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The agouti viable yellow (Avy) allele is an insertional mutation in the mouse genome caused by a variably methylated intracisternal A particle (VM-IAP) retrotransposon. Avy expressivity is sensitive to a range of early-life chemical exposures and nutritional interventions, suggesting that environmental perturbations can have long-lasting effects on the methylome. However, the extent to which VM-IAP elements are environmentally labile with phenotypic implications is unknown. Using a recently identified repertoire of VM-IAPs, we assessed the epigenetic effects of different environmental contexts. A longitudinal aging analysis indicated that VM-IAPs are stable across the murine lifespan, with only small increases in DNA methylation detected for a subset of loci. No significant effects were observed after maternal exposure to the endocrine disruptor bisphenol A, an obesogenic diet or methyl donor supplementation. A genetic mouse model of abnormal folate metabolism exhibited shifted VM-IAP methylation levels and altered VM-IAP-associated gene expression, yet these effects are likely largely driven by differential targeting by polymorphic KRAB zinc finger proteins. We conclude that epigenetic variability at retrotransposons is not predictive of environmental susceptibility.
Tessa M Bertozzi; Jessica L Becker; Georgina E T Blake; Amita Bansal; Duy K Nguyen; Denise S Fernandez-Twinn; Susan E Ozanne; Marisa S Bartolomei; Rebecca A Simmons; Erica D Watson; Anne C Ferguson-Smith. Variably methylated retrotransposons are refractory to a range of environmental perturbations. Nature Genetics 2021, 53, 1233 -1242.
AMA StyleTessa M Bertozzi, Jessica L Becker, Georgina E T Blake, Amita Bansal, Duy K Nguyen, Denise S Fernandez-Twinn, Susan E Ozanne, Marisa S Bartolomei, Rebecca A Simmons, Erica D Watson, Anne C Ferguson-Smith. Variably methylated retrotransposons are refractory to a range of environmental perturbations. Nature Genetics. 2021; 53 (8):1233-1242.
Chicago/Turabian StyleTessa M Bertozzi; Jessica L Becker; Georgina E T Blake; Amita Bansal; Duy K Nguyen; Denise S Fernandez-Twinn; Susan E Ozanne; Marisa S Bartolomei; Rebecca A Simmons; Erica D Watson; Anne C Ferguson-Smith. 2021. "Variably methylated retrotransposons are refractory to a range of environmental perturbations." Nature Genetics 53, no. 8: 1233-1242.
Two commonly used approaches to study interactions among neurons are spike count correlation, which describes pairs of neurons, and dimensionality reduction, applied to a population of neurons. Although both approaches have been used to study trial-to-trial neuronal variability correlated among neurons, they are often used in isolation and have not been directly related. We first established concrete mathematical and empirical relationships between pairwise correlation and metrics of population-wide covariability based on dimensionality reduction. Applying these insights to macaque V4 population recordings, we found that the previously reported decrease in mean pairwise correlation associated with attention stemmed from three distinct changes in population-wide covariability. Overall, our work builds the intuition and formalism to bridge between pairwise correlation and population-wide covariability and presents a cautionary tale about the inferences one can make about population activity by using a single statistic, whether it be mean pairwise correlation or dimensionality.
Akash Umakantha; Rudina Morina; Benjamin R Cowley; Adam C Snyder; Matthew A Smith; Byron M Yu. Bridging neuronal correlations and dimensionality reduction. Neuron 2021, 1 .
AMA StyleAkash Umakantha, Rudina Morina, Benjamin R Cowley, Adam C Snyder, Matthew A Smith, Byron M Yu. Bridging neuronal correlations and dimensionality reduction. Neuron. 2021; ():1.
Chicago/Turabian StyleAkash Umakantha; Rudina Morina; Benjamin R Cowley; Adam C Snyder; Matthew A Smith; Byron M Yu. 2021. "Bridging neuronal correlations and dimensionality reduction." Neuron , no. : 1.
Aberrantly expressed fused in sarcoma (FUS) is a hallmark of FUS-related amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). Wildtype FUS localises to synapses and interacts with mitochondrial proteins while mutations have been shown to cause to pathological changes affecting mitochondria, synapses and the neuromuscular junction (NMJ). This indicates a crucial physiological role for FUS in regulating synaptic and mitochondrial function that is currently poorly understood. In this paper we provide evidence that mislocalised cytoplasmic FUS causes mitochondrial and synaptic changes and that FUS plays a vital role in maintaining neuronal health in vitro and in vivo. Overexpressing mutant FUS altered synaptic numbers and neuronal complexity in both primary neurons and zebrafish models. The degree to which FUS was mislocalised led to differences in the synaptic changes which was mirrored by changes in mitochondrial numbers and transport. Furthermore, we showed that FUS co-localises with the mitochondrial tethering protein Syntaphilin (SNPH), and that mutations in FUS affect this relationship. Finally, we demonstrated mutant FUS led to changes in global protein translation. This localisation between FUS and SNPH could explain the synaptic and mitochondrial defects observed leading to global protein translation defects. Importantly, our results support the ‘gain-of-function’ hypothesis for disease pathogenesis in FUS-related ALS.
Shaakir Salam; Sara Tacconelli; Bradley N. Smith; Jacqueline C. Mitchell; Elizabeth Glennon; Nikolas Nikolaou; Corinne Houart; Caroline Vance. Identification of a novel interaction of FUS and syntaphilin may explain synaptic and mitochondrial abnormalities caused by ALS mutations. Scientific Reports 2021, 11, 1 -17.
AMA StyleShaakir Salam, Sara Tacconelli, Bradley N. Smith, Jacqueline C. Mitchell, Elizabeth Glennon, Nikolas Nikolaou, Corinne Houart, Caroline Vance. Identification of a novel interaction of FUS and syntaphilin may explain synaptic and mitochondrial abnormalities caused by ALS mutations. Scientific Reports. 2021; 11 (1):1-17.
Chicago/Turabian StyleShaakir Salam; Sara Tacconelli; Bradley N. Smith; Jacqueline C. Mitchell; Elizabeth Glennon; Nikolas Nikolaou; Corinne Houart; Caroline Vance. 2021. "Identification of a novel interaction of FUS and syntaphilin may explain synaptic and mitochondrial abnormalities caused by ALS mutations." Scientific Reports 11, no. 1: 1-17.
