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797 results on '"Medical Research Council (UK)"'

1. A compendium of genetic regulatory effects across pig tissues

Author: National Natural Science Foundation of China, National Key Research and Development Program (China), Guangdong Province, National Supercomputer Center in Guangzhou, Earmarked Fund for China Agriculture Research System, Health Data Research UK, European Commission, Department of Agriculture (US), National Institute of Food and Agriculture (US), Agricultural Research Service (US), Medical Research Council (UK), Australian Research Council, Ballester, María [0000-0002-5413-4640], Crespo-Piazuelo, Daniel [0000-0001-7896-2507], Gòdia, Marta [0000-0002-0439-4014], Teng, Jinyan, Gao, Yahui, Yin, Hongwei, Bai, Zhonghao, Liu, Shuli, Zeng, Haonan, Bai, Lijing, Cai, Zexi, Zhao, Bingru, Li, Xiujin, Xu, Zhiting, Lin, Qing, Pan, Zhangyuan, Yang, Wenjing, Yu, Xiaoshan, Guan, Dailu, Hou, Yali, Keel, Brittney N., Rohrer, Gary A., Lindholm-Perry, Amanda K., Oliver, William T., Ballester, María, Crespo-Piazuelo, Daniel, Quintanilla, Raquel, Canela-Xandri, Oriol, Rawlik, Konrad, Xia, Charley, Yao, Yuelin, Zhao, Qianyi, Yao, Wenye, Yang, Liu, Li, Houcheng, Zhang, Huicong, Liao, Wang, Chen, Tianshuo, Karlskov-Mortensen, Peter, Fredholm, Merete, Amills, Marcel, Clop, Alex, Giuffra, Elisabetta, Wu, Jun, Cai, Xiaodian, Diao, Shuqi, Pan, Xiangchun, Wei, Chen, Li, Jinghui, Cheng, Hao, Wang, Sheng, Su, Guosheng, Sahana, Goutam, Lund, Mogens Sandø, Dekkers, Jack C. M., Kramer, Luke, Tuggle, Christopher K., Corbett, Ryan, Groenen, Martien A. M., Madsen, Ole, Gòdia, Marta, Rocha, Dominique, Charles, Mathieu, Li, Cong-Jun, Pausch, Hubert, Hu, Xiaoxiang, Frantz, Laurent, Luo, Yonglun, Lin, Lin, Zhou, Zhongyin, Zhang, Zhe, Chen, Zitao, Cui, Leilei, Xiang, Ruidong, Shen, Xia, Li, Pinghua, Huang, Ruihua, Tang, Guoqing, Li, Mingzhou, Zhao, Yunxiang, Yi, Guoqiang, Tang, Zhonglin, Jiang, Jicai, Zhao, Fuping, Yuan, Xiaolong, Liu, Xiaohong, Chen, Yaosheng, Xu, Xuewen, Zhao, Shuhong, Zhao, Pengju, Haley, Chris, Zhou, Huaijun, Wang, Qishan, Pan, Yuchun, Ding, Xiangdong, Ma, Li, Li, Jiaqi, Navarro, Pau, Zhang, Qin, Li, Bingjie, Tenesa, Albert, Li, Kui, Liu, George E., Fang, Lingzhao, National Natural Science Foundation of China, National Key Research and Development Program (China), Guangdong Province, National Supercomputer Center in Guangzhou, Earmarked Fund for China Agriculture Research System, Health Data Research UK, European Commission, Department of Agriculture (US), National Institute of Food and Agriculture (US), Agricultural Research Service (US), Medical Research Council (UK), Australian Research Council, Ballester, María [0000-0002-5413-4640], Crespo-Piazuelo, Daniel [0000-0001-7896-2507], Gòdia, Marta [0000-0002-0439-4014], Teng, Jinyan, Gao, Yahui, Yin, Hongwei, Bai, Zhonghao, Liu, Shuli, Zeng, Haonan, Bai, Lijing, Cai, Zexi, Zhao, Bingru, Li, Xiujin, Xu, Zhiting, Lin, Qing, Pan, Zhangyuan, Yang, Wenjing, Yu, Xiaoshan, Guan, Dailu, Hou, Yali, Keel, Brittney N., Rohrer, Gary A., Lindholm-Perry, Amanda K., Oliver, William T., Ballester, María, Crespo-Piazuelo, Daniel, Quintanilla, Raquel, Canela-Xandri, Oriol, Rawlik, Konrad, Xia, Charley, Yao, Yuelin, Zhao, Qianyi, Yao, Wenye, Yang, Liu, Li, Houcheng, Zhang, Huicong, Liao, Wang, Chen, Tianshuo, Karlskov-Mortensen, Peter, Fredholm, Merete, Amills, Marcel, Clop, Alex, Giuffra, Elisabetta, Wu, Jun, Cai, Xiaodian, Diao, Shuqi, Pan, Xiangchun, Wei, Chen, Li, Jinghui, Cheng, Hao, Wang, Sheng, Su, Guosheng, Sahana, Goutam, Lund, Mogens Sandø, Dekkers, Jack C. M., Kramer, Luke, Tuggle, Christopher K., Corbett, Ryan, Groenen, Martien A. M., Madsen, Ole, Gòdia, Marta, Rocha, Dominique, Charles, Mathieu, Li, Cong-Jun, Pausch, Hubert, Hu, Xiaoxiang, Frantz, Laurent, Luo, Yonglun, Lin, Lin, Zhou, Zhongyin, Zhang, Zhe, Chen, Zitao, Cui, Leilei, Xiang, Ruidong, Shen, Xia, Li, Pinghua, Huang, Ruihua, Tang, Guoqing, Li, Mingzhou, Zhao, Yunxiang, Yi, Guoqiang, Tang, Zhonglin, Jiang, Jicai, Zhao, Fuping, Yuan, Xiaolong, Liu, Xiaohong, Chen, Yaosheng, Xu, Xuewen, Zhao, Shuhong, Zhao, Pengju, Haley, Chris, Zhou, Huaijun, Wang, Qishan, Pan, Yuchun, Ding, Xiangdong, Ma, Li, Li, Jiaqi, Navarro, Pau, Zhang, Qin, Li, Bingjie, Tenesa, Albert, Li, Kui, Liu, George E., and Fang, Lingzhao
Abstract: The Farm Animal Genotype-Tissue Expression (FarmGTEx) project has been established to develop a public resource of genetic regulatory variants in livestock, which is essential for linking genetic polymorphisms to variation in phenotypes, helping fundamental biological discovery and exploitation in animal breeding and human biomedicine. Here we show results from the pilot phase of PigGTEx by processing 5,457 RNA-sequencing and 1,602 whole-genome sequencing samples passing quality control from pigs. We build a pig genotype imputation panel and associate millions of genetic variants with five types of transcriptomic phenotypes in 34 tissues. We evaluate tissue specificity of regulatory effects and elucidate molecular mechanisms of their action using multi-omics data. Leveraging this resource, we decipher regulatory mechanisms underlying 207 pig complex phenotypes and demonstrate the similarity of pigs to humans in gene expression and the genetic regulation behind complex phenotypes, supporting the importance of pigs as a human biomedical model.
Published: 2024

