in invasive bladder cancer

      Khan, Mairah T.; Irlam-Jones, Joely J.; Pereira, Ronnie Rodrigues; Lane, Brian; Valentine, Helen R.; Aragaki, Kai; Dyrskjøt, Lars; McConkey, David J.; Hoskin, Peter J.; Choudhury, Ananya; et al. (Nature Publishing Group UK, 2021-04-12)
      Abstract: Background: miRNAs are promising biomarkers in oncology as their small size makes them less susceptible to degradation than mRNA in FFPE tissue. We aimed to derive a hypoxia-associated miRNA signature for bladder cancer. Methods: Taqman miRNA array cards identified miRNA seed genes induced under hypoxia in bladder cancer cell lines. A signature was derived using feature selection methods in a TCGA BLCA training data set. miRNA expression data were generated for 190 tumours from the BCON Phase 3 trial and used for independent validation. Results: A 14-miRNA hypoxia signature was derived, which was prognostic for poorer overall survival in the TCGA BLCA cohort (n = 403, p = 0.001). Univariable analysis showed that the miRNA signature predicted an overall survival benefit from having carbogen–nicotinamide with radiotherapy (HR = 0.30, 95% CI 0.094–0.95, p = 0.030) and performed similarly to a 24-gene mRNA signature (HR = 0.47, 95% CI 0.24–0.92, p = 0.025). Combining the signatures improved performance (HR = 0.26, 95% CI 0.08–0.82, p = 0.014) with borderline significance for an interaction test (p = 0.065). The interaction test was significant for local relapse-free survival LRFS (p = 0.033). Conclusion: A 14-miRNA hypoxia signature can be used with an mRNA hypoxia signature to identify bladder cancer patients benefitting most from having carbogen and nicotinamide with radiotherapy.
    • Altered protein O-GlcNAcylation in placentas from mothers with diabetes causes aberrant endocytosis in placental trophoblast cells

      Palin, Victoria; Russell, Matthew; Graham, Robert; Aplin, John D.; Westwood, Melissa; email: melissa.westwood@manchester.ac.uk (Nature Publishing Group UK, 2021-10-19)
      Abstract: Women with pre-existing diabetes have an increased risk of poor pregnancy outcomes, including disordered fetal growth, caused by changes to placental function. Here we investigate the possibility that the hexosamine biosynthetic pathway, which utilises cellular nutrients to regulate protein function via post-translationally modification with O-linked N-acetylglucosamine (GlcNAc), mediates the placental response to the maternal metabolic milieu. Mass spectrometry analysis revealed that the placental O-GlcNAcome is altered in women with type 1 (n = 6) or type 2 (n = 6) diabetes T2D (≥ twofold change in abundance in 162 and 165 GlcNAcylated proteins respectively compared to BMI-matched controls n = 11). Ingenuity pathway analysis indicated changes to clathrin-mediated endocytosis (CME) and CME-associated proteins, clathrin, Transferrin (TF), TF receptor and multiple Rabs, were identified as O-GlcNAcylation targets. Stimulating protein O-GlcNAcylation using glucosamine (2.5 mM) increased the rate of TF endocytosis by human placental cells (p = 0.02) and explants (p = 0.04). Differential GlcNAcylation of CME proteins suggests altered transfer of cargo by placentas of women with pre-gestational diabetes, which may contribute to alterations in fetal growth. The human placental O-GlcNAcome provides a resource to aid further investigation of molecular mechanisms governing placental nutrient sensing.
    • An alternative pathway for membrane protein biogenesis at the endoplasmic reticulum

      O’Keefe, Sarah; orcid: 0000-0002-1744-0198; email: sarah.okeefe@manchester.ac.uk; Zong, Guanghui; orcid: 0000-0002-7335-039X; Duah, Kwabena B.; Andrews, Lauren E.; Shi, Wei Q.; orcid: 0000-0001-5453-1753; High, Stephen; orcid: 0000-0002-4532-8152; email: stephen.high@manchester.ac.uk (Nature Publishing Group UK, 2021-07-01)
      Abstract: The heterotrimeric Sec61 complex is a major site for the biogenesis of transmembrane proteins (TMPs), accepting nascent TMP precursors that are targeted to the endoplasmic reticulum (ER) by the signal recognition particle (SRP). Unlike most single-spanning membrane proteins, the integration of type III TMPs is completely resistant to small molecule inhibitors of the Sec61 translocon. Using siRNA-mediated depletion of specific ER components, in combination with the potent Sec61 inhibitor ipomoeassin F (Ipom-F), we show that type III TMPs utilise a distinct pathway for membrane integration at the ER. Hence, following SRP-mediated delivery to the ER, type III TMPs can uniquely access the membrane insertase activity of the ER membrane complex (EMC) via a mechanism that is facilitated by the Sec61 translocon. This alternative EMC-mediated insertion pathway allows type III TMPs to bypass the Ipom-F-mediated blockade of membrane integration that is seen with obligate Sec61 clients.
    • Analysis of chromatin organization and gene expression in T cells identifies functional genes for rheumatoid arthritis