Merkel cell carcinoma (MCC) is a rare, but aggressive skin cancer the incidence of which has increased significantly in recent years. The majority of MCCs have incorporated Merkel cell polyomavirus (VP-MCC) while the remainder are virus-negative (VN-MCC). Although a variety of therapeutic options have shown promise in treating MCC, there remains a need for additional therapeutics as well as probes for better understanding MCC. A high-throughput screening campaign was used to assess the ability of > 25,000 synthetic and natural product compounds as well as > 20,000 natural product extracts to affect growth and survival of VN-MCC and VP-MCC cell lines. Sixteen active compounds were identified that have mechanisms of action reported in the literature along with a number of compounds with unknown mechanisms. Screening results with pure compounds suggest a range of potential targets for MCC including DNA damage, inhibition of DNA or protein synthesis, reactive oxygen species, and proteasome inhibition as well as NFκB inhibition while also suggesting the importance of zinc and/or copper binding. Many of the active compounds, particularly some of the natural products, have multiple reported targets suggesting that this strategy might be a particularly fruitful approach. Processing of several active natural product extracts resulted in the identification of additional MCC-active compounds. Based on these results, further investigations focused on natural products sources, particularly of fungal origin, are expected to yield further potentially useful modulators of MCC.
Emily A. Smith; Natasha T. Hill; Tara Gelb; Khalid A. Garman; Ekaterina I. Goncharova; Heidi R. Bokesch; Chang-Kwon Kim; Karen L. Wendt; Robert H. Cichewicz; Kirk R. Gustafson; Isaac Brownell; Curtis J. Henrich. Identification of natural product modulators of Merkel cell carcinoma cell growth and survival. Scientific Reports 2021, 11, 1 -10.
AMA StyleEmily A. Smith, Natasha T. Hill, Tara Gelb, Khalid A. Garman, Ekaterina I. Goncharova, Heidi R. Bokesch, Chang-Kwon Kim, Karen L. Wendt, Robert H. Cichewicz, Kirk R. Gustafson, Isaac Brownell, Curtis J. Henrich. Identification of natural product modulators of Merkel cell carcinoma cell growth and survival. Scientific Reports. 2021; 11 (1):1-10.
Chicago/Turabian StyleEmily A. Smith; Natasha T. Hill; Tara Gelb; Khalid A. Garman; Ekaterina I. Goncharova; Heidi R. Bokesch; Chang-Kwon Kim; Karen L. Wendt; Robert H. Cichewicz; Kirk R. Gustafson; Isaac Brownell; Curtis J. Henrich. 2021. "Identification of natural product modulators of Merkel cell carcinoma cell growth and survival." Scientific Reports 11, no. 1: 1-10.
White dwarfs represent the last stage of evolution of stars with mass less than about eight times that of the Sun and, like other stars, are often found in binaries1,2. If the orbital period of the binary is short enough, energy losses from gravitational-wave radiation can shrink the orbit until the two white dwarfs come into contact and merge3. Depending on the component masses, the merger can lead to a supernova of type Ia or result in a massive white dwarf4. In the latter case, the white dwarf remnant is expected to be highly magnetized5,6 because of the strong magnetic dynamo that should arise during the merger, and be rapidly spinning from the conservation of the orbital angular momentum7. Here we report observations of a white dwarf, ZTF J190132.9+145808.7, that exhibits these properties, but to an extreme: a rotation period of 6.94 minutes, a magnetic field ranging between 600 megagauss and 900 megagauss over its surface, and a stellar radius of $${2140}_{-230}^{+160}$$ kilometres, only slightly larger than the radius of the Moon. Such a small radius implies that the star’s mass is close to the maximum white dwarf mass, or Chandrasekhar mass. ZTF J190132.9+145808.7 is likely to be cooling through the Urca processes (neutrino emission from electron capture on sodium) because of the high densities reached in its core. A binary star merger has produced a white dwarf with a spin period of under 7 minutes, a magnetic field of 600 to 900 million gauss and a radius only slightly larger than that of our Moon.
Ilaria Caiazzo; Kevin B. Burdge; James Fuller; Jeremy Heyl; S. R. Kulkarni; Thomas A. Prince; Harvey B. Richer; Josiah Schwab; Igor Andreoni; Eric C. Bellm; Andrew Drake; Dmitry A. Duev; Matthew J. Graham; George Helou; Ashish A. Mahabal; Frank J. Masci; Roger Smith; Maayane T. Soumagnac. A highly magnetized and rapidly rotating white dwarf as small as the Moon. Nature 2021, 595, 39 -42.
AMA StyleIlaria Caiazzo, Kevin B. Burdge, James Fuller, Jeremy Heyl, S. R. Kulkarni, Thomas A. Prince, Harvey B. Richer, Josiah Schwab, Igor Andreoni, Eric C. Bellm, Andrew Drake, Dmitry A. Duev, Matthew J. Graham, George Helou, Ashish A. Mahabal, Frank J. Masci, Roger Smith, Maayane T. Soumagnac. A highly magnetized and rapidly rotating white dwarf as small as the Moon. Nature. 2021; 595 (7865):39-42.
Chicago/Turabian StyleIlaria Caiazzo; Kevin B. Burdge; James Fuller; Jeremy Heyl; S. R. Kulkarni; Thomas A. Prince; Harvey B. Richer; Josiah Schwab; Igor Andreoni; Eric C. Bellm; Andrew Drake; Dmitry A. Duev; Matthew J. Graham; George Helou; Ashish A. Mahabal; Frank J. Masci; Roger Smith; Maayane T. Soumagnac. 2021. "A highly magnetized and rapidly rotating white dwarf as small as the Moon." Nature 595, no. 7865: 39-42.
Bianca J. Lee; Jacob A. Boyer; G. Leslie Burnett; Arun P. Thottumkara; Nidhi Tibrewal; Stacy L. Wilson; Tientien Hsieh; Abby Marquez; Edward G. Lorenzana; James W. Evans; Laura Hulea; Gert Kiss; Hui Liu; Dong Lee; Ola Larsson; Shannon McLaughlan; Ivan Topisirovic; ZhengPing Wang; Zhican Wang; Yongyuan Zhao; David Wildes; James B. Aggen; Mallika Singh; Adrian L. Gill; Jacqueline A. M. Smith; Neal Rosen. Author Correction: Selective inhibitors of mTORC1 activate 4EBP1 and suppress tumor growth. Nature Chemical Biology 2021, 1 -1.