2. A Machine Learning Framework to Identify the Correlates of Disease Severity in Acute Arbovirus Infection

Author: University of Glasgow, Wellcome Trust, European Commission, Ministero della Salute, German Research Foundation, Medical Research Council (UK), Herder, Vanessa, Caporale, Marco, MacLean, Osacr A., Pintus, Davide, Huang, Xinyi, Nomikou, Kyriaki, Palmalux, Natasha, Nichols, Jenna, Scivoli, Rosario, Boutell, Chris, Taggart, Aislynn, Allan, Jay, Malik, Haris, Ilia, Georgios, Gu, Quan, Ronchi, Gaetano Federico, Furnon, Wilhelm, Zientara, Stephan, Bréard, Emmanuel, Antonucci, Daniela, Capista, Sara, Giansante, Daniele, Cocco, Antonio, Mercante, Maria Teresa, Di Ventura, Mauro, Da Silva Filipe, Ana, Puggioni, Giantonella, Sevilla, Noemí, Stewart, Meredith E., Ligios, Ciriaco, Palmarini, Massimo, University of Glasgow, Wellcome Trust, European Commission, Ministero della Salute, German Research Foundation, Medical Research Council (UK), Herder, Vanessa, Caporale, Marco, MacLean, Osacr A., Pintus, Davide, Huang, Xinyi, Nomikou, Kyriaki, Palmalux, Natasha, Nichols, Jenna, Scivoli, Rosario, Boutell, Chris, Taggart, Aislynn, Allan, Jay, Malik, Haris, Ilia, Georgios, Gu, Quan, Ronchi, Gaetano Federico, Furnon, Wilhelm, Zientara, Stephan, Bréard, Emmanuel, Antonucci, Daniela, Capista, Sara, Giansante, Daniele, Cocco, Antonio, Mercante, Maria Teresa, Di Ventura, Mauro, Da Silva Filipe, Ana, Puggioni, Giantonella, Sevilla, Noemí, Stewart, Meredith E., Ligios, Ciriaco, and Palmarini, Massimo
Abstract: Most viral diseases display a variable clinical outcome due to differences in virus strain virulence and/or individual host susceptibility to infection. Understanding the biological mechanisms differentiating a viral infection displaying severe clinical manifestations from its milder forms can provide the intellectual framework toward therapies and early prognostic markers. This is especially true in arbovirus infections, where most clinical cases are present as mild febrile illness. Here, we used a naturally occurring vector-borne viral disease of ruminants, bluetongue, as an experimental system to uncover the fundamental mechanisms of virus-host interactions resulting in distinct clinical outcomes. As with most viral diseases, clinical symptoms in bluetongue can vary dramatically. We reproduced experimentally distinct clinical forms of bluetongue infection in sheep using three bluetongue virus (BTV) strains (BTV-1IT2006, BTV-1IT2013 and BTV-8FRA2017). Infected animals displayed clinical signs varying from clinically unapparent, to mild and severe disease. We collected and integrated clinical, haematological, virological, and histopathological data resulting in the analyses of 332 individual parameters from each infected and uninfected control animal. We subsequently used machine learning to identify the key viral and host processes associated with disease pathogenesis. We identified five different fundamental processes affecting the severity of bluetongue: (i) virus load and replication in target organs, (ii) modulation of the host type-I IFN response, (iii) pro-inflammatory responses, (iv) vascular damage, and (v) immunosuppression. Overall, our study using an agnostic machine learning approach, can be used to prioritise the different pathogenetic mechanisms affecting the disease outcome of an arbovirus infection.
Published: 2024

3. Antagonistic interactions between phage and host factors control arbitrium lysis-lysogeny decision

Author: Ministerio de Ciencia e Innovación (España), Generalitat Valenciana, European Commission, CSIC - Plataforma Temática Interdisciplinar del CSIC Salud Global (PTI Salud Global), Medical Research Council (UK), Ministerio de Universidades (España), Biotechnology and Biological Sciences Research Council (UK), Marina, Alberto [0000-0002-1334-5273], Zamora-Caballero, Sara [0000-0003-4717-8845], Gallego del Sol, Francisca [0000-0001-9862-4505], Mancheño-Bonillo, Javier [0000-0001-5664-8752], Zamora-Caballero, Sara, Chmielowska, Cora, Quiles-Puchalt, Nuria, Brady, Aisling, Gallego del Sol, Francisca, Mancheño-Bonillo, Javier, Felipe-Ruiz, Alonso, Meijer, Wilfried J. J., Penadés, José R., Marina, Alberto, Ministerio de Ciencia e Innovación (España), Generalitat Valenciana, European Commission, CSIC - Plataforma Temática Interdisciplinar del CSIC Salud Global (PTI Salud Global), Medical Research Council (UK), Ministerio de Universidades (España), Biotechnology and Biological Sciences Research Council (UK), Marina, Alberto [0000-0002-1334-5273], Zamora-Caballero, Sara [0000-0003-4717-8845], Gallego del Sol, Francisca [0000-0001-9862-4505], Mancheño-Bonillo, Javier [0000-0001-5664-8752], Zamora-Caballero, Sara, Chmielowska, Cora, Quiles-Puchalt, Nuria, Brady, Aisling, Gallego del Sol, Francisca, Mancheño-Bonillo, Javier, Felipe-Ruiz, Alonso, Meijer, Wilfried J. J., Penadés, José R., and Marina, Alberto
Abstract: Phages can use a small-molecule communication arbitrium system to coordinate lysis-lysogeny decisions, but the underlying mechanism remains unknown. Here we determined that the arbitrium system in Bacillus subtilis phage phi3T modulates the bacterial toxin-antitoxin system MazE-MazF to regulate the phage life cycle. We show that phi3T expresses AimX and YosL, which bind to and inactivate MazF. AimX also inhibits the function of phi3T_93, a protein that promotes lysogeny by binding to MazE and releasing MazF. Overall, these mutually exclusive interactions promote the lytic cycle of the phage. After several rounds of infection, the phage-encoded AimP peptide accumulates intracellularly and inactivates the phage antiterminator AimR, a process that eliminates aimX expression from the aimP promoter. Therefore, when AimP increases, MazF activity promotes reversion back to lysogeny, since AimX is absent. Altogether, our study reveals the evolutionary strategy used by arbitrium to control lysis-lysogeny by domesticating and fine-tuning a phage-defence mechanism.
Published: 2024

