30 results on '"Rzechorzek, Nina M"'
Search Results
2. Macromolecular condensation buffers intracellular water potential
- Author
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Watson, Joseph L., Seinkmane, Estere, Styles, Christine T., Mihut, Andrei, Krüger, Lara K., McNally, Kerrie E., Planelles-Herrero, Vicente Jose, Dudek, Michal, McCall, Patrick M., Barbiero, Silvia, Vanden Oever, Michael, Peak-Chew, Sew Yeu, Porebski, Benjamin T., Zeng, Aiwei, Rzechorzek, Nina M., Wong, David C. S., Beale, Andrew D., Stangherlin, Alessandra, Riggi, Margot, Iwasa, Janet, Morf, Jörg, Miliotis, Christos, Guna, Alina, Inglis, Alison J., Brugués, Jan, Voorhees, Rebecca M., Chambers, Joseph E., Meng, Qing-Jun, O’Neill, John S., Edgar, Rachel S., and Derivery, Emmanuel
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- 2023
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3. Author Correction: Macromolecular condensation buffers intracellular water potential
- Author
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Watson, Joseph L., Seinkmane, Estere, Styles, Christine T., Mihut, Andrei, Krüger, Lara K., McNally, Kerrie E., Planelles-Herrero, Vicente Jose, Dudek, Michal, McCall, Patrick M., Barbiero, Silvia, Vanden Oever, Michael, Peak-Chew, Sew Yeu, Porebski, Benjamin T., Zeng, Aiwei, Rzechorzek, Nina M., Wong, David C. S., Beale, Andrew D., Stangherlin, Alessandra, Riggi, Margot, Iwasa, Janet, Morf, Jörg, Miliotis, Christos, Guna, Alina, Inglis, Alison J., Brugués, Jan, Voorhees, Rebecca M., Chambers, Joseph E., Meng, Qing-Jun, O’Neill, John S., Edgar, Rachel S., and Derivery, Emmanuel
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- 2024
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4. Human stem cell–derived astrocytes replicate human prions in a PRNP genotype–dependent manner
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Krejciova, Zuzana, Alibhai, James, Zhao, Chen, Krencik, Robert, Rzechorzek, Nina M, Ullian, Erik M, Manson, Jean, Ironside, James W, Head, Mark W, and Chandran, Siddharthan
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Transmissible Spongiform Encephalopathy (TSE) ,Stem Cell Research - Induced Pluripotent Stem Cell - Human ,Stem Cell Research ,Genetics ,Neurosciences ,Infectious Diseases ,Stem Cell Research - Induced Pluripotent Stem Cell ,Rare Diseases ,Neurodegenerative ,Brain Disorders ,Clinical Research ,Foodborne Illness ,Stem Cell Research - Nonembryonic - Human ,Emerging Infectious Diseases ,2.1 Biological and endogenous factors ,Aetiology ,Neurological ,Good Health and Well Being ,Adult ,Astrocytes ,Cells ,Cultured ,Codon ,Creutzfeldt-Jakob Syndrome ,Female ,Genotype ,Humans ,Induced Pluripotent Stem Cells ,Kinetics ,Male ,Middle Aged ,Prion Proteins ,Prions ,Young Adult ,Medical and Health Sciences ,Immunology - Abstract
Prions are infectious agents that cause neurodegenerative diseases such as Creutzfeldt-Jakob disease (CJD). The absence of a human cell culture model that replicates human prions has hampered prion disease research for decades. In this paper, we show that astrocytes derived from human induced pluripotent stem cells (iPSCs) support the replication of prions from brain samples of CJD patients. For experimental exposure of astrocytes to variant CJD (vCJD), the kinetics of prion replication occur in a prion protein codon 129 genotype-dependent manner, reflecting the genotype-dependent susceptibility to clinical vCJD found in patients. Furthermore, iPSC-derived astrocytes can replicate prions associated with the major sporadic CJD strains found in human patients. Lastly, we demonstrate the subpassage of prions from infected to naive astrocyte cultures, indicating the generation of prion infectivity in vitro. Our study addresses a long-standing gap in the repertoire of human prion disease research, providing a new in vitro system for accelerated mechanistic studies and drug discovery.