AMA StyleBianca J. Lee, Jacob A. Boyer, G. Leslie Burnett, Arun P. Thottumkara, Nidhi Tibrewal, Stacy L. Wilson, Tientien Hsieh, Abby Marquez, Edward G. Lorenzana, James W. Evans, Laura Hulea, Gert Kiss, Hui Liu, Dong Lee, Ola Larsson, Shannon McLaughlan, Ivan Topisirovic, ZhengPing Wang, Zhican Wang, Yongyuan Zhao, David Wildes, James B. Aggen, Mallika Singh, Adrian L. Gill, Jacqueline A. M. Smith, Neal Rosen. Author Correction: Selective inhibitors of mTORC1 activate 4EBP1 and suppress tumor growth. Nature Chemical Biology. 2021; ():1-1.
Chicago/Turabian StyleBianca J. Lee; Jacob A. Boyer; G. Leslie Burnett; Arun P. Thottumkara; Nidhi Tibrewal; Stacy L. Wilson; Tientien Hsieh; Abby Marquez; Edward G. Lorenzana; James W. Evans; Laura Hulea; Gert Kiss; Hui Liu; Dong Lee; Ola Larsson; Shannon McLaughlan; Ivan Topisirovic; ZhengPing Wang; Zhican Wang; Yongyuan Zhao; David Wildes; James B. Aggen; Mallika Singh; Adrian L. Gill; Jacqueline A. M. Smith; Neal Rosen. 2021. "Author Correction: Selective inhibitors of mTORC1 activate 4EBP1 and suppress tumor growth." Nature Chemical Biology , no. : 1-1.
Small studies show vaccines are safe for breastfeeding parents and could possibly provide some protection for the baby. Small studies show vaccines are safe for breastfeeding parents and could possibly provide some protection for the baby.
Noah Baker; Kerri Smith. Coronapod: should you have a COVID vaccine when breastfeeding? Nature 2021, 1 .
AMA StyleNoah Baker, Kerri Smith. Coronapod: should you have a COVID vaccine when breastfeeding? Nature. 2021; ():1.
Chicago/Turabian StyleNoah Baker; Kerri Smith. 2021. "Coronapod: should you have a COVID vaccine when breastfeeding?" Nature , no. : 1.
The clinical benefits of pan-mTOR active-site inhibitors are limited by toxicity and relief of feedback inhibition of receptor expression. To address these limitations, we designed a series of compounds that selectively inhibit mTORC1 and not mTORC2. These ‘bi-steric inhibitors’ comprise a rapamycin-like core moiety covalently linked to an mTOR active-site inhibitor. Structural modification of these components modulated their affinities for their binding sites on mTOR and the selectivity of the bi-steric compound. mTORC1-selective compounds potently inhibited 4EBP1 phosphorylation and caused regressions of breast cancer xenografts. Inhibition of 4EBP1 phosphorylation was sufficient to block cancer cell growth and was necessary for maximal antitumor activity. At mTORC1-selective doses, these compounds do not alter glucose tolerance, nor do they relieve AKT-dependent feedback inhibition of HER3. Thus, in preclinical models, selective inhibitors of mTORC1 potently inhibit tumor growth while causing less toxicity and receptor reactivation as compared to pan-mTOR inhibitors. Design of a bivalent inhibitor containing an ATP-competitive moiety and rapamycin-modified FRB binding ligand that selectively inhibits mTORC1 results in potent and durable inhibition of 4EBP1 phosphorylation and cell proliferation in vitro and in vivo.
Bianca J. Lee; Jacob A. Boyer; G. Leslie Burnett; Arun P. Thottumkara; Nidhi Tibrewal; Stacy L. Wilson; Tientien Hsieh; Abby Marquez; Edward G. Lorenzana; James W. Evans; Laura Hulea; Gert Kiss; Hui Liu; Dong Lee; Ola Larsson; Shannon McLaughlan; Ivan Topisirovic; ZhengPing Wang; Zhican Wang; Yongyuan Zhao; David Wildes; James B. Aggen; Mallika Singh; Adrian L. Gill; Jacqueline A. M. Smith; Neal Rosen. Selective inhibitors of mTORC1 activate 4EBP1 and suppress tumor growth. Nature Chemical Biology 2021, 1 -10.
AMA StyleBianca J. Lee, Jacob A. Boyer, G. Leslie Burnett, Arun P. Thottumkara, Nidhi Tibrewal, Stacy L. Wilson, Tientien Hsieh, Abby Marquez, Edward G. Lorenzana, James W. Evans, Laura Hulea, Gert Kiss, Hui Liu, Dong Lee, Ola Larsson, Shannon McLaughlan, Ivan Topisirovic, ZhengPing Wang, Zhican Wang, Yongyuan Zhao, David Wildes, James B. Aggen, Mallika Singh, Adrian L. Gill, Jacqueline A. M. Smith, Neal Rosen. Selective inhibitors of mTORC1 activate 4EBP1 and suppress tumor growth. Nature Chemical Biology. 2021; ():1-10.
Chicago/Turabian StyleBianca J. Lee; Jacob A. Boyer; G. Leslie Burnett; Arun P. Thottumkara; Nidhi Tibrewal; Stacy L. Wilson; Tientien Hsieh; Abby Marquez; Edward G. Lorenzana; James W. Evans; Laura Hulea; Gert Kiss; Hui Liu; Dong Lee; Ola Larsson; Shannon McLaughlan; Ivan Topisirovic; ZhengPing Wang; Zhican Wang; Yongyuan Zhao; David Wildes; James B. Aggen; Mallika Singh; Adrian L. Gill; Jacqueline A. M. Smith; Neal Rosen. 2021. "Selective inhibitors of mTORC1 activate 4EBP1 and suppress tumor growth." Nature Chemical Biology , no. : 1-10.