      Yang, Jing; McGovern, Amanda; orcid: 0000-0001-7727-3283; Martin, Paul; orcid: 0000-0002-1016-6851; Duffus, Kate; Ge, Xiangyu; Zarrineh, Peyman; Morris, Andrew P.; Adamson, Antony; orcid: 0000-0002-5408-0013; Fraser, Peter; orcid: 0000-0002-0041-1227; Rattray, Magnus; orcid: 0000-0001-8196-5565; email: magnus.rattray@manchester.ac.uk; et al. (Nature Publishing Group UK, 2020-09-02)
      Abstract: Genome-wide association studies have identified genetic variation contributing to complex disease risk. However, assigning causal genes and mechanisms has been more challenging because disease-associated variants are often found in distal regulatory regions with cell-type specific behaviours. Here, we collect ATAC-seq, Hi-C, Capture Hi-C and nuclear RNA-seq data in stimulated CD4+ T cells over 24 h, to identify functional enhancers regulating gene expression. We characterise changes in DNA interaction and activity dynamics that correlate with changes in gene expression, and find that the strongest correlations are observed within 200 kb of promoters. Using rheumatoid arthritis as an example of T cell mediated disease, we demonstrate interactions of expression quantitative trait loci with target genes, and confirm assigned genes or show complex interactions for 20% of disease associated loci, including FOXO1, which we confirm using CRISPR/Cas9.
    • Applying Machine Learning to Kinematic and Eye Movement Features of a Movement Imitation Task to Predict Autism Diagnosis

      Vabalas, Andrius; email: andrius.vabalas@manchester.ac.uk; Gowen, Emma; Poliakoff, Ellen; Casson, Alexander J. (Nature Publishing Group UK, 2020-05-20)
      Abstract: Autism is a developmental condition currently identified by experts using observation, interview, and questionnaire techniques and primarily assessing social and communication deficits. Motor function and movement imitation are also altered in autism and can be measured more objectively. In this study, motion and eye tracking data from a movement imitation task were combined with supervised machine learning methods to classify 22 autistic and 22 non-autistic adults. The focus was on a reliable machine learning application. We have used nested validation to develop models and further tested the models with an independent data sample. Feature selection was aimed at selection stability to assure result interpretability. Our models predicted diagnosis with 73% accuracy from kinematic features, 70% accuracy from eye movement features and 78% accuracy from combined features. We further explored features which were most important for predictions to better understand movement imitation differences in autism. Consistent with the behavioural results, most discriminative features were from the experimental condition in which non-autistic individuals tended to successfully imitate unusual movement kinematics while autistic individuals tended to fail. Machine learning results show promise that future work could aid in the diagnosis process by providing quantitative tests to supplement current qualitative ones.
    • Aridity-driven shift in biodiversity–soil multifunctionality relationships

      Hu, Weigang; orcid: 0000-0003-1422-3726; Ran, Jinzhi; Dong, Longwei; Du, Qiajun; Ji, Mingfei; Yao, Shuran; Sun, Yuan; Gong, Chunmei; Hou, Qingqing; Gong, Haiyang; et al. (Nature Publishing Group UK, 2021-09-09)
      Abstract: Relationships between biodiversity and multiple ecosystem functions (that is, ecosystem multifunctionality) are context-dependent. Both plant and soil microbial diversity have been reported to regulate ecosystem multifunctionality, but how their relative importance varies along environmental gradients remains poorly understood. Here, we relate plant and microbial diversity to soil multifunctionality across 130 dryland sites along a 4,000 km aridity gradient in northern China. Our results show a strong positive association between plant species richness and soil multifunctionality in less arid regions, whereas microbial diversity, in particular of fungi, is positively associated with multifunctionality in more arid regions. This shift in the relationships between plant or microbial diversity and soil multifunctionality occur at an aridity level of ∼0.8, the boundary between semiarid and arid climates, which is predicted to advance geographically ∼28% by the end of the current century. Our study highlights that biodiversity loss of plants and soil microorganisms may have especially strong consequences under low and high aridity conditions, respectively, which calls for climate-specific biodiversity conservation strategies to mitigate the effects of aridification.
    • Author Correction: Loss of mRNA surveillance pathways results in widespread protein aggregation