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- 2017
5. Circadian clocks in human cerebral organoids
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Rzechorzek, Nina M, primary, Sutcliffe, Magdalena A, additional, Mihut, Andrei, additional, Baranes, Koby, additional, Karam, Nuzli, additional, Sánchez, Daniel Lloyd-Davies, additional, Peak-Chew, Sew Y, additional, Zeng, Aiwei, additional, Poulin, Noah, additional, Seinkmane, Estere, additional, Karim, Kaiser, additional, Proctor, Christopher M, additional, Kotter, Mark, additional, Lancaster, Madeline A, additional, and Beale, Andrew D, additional
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- 2024
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6. Network analysis reveals distinct clinical syndromes underlying acute mountain sickness
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Hall, David P, MacCormick, Ian JC, Phythian-Adams, Alex T, Rzechorzek, Nina M, Hope-Jones, David, Cosens, Sorrel, Jackson, Stewart, Bates, Matthew GD, Collier, David J, Hume, David A, Freeman, Thomas, Thompson, AA Roger, and Baillie, J Kenneth
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Quantitative Biology - Quantitative Methods ,Statistics - Applications - Abstract
Acute mountain sickness (AMS) is a common problem among visitors at high altitude, and may progress to life-threatening pulmonary and cerebral oedema in a minority of cases. International consensus defines AMS as a constellation of subjective, non-specific symptoms. Specifically, headache, sleep disturbance, fatigue and dizziness are given equal diagnostic weighting. Different pathophysiological mechanisms are now thought to underlie headache and sleep disturbance during acute exposure to high altitude. Hence, these symptoms may not belong together as a single syndrome. Using a novel visual analogue scale (VAS), we sought to undertake a systematic exploration of the symptomatology of AMS using an unbiased, data-driven approach originally designed for analysis of gene expression. Symptom scores were collected from 293 subjects during 1110 subject-days at altitudes between 3650m and 5200m on Apex expeditions to Bolivia and Kilimanjaro. Three distinct patterns of symptoms were consistently identified. Although fatigue is a ubiquitous finding, sleep disturbance and headache are each commonly reported without the other. The commonest pattern of symptoms was sleep disturbance and fatigue, with little or no headache. In subjects reporting severe headache, 40% did not report sleep disturbance. Sleep disturbance correlates poorly with other symptoms of AMS (Pearson r = 0.31 vs headache). These results challenge the accepted paradigm that AMS is a single disease process and describe at least two distinct syndromes following acute ascent to high altitude. This approach to analysing symptom patterns has potential utility in other clinical syndromes.
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- 2013
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7. Network analysis of canine brain morphometry links tumour risk to oestrogen deficiency and accelerated brain ageing
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Rzechorzek, Nina M., Saunders, Olivia M., Hiscox, Lucy V., Schwarz, Tobias, Marioni-Henry, Katia, Argyle, David J., Schoenebeck, Jeffrey J., and Freeman, Tom C.
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- 2019
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8. Healthy human brains have a daily heatwave
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Rzechorzek, Nina M, primary and O’Neill, John S, additional
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- 2022
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9. Circadian regulation of protein turnover and proteome renewal
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Seinkmane, Estere, primary, Peak-Chew, Sew Y, additional, Zeng, Aiwei, additional, Rzechorzek, Nina M, additional, Beale, Andrew D, additional, Wong, David CS, additional, and O’Neill, John S, additional
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- 2022
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10. Modelling Neurological Diseases in Large Animals: Criteria for Model Selection and Clinical Assessment
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Eaton, Samantha L., primary, Murdoch, Fraser, additional, Rzechorzek, Nina M., additional, Thompson, Gerard, additional, Hartley, Claudia, additional, Blacklock, Benjamin Thomas, additional, Proudfoot, Chris, additional, Lillico, Simon G., additional, Tennant, Peter, additional, Ritchie, Adrian, additional, Nixon, James, additional, Brennan, Paul M., additional, Guido, Stefano, additional, Mitchell, Nadia L., additional, Palmer, David N., additional, Whitelaw, C. Bruce A., additional, Cooper, Jonathan D., additional, and Wishart, Thomas M., additional
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- 2022
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11. Healthy human brains have a daily heatwave.
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Rzechorzek, Nina M. and O'Neill, John S.