Each year hundreds of millions of birds cross the Atlantic Ocean during the peak of tropical cyclone activity. The extent and consequences of migrant-storm interactions remain unknown. We tracked whimbrels from two populations (Mackenzie Delta; Hudson Bay) to examine overlap between migration routes and storm activity and both the frequency and consequence of storm encounters. Here we show that Mackenzie Delta and Hudson Bay whimbrels follow different routes across the ocean and experience dramatically different rates of storm encounters. Mackenzie Delta whimbrels departed North America from Atlantic Canada, made long ( $$\bar{x}$$ x ¯ = 5440 ± 120.3 km) nonstop flights far out to sea that took several days ( $$\bar{x}$$ x ¯ = 6.1 ± 0.18) to complete and encountered storms during 3 of 22 crossings. Hudson Bay whimbrels departed North America from the south Atlantic Coast, made shorter ( $$\bar{x}$$ x ¯ = 3643 ± 196.2 km) nonstop flights across the Caribbean Basin that took less time ( $$\bar{x}$$ x ¯ = 4.5 ± 0.29) to complete and encountered storms during 13 of 18 crossings. More than half of Hudson Bay storm encounters resulted in groundings on Caribbean islands. Grounded birds required longer ( $$\bar{x}$$ x ¯ = 30.4 ± 5.32 days) to complete trans-Atlantic crossings and three were lost including 2 to hunters and 1 to a predator. One of the Mackenzie Delta whimbrels was lost at sea while crossing the Intertropical Convergence Zone. Whimbrels use two contrasting strategies to cross the Atlantic including (1) a long nonstop flight around the core of storm activity with a low likelihood of encountering storms but no safety net and (2) a shorter flight through the heart of Hurricane Alley with a high likelihood of encountering storms and a safety network of islands to use in the event of an encounter. Demographic consequences of storm encounters will likely play a role in the ongoing evolution of trans-Atlantic migration pathways as global temperatures continue to rise.
Bryan D. Watts; Fletcher M. Smith; Chance Hines; Laura Duval; Diana J. Hamilton; Tim Keyes; Julie Paquet; Lisa Pirie-Dominix; Jennie Rausch; Barry Truitt; Brad Winn; Paul Woodard. Whimbrel populations differ in trans-atlantic pathways and cyclone encounters. Scientific Reports 2021, 11, 1 -9.
AMA StyleBryan D. Watts, Fletcher M. Smith, Chance Hines, Laura Duval, Diana J. Hamilton, Tim Keyes, Julie Paquet, Lisa Pirie-Dominix, Jennie Rausch, Barry Truitt, Brad Winn, Paul Woodard. Whimbrel populations differ in trans-atlantic pathways and cyclone encounters. Scientific Reports. 2021; 11 (1):1-9.
Chicago/Turabian StyleBryan D. Watts; Fletcher M. Smith; Chance Hines; Laura Duval; Diana J. Hamilton; Tim Keyes; Julie Paquet; Lisa Pirie-Dominix; Jennie Rausch; Barry Truitt; Brad Winn; Paul Woodard. 2021. "Whimbrel populations differ in trans-atlantic pathways and cyclone encounters." Scientific Reports 11, no. 1: 1-9.
Diseases caused by heteroplasmic mitochondrial DNA mutations have no effective treatment or cure. In recent years, DNA editing enzymes were tested as tools to eliminate mutant mtDNA in heteroplasmic cells and tissues. Mitochondrial-targeted restriction endonucleases, ZFNs, and TALENs have been successful in shifting mtDNA heteroplasmy, but they all have drawbacks as gene therapy reagents, including: large size, heterodimeric nature, inability to distinguish single base changes, or low flexibility and effectiveness. Here we report the adaptation of a gene editing platform based on the I-CreI meganuclease known as ARCUS®. These mitochondrial-targeted meganucleases (mitoARCUS) have a relatively small size, are monomeric, and can recognize sequences differing by as little as one base pair. We show the development of a mitoARCUS specific for the mouse m.5024C>T mutation in the mt-tRNAAla gene and its delivery to mice intravenously using AAV9 as a vector. Liver and skeletal muscle show robust elimination of mutant mtDNA with concomitant restoration of mt-tRNAAla levels. We conclude that mitoARCUS is a potential powerful tool for the elimination of mutant mtDNA.
Ugne Zekonyte; Sandra R. Bacman; Jeff Smith; Wendy Shoop; Claudia V. Pereira; Ginger Tomberlin; James Stewart; Derek Jantz; Carlos T. Moraes. Mitochondrial targeted meganuclease as a platform to eliminate mutant mtDNA in vivo. Nature Communications 2021, 12, 1 -11.
AMA StyleUgne Zekonyte, Sandra R. Bacman, Jeff Smith, Wendy Shoop, Claudia V. Pereira, Ginger Tomberlin, James Stewart, Derek Jantz, Carlos T. Moraes. Mitochondrial targeted meganuclease as a platform to eliminate mutant mtDNA in vivo. Nature Communications. 2021; 12 (1):1-11.
Chicago/Turabian StyleUgne Zekonyte; Sandra R. Bacman; Jeff Smith; Wendy Shoop; Claudia V. Pereira; Ginger Tomberlin; James Stewart; Derek Jantz; Carlos T. Moraes. 2021. "Mitochondrial targeted meganuclease as a platform to eliminate mutant mtDNA in vivo." Nature Communications 12, no. 1: 1-11.
The publisher regrets that this article has been temporarily removed. A replacement will appear as soon as possible in which the reason for the removal of the article will be specified, or the article will be reinstated. The full Elsevier Policy on Article Withdrawal can be found at https://www.elsevier.com/about/our-business/policies/article-withdrawal
Megan A. Smith; Emily A. Burger; Alejandra Castanon; Inge M.C.M. de Kok; Sharon J.B. Hanley; Matejka Rebolj; Michaela T. Hall; Erik E.L. Jansen; James Killen; Xavier O'Farrell; Jane J. Kim; Karen Canfell. Impact of disruptions and recovery for established cervical screening programs across a range of high-income country program designs, using COVID-19 as an example: A modelled analysis. Preventive Medicine 2021, 151, 106623 .
AMA StyleMegan A. Smith, Emily A. Burger, Alejandra Castanon, Inge M.C.M. de Kok, Sharon J.B. Hanley, Matejka Rebolj, Michaela T. Hall, Erik E.L. Jansen, James Killen, Xavier O'Farrell, Jane J. Kim, Karen Canfell. Impact of disruptions and recovery for established cervical screening programs across a range of high-income country program designs, using COVID-19 as an example: A modelled analysis. Preventive Medicine. 2021; 151 ():106623.