      Jamar, Nur Hidayah; Kritsiligkou, Paraskevi; orcid: 0000-0003-2452-141X; Grant, Chris M.; orcid: 0000-0002-0616-6576; email: chris.grant@manchester.ac.uk (Nature Publishing Group UK, 2021-08-12)
    • Author Correction: Metacognitive Therapy versus Cognitive Behaviour Therapy in Adults with Major Depression: A Parallel Single-Blind Randomised Trial

      Callesen, Pia; Reeves, David; Heal, Calvin; Wells, Adrian; orcid: 0000-0001-7713-1592; email: adrian.wells@manchester.ac.uk (Nature Publishing Group UK, 2020-07-07)
      An amendment to this paper has been published and can be accessed via a link at the top of the paper.
    • Author Correction: Organic osmolytes preserve the function of the developing tight junction in ultraviolet B-irradiated rat epidermal keratinocytes

      El-Chami, Cécile; Haslam, Iain S.; orcid: 0000-0002-1008-2447; Steward, Martin C.; O’Neill, Catherine A.; email: catherine.a.oneill@manchester.ac.uk (Nature Publishing Group UK, 2020-05-20)
      An amendment to this paper has been published and can be accessed via a link at the top of the paper.
    • Author Correction: The T cell receptor repertoire of tumor infiltrating T cells is predictive and prognostic for cancer survival

      Valpione, Sara; Mundra, Piyushkumar A.; Galvani, Elena; Campana, Luca G.; orcid: 0000-0002-8466-8459; Lorigan, Paul; orcid: 0000-0002-8875-2164; De Rosa, Francesco; orcid: 0000-0003-0511-1298; Gupta, Avinash; Weightman, John; Mills, Sarah; Dhomen, Nathalie; et al. (Nature Publishing Group UK, 2021-07-22)
    • BioID-based proteomic analysis of the Bid interactome identifies novel proteins involved in cell-cycle-dependent apoptotic priming

      Pedley, Robert; orcid: 0000-0002-0801-7240; King, Louise E.; Mallikarjun, Venkatesh; Wang, Pengbo; Swift, Joe; Brennan, Keith; Gilmore, Andrew P.; orcid: 0000-0002-9988-0436; email: agilmore@manchester.ac.uk (Nature Publishing Group UK, 2020-10-16)
      Abstract: Apoptotic priming controls the commitment of cells to apoptosis by determining how close they lie to mitochondrial permeabilisation. Variations in priming are important for how both healthy and cancer cells respond to chemotherapeutic agents, but how it is dynamically coordinated by Bcl-2 proteins remains unclear. The Bcl-2 family protein Bid is phosphorylated when cells enter mitosis, increasing apoptotic priming and sensitivity to antimitotic drugs. Here, we report an unbiased proximity biotinylation (BioID) screen to identify regulators of apoptotic priming in mitosis, using Bid as bait. The screen primarily identified proteins outside of the canonical Bid interactome. Specifically, we found that voltage-dependent anion-selective channel protein 2 (VDAC2) was required for Bid phosphorylation-dependent changes in apoptotic priming during mitosis. These results highlight the importance of the wider Bcl-2 family interactome in regulating the temporal control of apoptotic priming.
    • Breast cancer management pathways during the COVID-19 pandemic: outcomes from the UK ‘Alert Level 4’ phase of the B-MaP-C study