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HEAT waves (Meteorology) , *BODY temperature , *NON-REM sleep , *RAPID eye movement sleep - Abstract
Some clinical studies report that I T i SB Br sb increases after brain injury and some patients undergo interventions to achieve a "normal" I T i SB Br sb . If I T i SB Br sb rhythms are similarly affected, it will be critical to establish how normal I T i SB Br sb variation interacts with the daily neural molecular clockwork before inferring a role for I T i SB Br sb disruption in disease. Daily variations in I T i SB Br sb are demonstrable in rodents and non-human primates; in the latter, I T i SB Br sb is consistently higher than carotid artery, aortic arch, and abdominal cavity temperature, and exhibits its own spatial gradient [[1]]. To address this gap, we undertook a retrospective analysis of I T i SB Br sb measured directly in patients with traumatic brain injury, alongside a prospective study of I T i SB Br sb measured non-invasively in healthy adults using magnetic resonance spectroscopy (MRS) [[1]]. [Extracted from the article]
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- 2023
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12. A daily temperature rhythm in the human brain predicts survival after brain injury
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Rzechorzek, N, Thrippleton, M, Chappell, F, Mair, G, Ercole, A, Cabeleira, M, Citerio, G, Rhodes, J, Marshall, I, O'Neill, J, Rzechorzek, Nina M, Thrippleton, Michael J, Chappell, Francesca M, Mair, Grant, Ercole, Ari, Cabeleira, Manuel, Citerio, Giuseppe, Rhodes, Jonathan, Marshall, Ian, O'Neill, John S, Rzechorzek, N, Thrippleton, M, Chappell, F, Mair, G, Ercole, A, Cabeleira, M, Citerio, G, Rhodes, J, Marshall, I, O'Neill, J, Rzechorzek, Nina M, Thrippleton, Michael J, Chappell, Francesca M, Mair, Grant, Ercole, Ari, Cabeleira, Manuel, Citerio, Giuseppe, Rhodes, Jonathan, Marshall, Ian, and O'Neill, John S
- Abstract
Patients undergo interventions to achieve a 'normal' brain temperature; a parameter that remains undefined for humans. The profound sensitivity of neuronal function to temperature implies the brain should be isothermal, but observations from patients and non-human primates suggest significant spatiotemporal variation. We aimed to determine the clinical relevance of brain temperature in patients by establishing how much it varies in healthy adults. We retrospectively screened data for all patients recruited to the Collaborative European NeuroTrauma Effectiveness Research in Traumatic Brain Injury (CENTER-TBI) High Resolution Intensive Care Unit Sub-Study. Only patients with direct brain temperature measurements and without targeted temperature management were included. To interpret patient analyses, we prospectively recruited 40 healthy adults (20 males, 20 females, 20-40 years) for brain thermometry using magnetic resonance spectroscopy. Participants were scanned in the morning, afternoon, and late evening of a single day. In patients (n = 114), brain temperature ranged from 32.6 to 42.3°C and mean brain temperature (38.5 ± 0.8°C) exceeded body temperature (37.5 ± 0.5°C, P < 0.0001). Of 100 patients eligible for brain temperature rhythm analysis, 25 displayed a daily rhythm, and the brain temperature range decreased in older patients (P = 0.018). In healthy participants, brain temperature ranged from 36.1 to 40.9°C; mean brain temperature (38.5 ± 0.4°C) exceeded oral temperature (36.0 ± 0.5°C) and was 0.36°C higher in luteal females relative to follicular females and males (P = 0.0006 and P < 0.0001, respectively). Temperature increased with age, most notably in deep brain regions (0.6°C over 20 years, P = 0.0002), and varied spatially by 2.41 ± 0.46°C with highest temperatures in the thalamus. Brain temperature varied by time of day, especially in deep regions (0.86°C, P = 0.0001), and was lowest at night. From the healthy data we built HEATWAVE - a 4D map of
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- 2022
13. A daily temperature rhythm in the human brain predicts survival after brain injury
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Rzechorzek, Nina M, Thrippleton, Michael J, Chappell, Francesca M, Mair, Grant, Ercole, Ari, Cabeleira, Manuel, Citerio, Giuseppe, Rhodes, Jonathan, Marshall, Ian, O'Neill, John S, Rzechorzek, N, Thrippleton, M, Chappell, F, Mair, G, Ercole, A, Cabeleira, M, Citerio, G, Rhodes, J, Marshall, I, O'Neill, J, Ercole, Ari [0000-0001-8350-8093], O'Neill, John [0000-0003-2204-6096], and Apollo - University of Cambridge Repository
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Adult ,Male ,Temperature ,Brain ,brain thermometry ,brain injury ,daily ,mortality ,Body Temperature ,Hypothermia, Induced ,Brain Injuries ,brain temperature ,Brain Injuries, Traumatic ,Humans ,Female ,Neurology (clinical) ,Aged ,Retrospective Studies - Abstract
Patients undergo interventions to achieve a ‘normal’ brain temperature; a parameter that remains undefined for humans. The profound sensitivity of neuronal function to temperature implies the brain should be isothermal, but observations from patients and non-human primates suggest significant spatiotemporal variation. We aimed to determine the clinical relevance of brain temperature in patients by establishing how much it varies in healthy adults. We retrospectively screened data for all patients recruited to the Collaborative European NeuroTrauma Effectiveness Research in Traumatic Brain Injury High Resolution Intensive Care Unit Sub-Study. Only patients with direct brain temperature measurements without targeted temperature management were included. To interpret patient analyses, we prospectively recruited 40 healthy adults (20 males, 20 females, 20-40 years) for brain thermometry using magnetic resonance spectroscopy. Participants were scanned in the morning, afternoon, and late evening of a single day. In patients (n=114), mean brain temperature (38.5±0.8°C) exceeded body temperature (37.5±0.5°C, P, The prospective study was funded by a Medical Research Council Clinician Scientist Fellowship awarded to N.M.R. (MR/S022023/1). J.S.O.N. is supported by the Medical Research Council (MC_UP_1201/4). Some of the data contributing to the retrospective analysis were obtained in the context of CENTER-TBI, a large collaborative project (EC grant 602150) supported by the European Union’s 7th Framework program (FP7/2007-2013). Additional funding for patient data collection was obtained from the Hannelore Kohl Stiftung (Germany), from OneMind (USA) and from Integra LifeSciences Corporation (USA). M.J.T. acknowledges funding from the NHS Lothian Research and Development Office.