Chicago/Turabian StyleMegan A. Smith; Emily A. Burger; Alejandra Castanon; Inge M.C.M. de Kok; Sharon J.B. Hanley; Matejka Rebolj; Michaela T. Hall; Erik E.L. Jansen; James Killen; Xavier O'Farrell; Jane J. Kim; Karen Canfell. 2021. "Impact of disruptions and recovery for established cervical screening programs across a range of high-income country program designs, using COVID-19 as an example: A modelled analysis." Preventive Medicine 151, no. : 106623.
The NF‐κB transcription factor c‐Rel is a critical regulator of regulatory T cell (Treg) ontogeny, controlling multiple points of the stepwise developmental pathway. Here, we found that the thymic Treg development defect in c‐Rel‐deficient (cRel–/–) mice is quantitative not qualitative based on analyses of T cell receptor (TCR) repertoire and TCR signalling strength. However, these parameters were altered in the thymic Treg‐precursor population, which is also markedly diminished in cRel–/– mice. Moreover, c‐Rel governs the transcriptional programme of both thymic and peripheral Tregs, controlling a core of genes involved with immune signalling, and separately in the periphery, cell cycle progression. Lastly, the immune suppressive function of peripheral cRel–/– tTregs is diminished in a lymphopenic model of T cell proliferation and is associated with decreased stability of Foxp3 expression. Collectively, we show that c‐Rel is a transcriptional regulator that controls multiple aspects of Treg development, differentiation and function via distinct mechanisms. This article is protected by copyright. All rights reserved
Thomas S. Fulford; Raelene Grumont; Rushika C. Wirasinha; Darcy Ellis; Adele Barugahare; Stephen J. Turner; Haroon Naeem; David Powell; Paul A. Lyons; Kenneth G. C. Smith; Sebastian Scheer; Colby Zaph; Ulf Klein; Stephen R. Daley; Steve Gerondakis. c‐Rel employs multiple mechanisms to promote the thymic development and peripheral function of regulatory T cells in mice. European Journal of Immunology 2021, 1 .
AMA StyleThomas S. Fulford, Raelene Grumont, Rushika C. Wirasinha, Darcy Ellis, Adele Barugahare, Stephen J. Turner, Haroon Naeem, David Powell, Paul A. Lyons, Kenneth G. C. Smith, Sebastian Scheer, Colby Zaph, Ulf Klein, Stephen R. Daley, Steve Gerondakis. c‐Rel employs multiple mechanisms to promote the thymic development and peripheral function of regulatory T cells in mice. European Journal of Immunology. 2021; ():1.
Chicago/Turabian StyleThomas S. Fulford; Raelene Grumont; Rushika C. Wirasinha; Darcy Ellis; Adele Barugahare; Stephen J. Turner; Haroon Naeem; David Powell; Paul A. Lyons; Kenneth G. C. Smith; Sebastian Scheer; Colby Zaph; Ulf Klein; Stephen R. Daley; Steve Gerondakis. 2021. "c‐Rel employs multiple mechanisms to promote the thymic development and peripheral function of regulatory T cells in mice." European Journal of Immunology , no. : 1.
Weaning from mechanical ventilation covers the process of liberating the patient from mechanical support and removing the associated endotracheal tube. The management of weaning from mechanical ventilation comprises a significant proportion of the care of critically ill intubated patients in Intensive Care Units (ICUs). Both prolonged dependence on mechanical ventilation and premature extubation expose patients to an increased risk of complications and increased health care costs. This work aims to develop a decision support model using routinely-recorded patient information to predict extubation readiness. In order to do so, we have deployed Convolutional Neural Networks (CNN) to predict the most appropriate treatment action in the next hour for a given patient state, using historical ICU data extracted from MIMIC-III. The model achieved 86% accuracy and 0.94 area under the receiver operating characteristic curve (AUC-ROC). We also performed feature importance analysis for the CNN model and interpreted these features using the DeepLIFT method. The results of the feature importance assessment show that the CNN model makes predictions using clinically meaningful and appropriate features. Finally, we implemented counterfactual explanations for the CNN model. This can help clinicians understand what feature changes for a particular patient would lead to a desirable outcome, i.e. readiness to extubate.
Yan Jia; Chaitanya Kaul; Tom Lawton; Roderick Murray-Smith; Ibrahim Habli. Prediction of weaning from mechanical ventilation using Convolutional Neural Networks. Artificial Intelligence in Medicine 2021, 117, 102087 .
AMA StyleYan Jia, Chaitanya Kaul, Tom Lawton, Roderick Murray-Smith, Ibrahim Habli. Prediction of weaning from mechanical ventilation using Convolutional Neural Networks. Artificial Intelligence in Medicine. 2021; 117 ():102087.
Chicago/Turabian StyleYan Jia; Chaitanya Kaul; Tom Lawton; Roderick Murray-Smith; Ibrahim Habli. 2021. "Prediction of weaning from mechanical ventilation using Convolutional Neural Networks." Artificial Intelligence in Medicine 117, no. : 102087.
The BCL-2 family of proteins (including the prosurvival proteins BCL-2, BCL-XL, and MCL-1) is an important target for the development of novel anticancer therapeutics. Despite the challenges of targeting protein–protein interaction (PPI) interfaces with small molecules, a number of inhibitors (called BH3 mimetics) have entered the clinic and the BCL-2 inhibitor, ABT-199/venetoclax, is already proving transformative. For BCL-XL, new validated chemical series are desirable. Here, we outline the crystallography-guided development of a structurally distinct series of BCL-XL/BCL-2 inhibitors based on a benzoylurea scaffold, originally proposed as α-helix mimetics. We describe structure-guided exploration of a cryptic “p5” pocket identified in BCL-XL. This work yields novel inhibitors with submicromolar binding, with marked selectivity toward BCL-XL. Extension into the hydrophobic p2 pocket yielded the most potent inhibitor in the series, binding strongly to BCL-XL and BCL-2 (nanomolar-range half-maximal inhibitory concentration (IC50)) and displaying mechanism-based killing in cells engineered to depend on BCL-XL for survival.