4. Transcriptome-wide RNA binding analysis of C9orf72 poly(PR) dipeptides

Author: Wellcome Trust, Academy of Medical Sciences (UK), Motor Neuron Disease Association, Alzheimer's Research UK, European Research Council, Dementia Research Institute (UK), Medical Research Council (UK), Alzheimer Society, AstraZeneca, Alzheimer's Association, European Commission, Balendra, Rubika, Ruiz de los Mozos, Igor, Odeh, Hana M., Glaria, Idoia, Milioto, Carmelo, Wilson, Katherine M., Ule, Agnieszka M., Hallegger, Martina, Masino, Laura, Martin, Stephen, Patani, Rickie, Shorter, James, Ule, Jernej, Isaacs, Adrian M., Wellcome Trust, Academy of Medical Sciences (UK), Motor Neuron Disease Association, Alzheimer's Research UK, European Research Council, Dementia Research Institute (UK), Medical Research Council (UK), Alzheimer Society, AstraZeneca, Alzheimer's Association, European Commission, Balendra, Rubika, Ruiz de los Mozos, Igor, Odeh, Hana M., Glaria, Idoia, Milioto, Carmelo, Wilson, Katherine M., Ule, Agnieszka M., Hallegger, Martina, Masino, Laura, Martin, Stephen, Patani, Rickie, Shorter, James, Ule, Jernej, and Isaacs, Adrian M.
Abstract: An intronic GGGGCC repeat expansion in C9orf72 is a common genetic cause of amyotrophic lateral sclerosis and frontotemporal dementia. The repeats are transcribed in both sense and antisense directions to generate distinct dipeptide repeat proteins, of which poly(GA), poly(GR), and poly(PR) have been implicated in contributing to neurodegeneration. Poly(PR) binding to RNA may contribute to toxicity, but analysis of poly(PR)-RNA binding on a transcriptome-wide scale has not yet been carried out. We therefore performed crosslinking and immunoprecipitation (CLIP) analysis in human cells to identify the RNA binding sites of poly(PR). We found that poly(PR) binds to nearly 600 RNAs, with the sequence GAAGA enriched at the binding sites. In vitro experiments showed that poly(GAAGA) RNA binds poly(PR) with higher affinity than control RNA and induces the phase separation of poly(PR) into condensates. These data indicate that poly(PR) preferentially binds to poly(GAAGA)-containing RNAs, which may have physiological consequences.
Published: 2023