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- 2022
14. CRYPTOCHROMES promote daily protein homeostasis
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Wong, David C S, primary, Seinkmane, Estere, additional, Zeng, Aiwei, additional, Stangherlin, Alessandra, additional, Rzechorzek, Nina M, additional, Beale, Andrew D, additional, Day, Jason, additional, Reed, Martin, additional, Peak‐Chew, Sew Y, additional, Styles, Christine T, additional, Edgar, Rachel S, additional, Putker, Marrit, additional, and O’Neill, John S, additional
- Published
- 2021
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15. CRYPTOCHROMES confer robustness, not rhythmicity, to circadian timekeeping
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Putker, Marrit, primary, Wong, David C S, additional, Seinkmane, Estere, additional, Rzechorzek, Nina M, additional, Zeng, Aiwei, additional, Hoyle, Nathaniel P, additional, Chesham, Johanna E, additional, Edwards, Mathew D, additional, Feeney, Kevin A, additional, Fischer, Robin, additional, Peschel, Nicolai, additional, Chen, Ko‐Fan, additional, Vanden Oever, Michael, additional, Edgar, Rachel S, additional, Selby, Christopher P, additional, Sancar, Aziz, additional, and O’Neill, John S, additional
- Published
- 2021
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16. CRYPTOCHROME suppresses the circadian proteome and promotes protein homeostasis
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Wong, David C.S., primary, Seinkmane, Estere, additional, Stangherlin, Alessandra, additional, Zeng, Aiwei, additional, Rzechorzek, Nina M., additional, Beale, Andrew D., additional, Day, Jason, additional, Reed, Martin, additional, Chew, Sew Peak, additional, Styles, Christine T., additional, Edgar, Rachel S., additional, Putker, Marrit, additional, and O’Neill, John S., additional
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- 2020
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17. CRYPTOCHROMES promote daily protein homeostasis.
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Wong, David C S, Seinkmane, Estere, Zeng, Aiwei, Stangherlin, Alessandra, Rzechorzek, Nina M, Beale, Andrew D, Day, Jason, Reed, Martin, Peak‐Chew, Sew Y, Styles, Christine T, Edgar, Rachel S, Putker, Marrit, and O'Neill, John S
- Subjects
CRYPTOCHROMES ,ION transport (Biology) ,CELL physiology ,HOMEOSTASIS ,PROTEINS ,MOLECULAR clock ,CIRCADIAN rhythms ,CLOCK genes - Abstract
The daily organisation of most mammalian cellular functions is attributed to circadian regulation of clock‐controlled protein expression, driven by daily cycles of CRYPTOCHROME‐dependent transcriptional feedback repression. To test this, we used quantitative mass spectrometry to compare wild‐type and CRY‐deficient fibroblasts under constant conditions. In CRY‐deficient cells, we found that temporal variation in protein, phosphopeptide, and K+ abundance was at least as great as wild‐type controls. Most strikingly, the extent of temporal variation within either genotype was much smaller than overall differences in proteome composition between WT and CRY‐deficient cells. This proteome imbalance in CRY‐deficient cells and tissues was associated with increased susceptibility to proteotoxic stress, which impairs circadian robustness, and may contribute to the wide‐ranging phenotypes of CRY‐deficient mice. Rather than generating large‐scale daily variation in proteome composition, we suggest it is plausible that the various transcriptional and post‐translational functions of CRY proteins ultimately act to maintain protein and osmotic homeostasis against daily perturbation. Synopsis: CRYPTOCHROMES regulate proteome composition but are not required for its circadian organisation. Loss of these global transcriptional regulators leads to proteotoxic stress, which impairs the daily organisation of physiology in both cells and mice. Circadian protein abundance, phosphorylation and ion transport do not require CRYPTOCHROMEs.CRYPTOCHROME‐deficient cells and tissues show increased proteotoxic stress.Proteotoxic stress impairs the robustness of circadian rhythms in cells and mice.CRYPTOCHROME primarily functions to suppress temporal variation in proteome composition. [ABSTRACT FROM AUTHOR]
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- 2022
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18. Network analysis of canine brain morphometry links tumour risk to oestrogen deficiency and accelerated brain ageing
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Rzechorzek, Nina M., primary, Saunders, Olivia M., additional, Hisco, Lucy, additional, Schwarz, Tobias, additional, Marioni-Henry, Katia, additional, Argyle, David J., additional, Schoenebeck, Jeffery J., additional, and Freeman, Tom C., additional
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- 2018
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19. Sheep Lung Segmental Delivery Strategy Demonstrates Adenovirus Priming of Local Lung Responses to Bacterial LPS and the Role of Elafin as a Response Modulator