Michael J. Roy; Amelia Vom; Toru Okamoto; Brian J. Smith; Richard W. Birkinshaw; Hong Yang; Houda Abdo; Christine. A. White; David Segal; David C. S. Huang; Jonathan B. Baell; Peter M. Colman; Peter E. Czabotar; Guillaume Lessene. Structure-Guided Development of Potent Benzoylurea Inhibitors of BCL-XL and BCL-2. Journal of Medicinal Chemistry 2021, 64, 5447 -5469.
AMA StyleMichael J. Roy, Amelia Vom, Toru Okamoto, Brian J. Smith, Richard W. Birkinshaw, Hong Yang, Houda Abdo, Christine. A. White, David Segal, David C. S. Huang, Jonathan B. Baell, Peter M. Colman, Peter E. Czabotar, Guillaume Lessene. Structure-Guided Development of Potent Benzoylurea Inhibitors of BCL-XL and BCL-2. Journal of Medicinal Chemistry. 2021; 64 (9):5447-5469.
Chicago/Turabian StyleMichael J. Roy; Amelia Vom; Toru Okamoto; Brian J. Smith; Richard W. Birkinshaw; Hong Yang; Houda Abdo; Christine. A. White; David Segal; David C. S. Huang; Jonathan B. Baell; Peter M. Colman; Peter E. Czabotar; Guillaume Lessene. 2021. "Structure-Guided Development of Potent Benzoylurea Inhibitors of BCL-XL and BCL-2." Journal of Medicinal Chemistry 64, no. 9: 5447-5469.
Analysis of human blood immune cells provides insights into the coordinated response to viral infections such as severe acute respiratory syndrome coronavirus 2, which causes coronavirus disease 2019 (COVID-19). We performed single-cell transcriptome, surface proteome and T and B lymphocyte antigen receptor analyses of over 780,000 peripheral blood mononuclear cells from a cross-sectional cohort of 130 patients with varying severities of COVID-19. We identified expansion of nonclassical monocytes expressing complement transcripts (CD16 + C1QA/B/C + ) that sequester platelets and were predicted to replenish the alveolar macrophage pool in COVID-19. Early, uncommitted CD34+ hematopoietic stem/progenitor cells were primed toward megakaryopoiesis, accompanied by expanded megakaryocyte-committed progenitors and increased platelet activation. Clonally expanded CD8+ T cells and an increased ratio of CD8+ effector T cells to effector memory T cells characterized severe disease, while circulating follicular helper T cells accompanied mild disease. We observed a relative loss of IgA2 in symptomatic disease despite an overall expansion of plasmablasts and plasma cells. Our study highlights the coordinated immune response that contributes to COVID-19 pathogenesis and reveals discrete cellular components that can be targeted for therapy.
Emily Stephenson; Gary Reynolds; Rachel A. Botting; Fernando J. Calero-Nieto; Michael D. Morgan; Zewen Kelvin Tuong; Karsten Bach; Waradon Sungnak; Kaylee B. Worlock; Masahiro Yoshida; Natsuhiko Kumasaka; Katarzyna Kania; Justin Engelbert; Bayanne Olabi; Jarmila Stremenova Spegarova; Nicola K. Wilson; Nicole Mende; Laura Jardine; Louis C. S. Gardner; Issac Goh; Dave Horsfall; Jim McGrath; Simone Webb; Michael W. Mather; Rik G. H. Lindeboom; Emma Dann; Ni Huang; Krzysztof Polanski; Elena Prigmore; Florian Gothe; Jonathan Scott; Rebecca P. Payne; Kenneth F. Baker; Aidan T. Hanrath; Ina C. D. Schim van der Loeff; Andrew S. Barr; Amada Sanchez-Gonzalez; Laura Bergamaschi; Federica Mescia; Josephine L. Barnes; Eliz Kilich; Angus de Wilton; Anita Saigal; Aarash Saleh; Sam M. Janes; Claire M. Smith; Nusayhah Gopee; Caroline Wilson; Paul Coupland; Jonathan M. Coxhead; Vladimir Yu Kiselev; Stijn van Dongen; Jaume Bacardit; Hamish W. King; Anthony J. Rostron; A. John Simpson; Sophie Hambleton; Elisa Laurenti; Paul A. Lyons; Kerstin B. Meyer; Marko Z. Nikolić; Christopher J. A. Duncan; Kenneth G. C. Smith; Sarah A. Teichmann; Menna R. Clatworthy; John C. Marioni; Berthold Göttgens; Muzlifah Haniffa. Single-cell multi-omics analysis of the immune response in COVID-19. Nature Medicine 2021, 27, 904 -916.
AMA StyleEmily Stephenson, Gary Reynolds, Rachel A. Botting, Fernando J. Calero-Nieto, Michael D. Morgan, Zewen Kelvin Tuong, Karsten Bach, Waradon Sungnak, Kaylee B. Worlock, Masahiro Yoshida, Natsuhiko Kumasaka, Katarzyna Kania, Justin Engelbert, Bayanne Olabi, Jarmila Stremenova Spegarova, Nicola K. Wilson, Nicole Mende, Laura Jardine, Louis C. S. Gardner, Issac Goh, Dave Horsfall, Jim McGrath, Simone Webb, Michael W. Mather, Rik G. H. Lindeboom, Emma Dann, Ni Huang, Krzysztof Polanski, Elena Prigmore, Florian Gothe, Jonathan Scott, Rebecca P. Payne, Kenneth F. Baker, Aidan T. Hanrath, Ina C. D. Schim van der Loeff, Andrew S. Barr, Amada Sanchez-Gonzalez, Laura Bergamaschi, Federica Mescia, Josephine L. Barnes, Eliz Kilich, Angus de Wilton, Anita Saigal, Aarash Saleh, Sam M. Janes, Claire M. Smith, Nusayhah Gopee, Caroline Wilson, Paul Coupland, Jonathan M. Coxhead, Vladimir Yu Kiselev, Stijn van Dongen, Jaume Bacardit, Hamish W. King, Anthony J. Rostron, A. John Simpson, Sophie Hambleton, Elisa Laurenti, Paul A. Lyons, Kerstin B. Meyer, Marko Z. Nikolić, Christopher J. A. Duncan, Kenneth G. C. Smith, Sarah A. Teichmann, Menna R. Clatworthy, John C. Marioni, Berthold Göttgens, Muzlifah Haniffa. Single-cell multi-omics analysis of the immune response in COVID-19. Nature Medicine. 2021; 27 (5):904-916.