5. Discovery of senolytics using machine learning

Author: Medical Research Council (UK), Cancer Research UK, University of Edinburgh, Ministerio de Ciencia e Innovación (España), Agencia Estatal de Investigación (España), Consejo Superior de Investigaciones Científicas (España), Government of the United Kingdom, Smer-Barreto, Vanessa, Quintanilla, Andrea, Elliott, Richard J. R., Dawson, John C., Sun, Jiugeng, Campa, Víctor M., Lorente-Macías, Álvaro, Unciti-Broceta, Asier, Carragher, Neil O., Acosta, Juan C., Oyarzún, Diego A., Medical Research Council (UK), Cancer Research UK, University of Edinburgh, Ministerio de Ciencia e Innovación (España), Agencia Estatal de Investigación (España), Consejo Superior de Investigaciones Científicas (España), Government of the United Kingdom, Smer-Barreto, Vanessa, Quintanilla, Andrea, Elliott, Richard J. R., Dawson, John C., Sun, Jiugeng, Campa, Víctor M., Lorente-Macías, Álvaro, Unciti-Broceta, Asier, Carragher, Neil O., Acosta, Juan C., and Oyarzún, Diego A.
Abstract: Cellular senescence is a stress response involved in ageing and diverse disease processes including cancer, type-2 diabetes, osteoarthritis and viral infection. Despite growing interest in targeted elimination of senescent cells, only few senolytics are known due to the lack of well-characterised molecular targets. Here, we report the discovery of three senolytics using cost-effective machine learning algorithms trained solely on published data. We computationally screened various chemical libraries and validated the senolytic action of ginkgetin, periplocin and oleandrin in human cell lines under various modalities of senescence. The compounds have potency comparable to known senolytics, and we show that oleandrin has improved potency over its target as compared to best-in-class alternatives. Our approach led to several hundred-fold reduction in drug screening costs and demonstrates that artificial intelligence can take maximum advantage of small and heterogeneous drug screening data, paving the way for new open science approaches to early-stage drug discovery.
Published: 2023

6. Redox regulation of KV7 channels through EF3 hand of calmodulin

Author: Ministerio de Ciencia e Innovación (España), Agencia Estatal de Investigación (España), Wellcome Trust, Medical Research Council (UK), Eusko Jaurlaritza, Ministerio de Ciencia, Innovación y Universidades (España), Urrutia, Janire [0000-0002-8546-292X], Gamper, Nikita [0000-0001-5806-0207], Villarroel, Álvaro [0000-0003-1096-7824], Núñez, Eider, Jones, Frederick, Muguruza-Montero, Arantza, Urrutia, Janire, Aguado, Alejandra, Malo, Covadonga, Bernardo-Seisdedos, Ganeko, Domene, Carmen, Millet, Óscar, Gamper, Nikita, Villarroel, Álvaro, Ministerio de Ciencia e Innovación (España), Agencia Estatal de Investigación (España), Wellcome Trust, Medical Research Council (UK), Eusko Jaurlaritza, Ministerio de Ciencia, Innovación y Universidades (España), Urrutia, Janire [0000-0002-8546-292X], Gamper, Nikita [0000-0001-5806-0207], Villarroel, Álvaro [0000-0003-1096-7824], Núñez, Eider, Jones, Frederick, Muguruza-Montero, Arantza, Urrutia, Janire, Aguado, Alejandra, Malo, Covadonga, Bernardo-Seisdedos, Ganeko, Domene, Carmen, Millet, Óscar, Gamper, Nikita, and Villarroel, Álvaro
Abstract: Neuronal KV7 channels, important regulators of cell excitability, are among the most sensitive proteins to reactive oxygen species. The S2S3 linker of the voltage sensor was reported as a site-mediating redox modulation of the channels. Recent structural insights reveal potential interactions between this linker and the Ca2+-binding loop of the third EF-hand of calmodulin (CaM), which embraces an antiparallel fork formed by the C-terminal helices A and B, constituting the calcium responsive domain (CRD). We found that precluding Ca2+ binding to the EF3 hand, but not to EF1, EF2, or EF4 hands, abolishes oxidation-induced enhancement of KV7.4 currents. Monitoring FRET (Fluorescence Resonance Energy Transfer) between helices A and B using purified CRDs tagged with fluorescent proteins, we observed that S2S3 peptides cause a reversal of the signal in the presence of Ca2+ but have no effect in the absence of this cation or if the peptide is oxidized. The capacity of loading EF3 with Ca2+ is essential for this reversal of the FRET signal, whereas the consequences of obliterating Ca2+ binding to EF1, EF2, or EF4 are negligible. Furthermore, we show that EF3 is critical for translating Ca2+ signals to reorient the AB fork. Our data are consistent with the proposal that oxidation of cysteine residues in the S2S3 loop relieves KV7 channels from a constitutive inhibition imposed by interactions between the EF3 hand of CaM which is crucial for this signaling.
Published: 2023