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Brown, Thomas I., Collie, David S., Shaw, Darren J., Rzechorzek, Nina M., and Sallenave, Jean-Michel
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Lipopolysaccharides ,Adenoviruses ,Livestock ,Neutrophils ,Adenoviridae Infections ,Respiratory System ,Genetic Vectors ,lcsh:Medicine ,Pathology and Laboratory Medicine ,Microbiology ,Adenoviridae ,Medicine and Health Sciences ,Animals ,Humans ,Transgenes ,Molecular Biology Techniques ,lcsh:Science ,Microbial Pathogens ,Molecular Biology ,Lung ,Sheep, Domestic ,Clinical Genetics ,Sheep ,lcsh:R ,Biology and Life Sciences ,Agriculture ,Gene Therapy ,Genetic Therapy ,respiratory system ,Elafin ,Animal Models of Infection ,Medical Microbiology ,Viral Pathogens ,lcsh:Q ,Anatomy ,Lungs ,Pathogens ,Research Article - Abstract
Viral lung infections increase susceptibility to subsequent bacterial infection. We questioned whether local lung administration of recombinant adenoviral vectors in the sheep would alter the susceptibility of the lung to subsequent challenge with bacterial lipopolysaccharide (LPS). We further questioned whether local lung expression of elafin, a locally produced alarm anti-LPS/anti-bacterial molecule, would modulate the challenge response. We established that adenoviral vector treatment primed the lung for an enhanced response to bacterial LPS. Whereas this local effect appeared to be independent of the transgene used (Ad-o-elafin or Ad-GFP), Ad-o-elafin treated sheep demonstrated a more profound lymphopenia in response to local lung administration of LPS. The local influence of elafin in modulating the response to LPS was restricted to maintaining neutrophil myeloperoxidase activity, and levels of alveolar macrophage and neutrophil phagocytosis at higher levels post-LPS. Adenoviral vector-bacterial synergism exists in the ovine lung and elafin expression modulates such synergism both locally and systemically.
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- 2014
20. Hypothermic modulation of human cortical neurons to explore a role for tau protein in neuroprotection
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Rzechorzek, Nina M, primary, Connick, Peter, additional, Livesey, Matthew R, additional, Borooah, Shyamanga, additional, Patani, Rickie, additional, Burr, Karen, additional, Story, David, additional, Wyllie, David J A, additional, Hardingham, Giles E, additional, and Chandran, Siddharthan, additional
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- 2016
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21. Hypothermic Preconditioning Reverses Tau Ontogenesis in Human Cortical Neurons and is Mimicked by Protein Phosphatase 2A Inhibition
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Rzechorzek, Nina M., primary, Connick, Peter, additional, Livesey, Matthew R., additional, Borooah, Shyamanga, additional, Patani, Rickie, additional, Burr, Karen, additional, Story, David, additional, Wyllie, David J.A., additional, Hardingham, Giles E., additional, and Chandran, Siddharthan, additional
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- 2016
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22. Sheep Lung Segmental Delivery Strategy Demonstrates Adenovirus Priming of Local Lung Responses to Bacterial LPS and the Role of Elafin as a Response Modulator
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Brown, Thomas I., primary, Collie, David S., additional, Shaw, Darren J., additional, Rzechorzek, Nina M., additional, and Sallenave, Jean-Michel, additional
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- 2014
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23. Maturation of AMPAR Composition and the GABAAR Reversal Potential in hPSC-Derived Cortical Neurons
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Livesey, Matthew R., primary, Bilican, Bilada, additional, Qiu, Jing, additional, Rzechorzek, Nina M., additional, Haghi, Ghazal, additional, Burr, Karen, additional, Hardingham, Giles E., additional, Chandran, Siddharthan, additional, and Wyllie, David J.A., additional
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- 2014
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24. Network Analysis Reveals Distinct Clinical Syndromes Underlying Acute Mountain Sickness
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Hall, David P., primary, MacCormick, Ian J. C., additional, Phythian-Adams, Alex T., additional, Rzechorzek, Nina M., additional, Hope-Jones, David, additional, Cosens, Sorrel, additional, Jackson, Stewart, additional, Bates, Matthew G. D., additional, Collier, David J., additional, Hume, David A., additional, Freeman, Thomas, additional, Thompson, A. A. Roger, additional, and Baillie, John Kenneth, additional
- Published
- 2014
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25. Maturation of AMPAR Composition and the GABAAR Reversal Potential in hPSC-Derived Cortical Neurons.