      Dave, Rajiv V.; orcid: 0000-0001-6827-8090; email: rajiv.dave@nhs.net; Kim, Baek; Courtney, Alona; O’Connell, Rachel; Rattay, Tim; Taxiarchi, Vicky P.; Kirkham, Jamie J.; Camacho, Elizabeth M.; Fairbrother, Patricia; Sharma, Nisha; et al. (Nature Publishing Group UK, 2021-03-25)
      Abstract: Background: The B-MaP-C study aimed to determine alterations to breast cancer (BC) management during the peak transmission period of the UK COVID-19 pandemic and the potential impact of these treatment decisions. Methods: This was a national cohort study of patients with early BC undergoing multidisciplinary team (MDT)-guided treatment recommendations during the pandemic, designated ‘standard’ or ‘COVID-altered’, in the preoperative, operative and post-operative setting. Findings: Of 3776 patients (from 64 UK units) in the study, 2246 (59%) had ‘COVID-altered’ management. ‘Bridging’ endocrine therapy was used (n = 951) where theatre capacity was reduced. There was increasing access to COVID-19 low-risk theatres during the study period (59%). In line with national guidance, immediate breast reconstruction was avoided (n = 299). Where adjuvant chemotherapy was omitted (n = 81), the median benefit was only 3% (IQR 2–9%) using ‘NHS Predict’. There was the rapid adoption of new evidence-based hypofractionated radiotherapy (n = 781, from 46 units). Only 14 patients (1%) tested positive for SARS-CoV-2 during their treatment journey. Conclusions: The majority of ‘COVID-altered’ management decisions were largely in line with pre-COVID evidence-based guidelines, implying that breast cancer survival outcomes are unlikely to be negatively impacted by the pandemic. However, in this study, the potential impact of delays to BC presentation or diagnosis remains unknown.
    • Breast cancer management pathways during the COVID-19 pandemic: outcomes from the UK ‘Alert Level 4’ phase of the B-MaP-C study

      Dave, Rajiv V.; orcid: 0000-0001-6827-8090; email: rajiv.dave@nhs.net; Kim, Baek; Courtney, Alona; O’Connell, Rachel; Rattay, Tim; Taxiarchi, Vicky P.; Kirkham, Jamie J.; Camacho, Elizabeth M.; Fairbrother, Patricia; Sharma, Nisha; et al. (Nature Publishing Group UK, 2021-03-25)
      Abstract: Background: The B-MaP-C study aimed to determine alterations to breast cancer (BC) management during the peak transmission period of the UK COVID-19 pandemic and the potential impact of these treatment decisions. Methods: This was a national cohort study of patients with early BC undergoing multidisciplinary team (MDT)-guided treatment recommendations during the pandemic, designated ‘standard’ or ‘COVID-altered’, in the preoperative, operative and post-operative setting. Findings: Of 3776 patients (from 64 UK units) in the study, 2246 (59%) had ‘COVID-altered’ management. ‘Bridging’ endocrine therapy was used (n = 951) where theatre capacity was reduced. There was increasing access to COVID-19 low-risk theatres during the study period (59%). In line with national guidance, immediate breast reconstruction was avoided (n = 299). Where adjuvant chemotherapy was omitted (n = 81), the median benefit was only 3% (IQR 2–9%) using ‘NHS Predict’. There was the rapid adoption of new evidence-based hypofractionated radiotherapy (n = 781, from 46 units). Only 14 patients (1%) tested positive for SARS-CoV-2 during their treatment journey. Conclusions: The majority of ‘COVID-altered’ management decisions were largely in line with pre-COVID evidence-based guidelines, implying that breast cancer survival outcomes are unlikely to be negatively impacted by the pandemic. However, in this study, the potential impact of delays to BC presentation or diagnosis remains unknown.
    • Breast cancer management pathways during the COVID-19 pandemic: outcomes from the UK ‘Alert Level 4’ phase of the B-MaP-C study

      Dave, Rajiv V.; orcid: 0000-0001-6827-8090; email: rajiv.dave@nhs.net; Kim, Baek; Courtney, Alona; O’Connell, Rachel; Rattay, Tim; Taxiarchi, Vicky P.; Kirkham, Jamie J.; Camacho, Elizabeth M.; Fairbrother, Patricia; Sharma, Nisha; et al. (Nature Publishing Group UK, 2021-03-25)
      Abstract: Background: The B-MaP-C study aimed to determine alterations to breast cancer (BC) management during the peak transmission period of the UK COVID-19 pandemic and the potential impact of these treatment decisions. Methods: This was a national cohort study of patients with early BC undergoing multidisciplinary team (MDT)-guided treatment recommendations during the pandemic, designated ‘standard’ or ‘COVID-altered’, in the preoperative, operative and post-operative setting. Findings: Of 3776 patients (from 64 UK units) in the study, 2246 (59%) had ‘COVID-altered’ management. ‘Bridging’ endocrine therapy was used (n = 951) where theatre capacity was reduced. There was increasing access to COVID-19 low-risk theatres during the study period (59%). In line with national guidance, immediate breast reconstruction was avoided (n = 299). Where adjuvant chemotherapy was omitted (n = 81), the median benefit was only 3% (IQR 2–9%) using ‘NHS Predict’. There was the rapid adoption of new evidence-based hypofractionated radiotherapy (n = 781, from 46 units). Only 14 patients (1%) tested positive for SARS-CoV-2 during their treatment journey. Conclusions: The majority of ‘COVID-altered’ management decisions were largely in line with pre-COVID evidence-based guidelines, implying that breast cancer survival outcomes are unlikely to be negatively impacted by the pandemic. However, in this study, the potential impact of delays to BC presentation or diagnosis remains unknown.
    • Breast cancer management pathways during the COVID-19 pandemic: outcomes from the UK ‘Alert Level 4’ phase of the B-MaP-C study