7. Association Between Childhood Adversity and Functional Outcomes in People With Psychosis: A Meta-analysis

Author: Fundación Alicia Koplowitz, Janssen Biotech, Deakin University, Rotary Club of Geelong, Brain and Behavior Research Foundation, Medical Research Council (UK), Christy, Angeline, Cavero, Daniela, Navajeeva, Sujeena, Murray-O'Shea, Rachel, Rodríguez, Victoria, Aas, Monica, Trotta, Giulia, Moudiab, Socayna, Garrido-Torres, Nathalia, Zamora, Blanca, Sideli, Lucia, Wrobel, Anna L., Salazar de Pablo, Gonzalo, Alameda, Luis, Fundación Alicia Koplowitz, Janssen Biotech, Deakin University, Rotary Club of Geelong, Brain and Behavior Research Foundation, Medical Research Council (UK), Christy, Angeline, Cavero, Daniela, Navajeeva, Sujeena, Murray-O'Shea, Rachel, Rodríguez, Victoria, Aas, Monica, Trotta, Giulia, Moudiab, Socayna, Garrido-Torres, Nathalia, Zamora, Blanca, Sideli, Lucia, Wrobel, Anna L., Salazar de Pablo, Gonzalo, and Alameda, Luis
Abstract: Despite the accepted link between childhood adversity (CA) and psychotic disorders, evidence on the relationship between CA and poor functional outcome remains less consistent and has never been reviewed quantitatively. The aim of this meta-analysis was to systematically examine the association between CA and functional outcomes in people with psychotic disorders.
Published: 2023

8. Enhancing European capabilities for application of multi-omics studies in biology and biomedicine space research

Author: European Space Agency, NASA Astrobiology Institute (US), University of Nottingham, Medical Research Council (UK), Comunidad de Madrid, Manzano, Aranzazu [0000-0002-0150-0803], Weging, Silvio [0000-0002-8484-4352], Bezdan, Daniela [0000-0002-1203-8239], Cahill, Thomas [0000-0003-3607-6069], Carnero-Díaz, Eugénie [0000-0002-3771-3106], Cope, Henry [0000-0002-4984-0567], Deane, Colleen S. [0000-0002-2281-6479], Etheridge,Timothy [0000-0002-3588-8711], Giacomello, Stefania [0000-0003-0738-1574], Hardiman, Gary [0000-0003-4558-0400], Leys, Natalie [0000-0002-4556-5211], Madrigal, Pedro [0000-0003-1959-8199], Mastroleo, Felice [0000-0002-9815-8038], Medina, F. Javier [0000-0002-0866-7710], Mieczkowski, Jakub [0000-0002-2091-012X], Fernández-Rojo, Manuel A. [0000-0002-2240-1951], Siew, Keith [0000-0002-6502-5095], Szewczyk, Nathaniel [0000-0003-4425-9746], Walsh, Stephen B. [0000-0002-8693-1353], Da Silveira, William A. [0000-0001-6370-2884], Herranz, Raúl [0000-0002-0246-9449], Manzano, Aranzazu, Weging, Silvio, Bezdan, Daniela, Borg, Joseph, Cahill, Thomas, Carnero-Díaz, Eugénie, Cope, Henry, Deane, Colleen S., Etheridge,Timothy, Giacomello, Stefania, Hardiman, Gary, Leys, Natalie, Madrigal, Pedro, Mastroleo, Felice, Medina, F. Javier, Mieczkowski, Jakub, Fernández-Rojo, Manuel A., Siew, Keith, Szewczyk, Nathaniel, Walsh, Stephen B., Da Silveira, William A., Herranz, Raúl, European Space Agency, NASA Astrobiology Institute (US), University of Nottingham, Medical Research Council (UK), Comunidad de Madrid, Manzano, Aranzazu [0000-0002-0150-0803], Weging, Silvio [0000-0002-8484-4352], Bezdan, Daniela [0000-0002-1203-8239], Cahill, Thomas [0000-0003-3607-6069], Carnero-Díaz, Eugénie [0000-0002-3771-3106], Cope, Henry [0000-0002-4984-0567], Deane, Colleen S. [0000-0002-2281-6479], Etheridge,Timothy [0000-0002-3588-8711], Giacomello, Stefania [0000-0003-0738-1574], Hardiman, Gary [0000-0003-4558-0400], Leys, Natalie [0000-0002-4556-5211], Madrigal, Pedro [0000-0003-1959-8199], Mastroleo, Felice [0000-0002-9815-8038], Medina, F. Javier [0000-0002-0866-7710], Mieczkowski, Jakub [0000-0002-2091-012X], Fernández-Rojo, Manuel A. [0000-0002-2240-1951], Siew, Keith [0000-0002-6502-5095], Szewczyk, Nathaniel [0000-0003-4425-9746], Walsh, Stephen B. [0000-0002-8693-1353], Da Silveira, William A. [0000-0001-6370-2884], Herranz, Raúl [0000-0002-0246-9449], Manzano, Aranzazu, Weging, Silvio, Bezdan, Daniela, Borg, Joseph, Cahill, Thomas, Carnero-Díaz, Eugénie, Cope, Henry, Deane, Colleen S., Etheridge,Timothy, Giacomello, Stefania, Hardiman, Gary, Leys, Natalie, Madrigal, Pedro, Mastroleo, Felice, Medina, F. Javier, Mieczkowski, Jakub, Fernández-Rojo, Manuel A., Siew, Keith, Szewczyk, Nathaniel, Walsh, Stephen B., Da Silveira, William A., and Herranz, Raúl
Abstract: Following on from the NASA twins’ study there has been a tremendous interest in the use of omics techniques in spaceflight. The individual space agency’s, NASA’s GeneLab, JAXA´s ibSLS and ESA-funded Space Omics Topical Team and the International Standards for Space Omics Processing (ISSOP) group have established several initiatives to support this growth. Here, we present recommendations from the Space Omics Topical Team to promote standard application of space omics in Europe. We focus on four main themes: i) continued participation in and co-ordination with international omics endeavours; ii) strengthening of the European space omics infrastructure including workforce and facilities; iii) capitalizing on the emerging opportunities in the commercial space sector, and iv) capitalizing on the emerging opportunities in human subjects research.
Published: 2023