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Livesey, Matthew R., Bilican, Bilada, Jing Qiu, Rzechorzek, Nina M., Haghi, Ghazal, Burr, Karen, Hardingham, Giles E., Chandran, Siddharthan, and Wyllie, David J. A.
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NEURONS ,EXCITATION (Physiology) ,PLURIPOTENT stem cells ,HUMAN stem cells ,NEUROTROPHINS - Abstract
Rodent-based studies have shown that neurons undergo major developmental changes to ion channel expression and ionic gradients that determine their excitation-inhibition balance. Neurons derived from human pluripotent stem cells theoretically offer the potential to study classical developmental processes in a human-relevant system, although this is currently not well explored. Here, we show that excitatory cortical-patterned neurons derived from multiple human pluripotent stem cell lines exhibit native-like maturation changes inAMPARcomposition such that there is an increase in the expression of GluA2(R) subunits. Moreover, we observe a dynamic shift in intracellular Cl
- levels, which determines the reversal potential ofGABAAR-mediated currents and is influenced by neurotrophic factors. The shift is concomitant with changes in KCC2 and NKCC1 expression. Because some human diseases are thought to involve perturbations to AMPAR GluA2 content and others in the chloride reversal potential,humanstem-cell-derived neurons represent a valuable tool for studying these fundamental properties. [ABSTRACT FROM AUTHOR]- Published
- 2014
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26. Network analysis of canine brain morphometry links tumour risk to oestrogen deficiency and accelerated brain ageing
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Rzechorzek, Nina M, Saunders, Olivia M, Hiscox, Lucy V, Schwarz, Tobias, Marioni-Henry, Katia, Argyle, David J, Schoenebeck, Jeffrey J, and Freeman, Tom C
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Cohort Studies ,Male ,Dogs ,Brain Neoplasms ,Animals ,Brain ,Estrogens ,Female ,Dog Diseases ,Organ Size ,Breeding ,10. No inequality - Abstract
Structural 'brain age' is a valuable but complex biomarker for several brain disorders. The dog is an unrivalled comparator for neurological disease modeling, however canine brain morphometric diversity creates computational and statistical challenges. Using a data-driven approach, we explored complex interactions between patient metadata, brain morphometry, and neurological disease. Twenty-four morphometric parameters measured from 286 canine brain magnetic resonance imaging scans were combined with clinical parameters to generate 9,438 data points. Network analysis was used to cluster patients according to their brain morphometry profiles. An 'aged-brain' profile, defined by a small brain width and volume combined with ventriculomegaly, was revealed in the Boxer breed. Key features of this profile were paralleled in neutered female dogs which, relative to un-neutered females, had an 11-fold greater risk of developing brain tumours. Boxer dog and geriatric dog groups were both enriched for brain tumour diagnoses, despite a lack of geriatric Boxers within the cohort. Our findings suggest that advanced brain ageing enhances brain tumour risk in dogs and may be influenced by oestrogen deficiency-a risk factor for dementia and brain tumours in humans. Morphometric features of brain ageing in dogs, like humans, might better predict neurological disease risk than patient chronological age.
27. CRYPTOCHROMES promote daily protein homeostasis
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John S. O’Neill, Christine T. Styles, Nina M Rzechorzek, Marrit Putker, Andrew D. Beale, Alessandra Stangherlin, Martin Reed, Aiwei Zeng, Jason Day, Sew Y. Peak-Chew, David C S Wong, Rachel S. Edgar, Estere Seinkmane, Wong, David CS [0000-0002-1712-9527], Seinkmane, Estere [0000-0002-3636-4709], Zeng, Aiwei [0000-0003-0354-2529], Stangherlin, Alessandra [0000-0001-7296-1183], Rzechorzek, Nina M [0000-0003-3209-5019], Beale, Andrew D [0000-0002-2051-0919], Day, Jason [0000-0002-3078-0963], Peak-Chew, Sew Y [0000-0002-7602-6384], Styles, Christine T [0000-0001-7337-2540], Edgar, Rachel S [0000-0002-3348-0851], Putker, Marrit [0000-0001-9290-408X], O'Neill, John S [0000-0003-2204-6096], and Apollo - University of Cambridge Repository
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circadian rhythm ,Proteomics ,endocrine system ,Proteasome Endopeptidase Complex ,Time Factors ,Proteome ,Biology ,Article ,General Biochemistry, Genetics and Molecular Biology ,proteotoxic stress ,Mice ,Post-translational Modifications & Proteolysis ,Cryptochrome ,Stress, Physiological ,Genotype ,Animals ,CRYPTOCHROME ,Circadian rhythm ,Molecular Biology ,Psychological repression ,protein homeostasis ,Ion Transport ,General Immunology and Microbiology ,General Neuroscience ,Robustness (evolution) ,Reproducibility of Results ,Articles ,clock mutant ,Phosphoproteins ,Phenotype ,Cell biology ,Cryptochromes ,Metabolism ,Proteostasis ,Homeostasis - Abstract
The daily organisation of most mammalian cellular functions is attributed to circadian regulation of clock‐controlled protein expression, driven by daily cycles of CRYPTOCHROME‐dependent transcriptional feedback repression. To test this, we used quantitative mass spectrometry to compare wild‐type and CRY‐deficient fibroblasts under constant conditions. In CRY‐deficient cells, we found that temporal variation in protein, phosphopeptide, and K+ abundance was at least as great as wild‐type controls. Most strikingly, the extent of temporal variation within either genotype was much smaller than overall differences in proteome composition between WT and CRY‐deficient cells. This proteome imbalance in CRY‐deficient cells and tissues was associated with increased susceptibility to proteotoxic stress, which impairs circadian robustness, and may contribute to the wide‐ranging phenotypes of CRY‐deficient mice. Rather than generating large‐scale daily variation in proteome composition, we suggest it is plausible that the various transcriptional and post‐translational functions of CRY proteins ultimately act to maintain protein and osmotic homeostasis against daily perturbation., CRYPTOCHROMES are not essential for circadian proteome oscillations but play a crucial role in the temporal regulation of protein and osmotic homeostasis.