Chicago/Turabian StyleEmily Stephenson; Gary Reynolds; Rachel A. Botting; Fernando J. Calero-Nieto; Michael D. Morgan; Zewen Kelvin Tuong; Karsten Bach; Waradon Sungnak; Kaylee B. Worlock; Masahiro Yoshida; Natsuhiko Kumasaka; Katarzyna Kania; Justin Engelbert; Bayanne Olabi; Jarmila Stremenova Spegarova; Nicola K. Wilson; Nicole Mende; Laura Jardine; Louis C. S. Gardner; Issac Goh; Dave Horsfall; Jim McGrath; Simone Webb; Michael W. Mather; Rik G. H. Lindeboom; Emma Dann; Ni Huang; Krzysztof Polanski; Elena Prigmore; Florian Gothe; Jonathan Scott; Rebecca P. Payne; Kenneth F. Baker; Aidan T. Hanrath; Ina C. D. Schim van der Loeff; Andrew S. Barr; Amada Sanchez-Gonzalez; Laura Bergamaschi; Federica Mescia; Josephine L. Barnes; Eliz Kilich; Angus de Wilton; Anita Saigal; Aarash Saleh; Sam M. Janes; Claire M. Smith; Nusayhah Gopee; Caroline Wilson; Paul Coupland; Jonathan M. Coxhead; Vladimir Yu Kiselev; Stijn van Dongen; Jaume Bacardit; Hamish W. King; Anthony J. Rostron; A. John Simpson; Sophie Hambleton; Elisa Laurenti; Paul A. Lyons; Kerstin B. Meyer; Marko Z. Nikolić; Christopher J. A. Duncan; Kenneth G. C. Smith; Sarah A. Teichmann; Menna R. Clatworthy; John C. Marioni; Berthold Göttgens; Muzlifah Haniffa. 2021. "Single-cell multi-omics analysis of the immune response in COVID-19." Nature Medicine 27, no. 5: 904-916.
Initially, three-dose schedules were recommended for vaccines against human papillomavirus (HPV); subsequently recommendations have been updated to a schedule of two doses delivered at least six (minimum five) months apart for those aged 151 days apart)), or at least one dose; ii) for each birth cohort offered vaccination, the percentage of the initially targeted cohort with a complete course, or at least one dose (reflecting uptake at the time the vaccine was offered); and iii) among two-dose only recipients, the percentage who missed each of three school visits. Including those with two sufficiently-spaced doses increased end-2017 coverage by 1.3–2.8% points in those vaccinated at school. Including those with at least one dose increased coverage further, by 6.5–9.5% points, mostly due to including those receiving multiple too-closely-spaced doses. One-dose coverage reached 90.9% and 86.9% in females and males respectively born in 2002. Among those vaccinated at school who received only two doses, it was much more common to miss the first (31.0% females; 32.5% males) or the third visit in the school year (54.6% females; 48.6% males) than the second (14.1% females; 18.8% males). Including those with two sufficiently-spaced doses has a very modest impact on HPV vaccine coverage in Australia. If receiving at least one dose offers substantial protection, these data suggest that the school-based program is now achieving close to 90% coverage on this measure.
Megan A. Smith; Karen Winch; Karen Canfell; Julia Ml. Brotherton. Effective HPV vaccination coverage in Australia by number of doses and two-dose spacing: What if one or two doses are sufficient? Tumour Virus Research 2021, 11, 200216 .
AMA StyleMegan A. Smith, Karen Winch, Karen Canfell, Julia Ml. Brotherton. Effective HPV vaccination coverage in Australia by number of doses and two-dose spacing: What if one or two doses are sufficient? Tumour Virus Research. 2021; 11 ():200216.
Chicago/Turabian StyleMegan A. Smith; Karen Winch; Karen Canfell; Julia Ml. Brotherton. 2021. "Effective HPV vaccination coverage in Australia by number of doses and two-dose spacing: What if one or two doses are sufficient?" Tumour Virus Research 11, no. : 200216.
Chronic pain is highly prevalent worldwide and imparts a significant socioeconomic and public health burden. Factors influencing susceptibility to, and mechanisms of, chronic pain development, are not fully understood, but sex is thought to play a significant role, and chronic pain is more prevalent in women than in men. To investigate sex differences in chronic pain, we carried out a sex-stratified genome-wide association study of Multisite Chronic Pain (MCP), a derived chronic pain phenotype, in UK Biobank on 178,556 men and 209,093 women, as well as investigating sex-specific genetic correlations with a range of psychiatric, autoimmune and anthropometric phenotypes and the relationship between sex-specific polygenic risk scores for MCP and chronic widespread pain. We also assessed whether MCP-associated genes showed expression pattern enrichment across tissues. A total of 123 SNPs at five independent loci were significantly associated with MCP in men. In women, a total of 286 genome-wide significant SNPs at ten independent loci were discovered. Meta-analysis of sex-stratified GWAS outputs revealed a further 87 independent associated SNPs. Gene-level analyses revealed sex-specific MCP associations, with 31 genes significantly associated in females, 37 genes associated in males, and a single gene, DCC, associated in both sexes. We found evidence for sex-specific pleiotropy and risk for MCP was found to be associated with chronic widespread pain in a sex-differential manner. Male and female MCP were highly genetically correlated, but at an rg of significantly less than 1 (0.92). All 37 male MCP-associated genes and all but one of 31 female MCP-associated genes were found to be expressed in the dorsal root ganglion, and there was a degree of enrichment for expression in sex-specific tissues. Overall, the findings indicate that sex differences in chronic pain exist at the SNP, gene and transcript abundance level, and highlight possible sex-specific pleiotropy for MCP. Results support the proposition of a strong central nervous-system component to chronic pain in both sexes, additionally highlighting a potential role for the DRG and nociception.
Keira J. A. Johnston; Joey Ward; Pradipta R. Ray; Mark J. Adams; Andrew M. McIntosh; Blair H. Smith; Rona J. Strawbridge; Theodore J. Price; Daniel J. Smith; Barbara I. Nicholl; Mark E. S. Bailey. Sex-stratified genome-wide association study of multisite chronic pain in UK Biobank. PLOS Genetics 2021, 17, e1009428 .