9. Affinity-enhanced RNA-binding domains as tools to understand RNA recognition

Author: Medical Research Council (UK), University College London, Francis Crick Institute, Cancer Research UK, Wellcome Trust, Chaves-Arquero, Belén [0000-0002-2761-2336], Abis, Giancarlo [0000-0003-1440-7832], Kelly, Geoff [0000-0002-1149-0717], Christodoulou, Evangelos [0000-0001-8464-1558], Taylor, Ian A. [0000-0002-6763-3852], Ramos, Andrés [0000-0002-9295-8042], Chaves-Arquero, Belén, Collins, Katherine M., Abis, Giancarlo, Kelly, Geoff, Christodoulou, Evangelos, Taylor, Ian A., Ramos, Andrés, Medical Research Council (UK), University College London, Francis Crick Institute, Cancer Research UK, Wellcome Trust, Chaves-Arquero, Belén [0000-0002-2761-2336], Abis, Giancarlo [0000-0003-1440-7832], Kelly, Geoff [0000-0002-1149-0717], Christodoulou, Evangelos [0000-0001-8464-1558], Taylor, Ian A. [0000-0002-6763-3852], Ramos, Andrés [0000-0002-9295-8042], Chaves-Arquero, Belén, Collins, Katherine M., Abis, Giancarlo, Kelly, Geoff, Christodoulou, Evangelos, Taylor, Ian A., and Ramos, Andrés
Abstract: Understanding how the RNA-binding domains of a protein regulator are used to recognize its RNA targets is a key problem in RNA biology, but RNA-binding domains with very low affinity do not perform well in the methods currently available to characterize protein-RNA interactions. Here, we propose to use conservative mutations that enhance the affinity of RNA-binding domains to overcome this limitation. As a proof of principle, we have designed and validated an affinity-enhanced K-homology (KH) domain mutant of the fragile X syndrome protein FMRP, a key regulator of neuronal development, and used this mutant to determine the domain’s sequence preference and to explain FMRP recognition of specific RNA motifs in the cell. Our results validate our concept and our nuclear magnetic resonance (NMR)-based workflow. While effective mutant design requires an understanding of the underlying principles of RNA recognition by the relevant domain type, we expect the method will be used effectively in many RNA-binding domains.
Published: 2023