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- 2022
28. Network analysis of canine brain morphometry links tumour risk to oestrogen deficiency and accelerated brain ageing
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Jeffrey J. Schoenebeck, David Argyle, Katia Marioni-Henry, Tobias Schwarz, Olivia M. Saunders, Nina Marie Rzechorzek, Tom C. Freeman, Lucy V Hiscox, Rzechorzek, Nina M [0000-0003-3209-5019], Schoenebeck, Jeffrey J [0000-0003-4964-2138], and Apollo - University of Cambridge Repository
- Subjects
Male ,040301 veterinary sciences ,lcsh:Medicine ,Disease ,Breeding ,Predictive markers ,Bioinformatics ,Cohort Studies ,0403 veterinary science ,03 medical and health sciences ,Dogs ,Cancer epidemiology ,0302 clinical medicine ,medicine ,Animals ,Dementia ,Dog Diseases ,Risk factor ,lcsh:Science ,10. No inequality ,Brain Neoplasms ,business.industry ,lcsh:R ,Brain morphometry ,Brain ,Estrogens ,Organ Size ,04 agricultural and veterinary sciences ,Neural ageing ,medicine.disease ,CNC Cancer ,Ageing ,Cohort ,Biomarker (medicine) ,Female ,lcsh:Q ,business ,030217 neurology & neurosurgery ,Ventriculomegaly - Abstract
BackgroundStructural ‘brain age’ is a valuable but complex biomarker for several brain disorders. The dog is an unrivalled comparator for neurological disease modeling, however brain phenotypic diversity among pedigrees creates computational and statistical challenges.MethodsWe applied unbiased network correlation analysis in dogs to explore complex interactions between brain morphometrics, patient metadata, and neurological disease. Twenty-four parameters measured from each of 286 brain magnetic resonance imaging scans generated 9,438 data points that were used to cluster canine patients according to their brain morphometry profiles. The network was then explored for statistically significant enrichments within breed, sex, age, and diagnostic categories.FindingsMorphometric comparisons revealed an advanced ‘aged-brain’ profile in the Boxer breed, consisting of a small brain length, width, and volume, combined with ventriculomegaly. Key features of this profile were paralleled in neutered female dogs which, relative to un-neutered females, had an 11-fold greater risk of developing primary brain tumours. Enrichment analysis confirmed that Boxers and geriatric individuals were enriched for brain tumour diagnoses, despite a lack of geriatric Boxers within the cohort.InterpretationThese findings suggest that accelerated brain ageing might contribute to tumour risk in Boxers and may be influenced by oestrogen deficiency — a risk factor for dementia and brain tumours in humans. We propose that morphometric features of brain ageing in dogs, like humans, might better predict neurological disease risk than a patient’s chronological age.FundingWellcome Trust Integrated Training Fellowship for Veterinarians (096409/Z/11/Z to N.M.R) and an MSD Animal Health Connect Bursary (to O.M.S.).