      Dave, Rajiv V.; orcid: 0000-0001-6827-8090; email: rajiv.dave@nhs.net; Kim, Baek; Courtney, Alona; O’Connell, Rachel; Rattay, Tim; Taxiarchi, Vicky P.; Kirkham, Jamie J.; Camacho, Elizabeth M.; Fairbrother, Patricia; Sharma, Nisha; et al. (Nature Publishing Group UK, 2021-03-25)
      Abstract: Background: The B-MaP-C study aimed to determine alterations to breast cancer (BC) management during the peak transmission period of the UK COVID-19 pandemic and the potential impact of these treatment decisions. Methods: This was a national cohort study of patients with early BC undergoing multidisciplinary team (MDT)-guided treatment recommendations during the pandemic, designated ‘standard’ or ‘COVID-altered’, in the preoperative, operative and post-operative setting. Findings: Of 3776 patients (from 64 UK units) in the study, 2246 (59%) had ‘COVID-altered’ management. ‘Bridging’ endocrine therapy was used (n = 951) where theatre capacity was reduced. There was increasing access to COVID-19 low-risk theatres during the study period (59%). In line with national guidance, immediate breast reconstruction was avoided (n = 299). Where adjuvant chemotherapy was omitted (n = 81), the median benefit was only 3% (IQR 2–9%) using ‘NHS Predict’. There was the rapid adoption of new evidence-based hypofractionated radiotherapy (n = 781, from 46 units). Only 14 patients (1%) tested positive for SARS-CoV-2 during their treatment journey. Conclusions: The majority of ‘COVID-altered’ management decisions were largely in line with pre-COVID evidence-based guidelines, implying that breast cancer survival outcomes are unlikely to be negatively impacted by the pandemic. However, in this study, the potential impact of delays to BC presentation or diagnosis remains unknown.
    • Capturing convection essential for projections of climate change in African dust emission

      Garcia-Carreras, Luis; orcid: 0000-0002-9844-3170; email: luis.garcia-carreras@manchester.ac.uk; Marsham, John H.; orcid: 0000-0003-3219-8472; Stratton, Rachel A.; Tucker, Simon (Nature Publishing Group UK, 2021-09-24)
      Abstract: The summertime Sahara and Sahel are the world’s largest source of airborne mineral dust. Cold-pool outflows from moist convection (‘haboobs’) are a dominant source of summertime uplift but are essentially missing in global models, raising major questions on the reliability of climate projections of dust and dust impacts. Here we use convection-permitting simulations of pan-African climate change, which explicitly capture haboobs, to investigate whether this key limitation of global models affects projections. We show that explicit convection is key to capturing the observed summertime maximum of dust-generating winds, which is missed with parameterised convection. Despite this, future climate changes in dust-generating winds are more sensitive to the effects of explicit convection on the wider meteorology than they are to the haboobs themselves, with model differences in the change in dust-generating winds reaching 60% of current values. The results therefore show the importance of improving convection in climate models for dust projections.
    • Chronic glucocorticoid treatment induces hepatic lipid accumulation and hyperinsulinaemia in part through actions on AgRP neurons