AMA StyleKeira J. A. Johnston, Joey Ward, Pradipta R. Ray, Mark J. Adams, Andrew M. McIntosh, Blair H. Smith, Rona J. Strawbridge, Theodore J. Price, Daniel J. Smith, Barbara I. Nicholl, Mark E. S. Bailey. Sex-stratified genome-wide association study of multisite chronic pain in UK Biobank. PLOS Genetics. 2021; 17 (4):e1009428.
Chicago/Turabian StyleKeira J. A. Johnston; Joey Ward; Pradipta R. Ray; Mark J. Adams; Andrew M. McIntosh; Blair H. Smith; Rona J. Strawbridge; Theodore J. Price; Daniel J. Smith; Barbara I. Nicholl; Mark E. S. Bailey. 2021. "Sex-stratified genome-wide association study of multisite chronic pain in UK Biobank." PLOS Genetics 17, no. 4: e1009428.
A Correction to this paper has been published: https://doi.org/10.1038/s41467-021-22411-w
David M. Howard; Mark J. Adams; Masoud Shirali; Toni-Kim Clarke; Riccardo E. Marioni; Gail Davies; Jonathan R. I. Coleman; Clara Alloza; Xueyi Shen; Miruna C. Barbu; Eleanor M. Wigmore; Jude Gibson; Saskia P. Hagenaars; Cathryn M. Lewis; Joey Ward; Daniel J. Smith; Patrick F. Sullivan; Chris S. Haley; Gerome Breen; Ian J. Deary; Andrew M. McIntosh. Author Correction: Genome-wide association study of depression phenotypes in UK Biobank identifies variants in excitatory synaptic pathways. Nature Communications 2021, 12, 1 -1.
AMA StyleDavid M. Howard, Mark J. Adams, Masoud Shirali, Toni-Kim Clarke, Riccardo E. Marioni, Gail Davies, Jonathan R. I. Coleman, Clara Alloza, Xueyi Shen, Miruna C. Barbu, Eleanor M. Wigmore, Jude Gibson, Saskia P. Hagenaars, Cathryn M. Lewis, Joey Ward, Daniel J. Smith, Patrick F. Sullivan, Chris S. Haley, Gerome Breen, Ian J. Deary, Andrew M. McIntosh. Author Correction: Genome-wide association study of depression phenotypes in UK Biobank identifies variants in excitatory synaptic pathways. Nature Communications. 2021; 12 (1):1-1.
Chicago/Turabian StyleDavid M. Howard; Mark J. Adams; Masoud Shirali; Toni-Kim Clarke; Riccardo E. Marioni; Gail Davies; Jonathan R. I. Coleman; Clara Alloza; Xueyi Shen; Miruna C. Barbu; Eleanor M. Wigmore; Jude Gibson; Saskia P. Hagenaars; Cathryn M. Lewis; Joey Ward; Daniel J. Smith; Patrick F. Sullivan; Chris S. Haley; Gerome Breen; Ian J. Deary; Andrew M. McIntosh. 2021. "Author Correction: Genome-wide association study of depression phenotypes in UK Biobank identifies variants in excitatory synaptic pathways." Nature Communications 12, no. 1: 1-1.
Intracisternal A-particles (IAPs) are endogenous retroviruses (ERVs) responsible for most insertional mutations in the mouse. Full-length IAPs harbour genes flanked by long terminal repeats (LTRs). Here, we identify a solo LTR IAP variant (Iap5-1solo ) recently formed in the inbred C57BL/6J mouse strain. In contrast to the C57BL/6J full-length IAP at this locus (Iap5-1full ), Iap5-1solo lacks DNA methylation and H3K9 trimethylation. The distinct DNA methylation levels between the two alleles are established during preimplantation development, likely due to loss of KRAB zinc finger protein binding at the Iap5-1solo variant. Iap5-1solo methylation increases and becomes more variable in a hybrid genetic background yet is unresponsive to maternal dietary methyl supplementation. Differential epigenetic modification of the two variants is associated with metabolic differences and tissue-specific changes in adjacent gene expression. Our characterisation of Iap5-1 as a genetically induced epiallele with functional consequences establishes a new model to study transposable element repression and host-element co-evolution.
Tessa M Bertozzi; Nozomi Takahashi; Geula Hanin; Anastasiya Kazachenka; Anne C Ferguson-Smith. A spontaneous genetically induced epiallele at a retrotransposon shapes host genome function. eLife 2021, 10, 1 .
AMA StyleTessa M Bertozzi, Nozomi Takahashi, Geula Hanin, Anastasiya Kazachenka, Anne C Ferguson-Smith. A spontaneous genetically induced epiallele at a retrotransposon shapes host genome function. eLife. 2021; 10 ():1.
Chicago/Turabian StyleTessa M Bertozzi; Nozomi Takahashi; Geula Hanin; Anastasiya Kazachenka; Anne C Ferguson-Smith. 2021. "A spontaneous genetically induced epiallele at a retrotransposon shapes host genome function." eLife 10, no. : 1.
The aqueous solubility is predicted here using quantitative structure property relationship (QSPR) models. In this study, we examine whether descriptors that individually yield favorable models for the prediction of the Gibbs energy of solvation and sublimation can be used in combination with octanol-water partition coefficient to produce QSPR models for the prediction of aqueous solubility. Based on this strategy, applied to seven distinct datasets, all models exhibited an R2 greater than 0.7 and Q2 greater than 0.6 for the estimation of aqueous solubility. We also determined how uncoupling the descriptors used to create QSPR models in the prediction of Gibbs energy of sublimation yielded an improved model. Model refinement using an artificial neural network applying the same descriptors generated significantly better models with improved R2 and standard deviation.
Nastaran Meftahi; Michael L. Walker; Brian J. Smith. Predicting aqueous solubility by QSPR modeling. Journal of Molecular Graphics and Modelling 2021, 106, 107901 .
AMA StyleNastaran Meftahi, Michael L. Walker, Brian J. Smith. Predicting aqueous solubility by QSPR modeling. Journal of Molecular Graphics and Modelling. 2021; 106 ():107901.
Chicago/Turabian StyleNastaran Meftahi; Michael L. Walker; Brian J. Smith. 2021. "Predicting aqueous solubility by QSPR modeling." Journal of Molecular Graphics and Modelling 106, no. : 107901.