- Published
- 2018
29. A daily temperature rhythm in the human brain predicts survival after brain injury.
- Author
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Rzechorzek NM, Thrippleton MJ, Chappell FM, Mair G, Ercole A, Cabeleira M, Rhodes J, Marshall I, and O'Neill JS
- Subjects
- Adult, Aged, Body Temperature physiology, Brain physiology, Female, Humans, Male, Retrospective Studies, Temperature, Brain Injuries complications, Brain Injuries, Traumatic complications, Hypothermia, Induced
- Abstract
Patients undergo interventions to achieve a 'normal' brain temperature; a parameter that remains undefined for humans. The profound sensitivity of neuronal function to temperature implies the brain should be isothermal, but observations from patients and non-human primates suggest significant spatiotemporal variation. We aimed to determine the clinical relevance of brain temperature in patients by establishing how much it varies in healthy adults. We retrospectively screened data for all patients recruited to the Collaborative European NeuroTrauma Effectiveness Research in Traumatic Brain Injury (CENTER-TBI) High Resolution Intensive Care Unit Sub-Study. Only patients with direct brain temperature measurements and without targeted temperature management were included. To interpret patient analyses, we prospectively recruited 40 healthy adults (20 males, 20 females, 20-40 years) for brain thermometry using magnetic resonance spectroscopy. Participants were scanned in the morning, afternoon, and late evening of a single day. In patients (n = 114), brain temperature ranged from 32.6 to 42.3°C and mean brain temperature (38.5 ± 0.8°C) exceeded body temperature (37.5 ± 0.5°C, P < 0.0001). Of 100 patients eligible for brain temperature rhythm analysis, 25 displayed a daily rhythm, and the brain temperature range decreased in older patients (P = 0.018). In healthy participants, brain temperature ranged from 36.1 to 40.9°C; mean brain temperature (38.5 ± 0.4°C) exceeded oral temperature (36.0 ± 0.5°C) and was 0.36°C higher in luteal females relative to follicular females and males (P = 0.0006 and P < 0.0001, respectively). Temperature increased with age, most notably in deep brain regions (0.6°C over 20 years, P = 0.0002), and varied spatially by 2.41 ± 0.46°C with highest temperatures in the thalamus. Brain temperature varied by time of day, especially in deep regions (0.86°C, P = 0.0001), and was lowest at night. From the healthy data we built HEATWAVE-a 4D map of human brain temperature. Testing the clinical relevance of HEATWAVE in patients, we found that lack of a daily brain temperature rhythm increased the odds of death in intensive care 21-fold (P = 0.016), whilst absolute temperature maxima or minima did not predict outcome. A warmer mean brain temperature was associated with survival (P = 0.035), however, and ageing by 10 years increased the odds of death 11-fold (P = 0.0002). Human brain temperature is higher and varies more than previously assumed-by age, sex, menstrual cycle, brain region, and time of day. This has major implications for temperature monitoring and management, with daily brain temperature rhythmicity emerging as one of the strongest single predictors of survival after brain injury. We conclude that daily rhythmic brain temperature variation-not absolute brain temperature-is one way in which human brain physiology may be distinguished from pathophysiology., (© The Author(s) 2022. Published by Oxford University Press on behalf of the Guarantors of Brain.)
- Published
- 2022
- Full Text
- View/download PDF
30. Hypothermic Preconditioning Reverses Tau Ontogenesis in Human Cortical Neurons and is Mimicked by Protein Phosphatase 2A Inhibition.
- Author
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Rzechorzek NM, Connick P, Livesey MR, Borooah S, Patani R, Burr K, Story D, Wyllie DJA, Hardingham GE, and Chandran S
- Subjects
- Gene Expression, Glutamic Acid toxicity, Humans, Hypothermia, Induced, Neural Stem Cells cytology, Neural Stem Cells metabolism, Neurons cytology, Neurons drug effects, Oxidative Stress, Phosphorylation, Protein Phosphatase 2 metabolism, Receptors, N-Methyl-D-Aspartate metabolism, Temperature, tau Proteins genetics, Cerebral Cortex cytology, Cerebral Cortex metabolism, Hypothermia, Neurons metabolism, Protein Phosphatase 2 antagonists & inhibitors, tau Proteins metabolism
- Abstract
Hypothermia is potently neuroprotective, but the molecular basis of this effect remains obscure. Changes in neuronal tau protein are of interest, since tau becomes hyperphosphorylated in injury-resistant, hypothermic brains. Noting inter-species differences in tau isoforms, we have used functional cortical neurons differentiated from human pluripotent stem cells (hCNs) to interrogate tau modulation during hypothermic preconditioning at clinically-relevant temperatures. Key tau developmental transitions (phosphorylation status and splicing shift) are recapitulated during hCN differentiation and subsequently reversed by mild (32 °C) to moderate (28 °C) cooling--conditions which reduce oxidative and excitotoxic stress-mediated injury in hCNs. Blocking a major tau kinase decreases hCN tau phosphorylation and abrogates hypothermic neuroprotection, whilst inhibition of protein phosphatase 2A mimics cooling-induced tau hyperphosphorylation and protects normothermic hCNs from oxidative stress. These findings indicate a possible role for phospho-tau in hypothermic preconditioning, and suggest that cooling drives human tau towards an earlier ontogenic phenotype whilst increasing neuronal resilience to common neurotoxic insults. This work provides a critical step forward in understanding how we might exploit the neuroprotective benefits of cooling without cooling patients.
- Published
- 2015
- Full Text
- View/download PDF
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