      Harno, Erika; email: erika.harno@manchester.ac.uk; Sefton, Charlotte; Wray, Jonathan R.; Allen, Tiffany-Jayne; Davies, Alison; Coll, Anthony P.; White, Anne; email: anne.white@manchester.ac.uk (Nature Publishing Group UK, 2021-07-02)
      Abstract: Glucocorticoids (GCs) are widely prescribed anti-inflammatory medicines, but their use can lead to metabolic side-effects. These may occur through direct actions of GCs on peripheral organs, but could also be mediated by the hypothalamic AgRP neurons, which can increase food intake and modify peripheral metabolism. Therefore, the aim of this study was to examine the metabolic effects of chronic treatment with the GC corticosterone (Cort, 75 μg/ml in drinking water) in mice lacking the glucocorticoid receptor (GR) on AgRP neurons. Female AgRP-GR KO mice had delayed onset of Cort-induced hyperphagia. However, AgRP-GR KO had little impact on the increased body weight or adiposity seen with 3 weeks Cort treatment. Cort caused hepatic steatosis in control mice, but in Cort treated female AgRP-GR KO mice there was a 25% reduction in liver lipid content and lower plasma triglycerides. Additionally, Cort treatment led to hyperinsulinaemia, but compared to controls, Cort-treated AgRP-GR KO mice had both lower fasting insulin levels and lower insulin levels during a glucose tolerance test. In conclusion, these data indicate that GCs do act through AgRP neurons to contribute, at least in part, to the adverse metabolic consequences of chronic GC treatment.
    • Circadian clock mechanism driving mammalian photoperiodism

      Wood, S. H.; orcid: 0000-0002-8273-4045; Hindle, M. M.; orcid: 0000-0002-6870-4069; Mizoro, Y.; Cheng, Y.; orcid: 0000-0002-1747-9308; Saer, B. R. C.; Miedzinska, K.; Christian, H. C.; orcid: 0000-0002-4263-5499; Begley, N.; McNeilly, J.; McNeilly, A. S.; et al. (Nature Publishing Group UK, 2020-08-27)
      Abstract: The annual photoperiod cycle provides the critical environmental cue synchronizing rhythms of life in seasonal habitats. In 1936, Bünning proposed a circadian-based coincidence timer for photoperiodic synchronization in plants. Formal studies support the universality of this so-called coincidence timer, but we lack understanding of the mechanisms involved. Here we show in mammals that long photoperiods induce the circadian transcription factor BMAL2, in the pars tuberalis of the pituitary, and triggers summer biology through the eyes absent/thyrotrophin (EYA3/TSH) pathway. Conversely, long-duration melatonin signals on short photoperiods induce circadian repressors including DEC1, suppressing BMAL2 and the EYA3/TSH pathway, triggering winter biology. These actions are associated with progressive genome-wide changes in chromatin state, elaborating the effect of the circadian coincidence timer. Hence, circadian clock-pituitary epigenetic pathway interactions form the basis of the mammalian coincidence timer mechanism. Our results constitute a blueprint for circadian-based seasonal timekeeping in vertebrates.
    • Climate change alters temporal dynamics of alpine soil microbial functioning and biogeochemical cycling via earlier snowmelt

      Broadbent, Arthur A. D.; orcid: 0000-0002-8438-7163; email: arthur.broadbent@manchester.ac.uk; Snell, Helen S. K.; Michas, Antonios; Pritchard, William J.; Newbold, Lindsay; orcid: 0000-0001-8895-1406; Cordero, Irene; orcid: 0000-0002-6249-8348; Goodall, Tim; orcid: 0000-0002-1526-4071; Schallhart, Nikolaus; Kaufmann, Ruediger; Griffiths, Robert I.; orcid: 0000-0002-3341-4547; et al. (Nature Publishing Group UK, 2021-02-22)
      Abstract: Soil microbial communities regulate global biogeochemical cycles and respond rapidly to changing environmental conditions. However, understanding how soil microbial communities respond to climate change, and how this influences biogeochemical cycles, remains a major challenge. This is especially pertinent in alpine regions where climate change is taking place at double the rate of the global average, with large reductions in snow cover and earlier spring snowmelt expected as a consequence. Here, we show that spring snowmelt triggers an abrupt transition in the composition of soil microbial communities of alpine grassland that is closely linked to shifts in soil microbial functioning and biogeochemical pools and fluxes. Further, by experimentally manipulating snow cover we show that this abrupt seasonal transition in wide-ranging microbial and biogeochemical soil properties is advanced by earlier snowmelt. Preceding winter conditions did not change the processes that take place during snowmelt. Our findings emphasise the importance of seasonal dynamics for soil microbial communities and the biogeochemical cycles that they regulate. Moreover, our findings suggest that earlier spring snowmelt due to climate change will have far reaching consequences for microbial communities and nutrient cycling in these globally widespread alpine ecosystems.