10. Brain magnetic resonance imaging in the DE50-MD dog model of Duchenne muscular dystrophy reveals regional reductions in cerebral gray matter

Author: Wellcome Trust, Medical Research Council (UK), British Heart Foundation, British Thoracic Society, Queen's University Belfast, Instituto de Salud Carlos III, Crawford, Abbe H., Hornby, Natasha L., Fuente, Alerie G. de la, Piercy, Richard J., Wellcome Trust, Medical Research Council (UK), British Heart Foundation, British Thoracic Society, Queen's University Belfast, Instituto de Salud Carlos III, Crawford, Abbe H., Hornby, Natasha L., Fuente, Alerie G. de la, and Piercy, Richard J.
Abstract: [Background]: Duchenne muscular dystrophy is a X-linked disease characterized by severe and progressive muscle weakness, alongside cognitive impairment and a range of neurobehavioral disorders secondary to brain dystrophin deficiency. Duchenne muscular dystrophy patients have reduced cerebral gray matter and altered white matter ultrastructure (detected by magnetic resonance imaging) compared to age-matched controls., [Methods]: We studied the DE50-MD canine model of Duchenne muscular dystrophy, which is deficient in full length brain dystrophin (Dp427) isoforms and has a neurocognitive phenotype. Eight DE50-MD and 6 age-matched littermate wild type male dogs underwent serial brain magnetic resonance imaging from 14 to 33 months of age., [Results]: Reduced regional gray matter was detected in DE50-MD dogs compared with wildtype, including the piriform lobe, hippocampus and cingulate gyrus. Lateral ventricle volume was larger in DE50-MD dogs. Differences did not progress over time. White matter volume did not differ between DE50-MD and wildtype dogs. There was no difference in brain nor cranial vault volume between DE50-MD and wildtype dogs., [Conclusion]: Dystrophin deficiency in the canine brain results in structural changes that likely contribute to the neurocognitive phenotype.
Published: 2023

11. SARM1 detection in myelinating glia: sarm1/Sarm1 is dispensable for PNS and CNS myelination in zebrafish and mice

Author: Medical Research Council (UK), Wellcome Trust, Royal Society (UK), National Institute of Neurological Disorders and Stroke (US), Instituto de Salud Carlos III, Generalitat Valenciana, Ministerio de Ciencia, Innovación y Universidades (España), Agencia Estatal de Investigación (España), Ministerio de Economía y Competitividad (España), Academia Sinica (Taiwan), Fazal, Shaline V., Mutschler, Clara, Chen, Civia Z., Turmaine, Mark, Chen, Chiung-Ya, Hsueh, Yi-Ping, Ibañez-Grau, Andrea, Loreto, Andrea, Casillas-Bajo, Angeles, Cabedo, Hugo, Franklin, Robin J. M., Barker, Roger A., Monk, Kelly R., Steventon, Benjamin J., Coleman, Michael P., Gómez-Sánchez, José A., Arthur-Farraj, Peter, Medical Research Council (UK), Wellcome Trust, Royal Society (UK), National Institute of Neurological Disorders and Stroke (US), Instituto de Salud Carlos III, Generalitat Valenciana, Ministerio de Ciencia, Innovación y Universidades (España), Agencia Estatal de Investigación (España), Ministerio de Economía y Competitividad (España), Academia Sinica (Taiwan), Fazal, Shaline V., Mutschler, Clara, Chen, Civia Z., Turmaine, Mark, Chen, Chiung-Ya, Hsueh, Yi-Ping, Ibañez-Grau, Andrea, Loreto, Andrea, Casillas-Bajo, Angeles, Cabedo, Hugo, Franklin, Robin J. M., Barker, Roger A., Monk, Kelly R., Steventon, Benjamin J., Coleman, Michael P., Gómez-Sánchez, José A., and Arthur-Farraj, Peter
Abstract: Since SARM1 mutations have been identified in human neurological disease, SARM1 inhibition has become an attractive therapeutic strategy to preserve axons in a variety of disorders of the peripheral (PNS) and central nervous system (CNS). While SARM1 has been extensively studied in neurons, it remains unknown whether SARM1 is present and functional in myelinating glia? This is an important question to address. Firstly, to identify whether SARM1 dysfunction in other cell types in the nervous system may contribute to neuropathology in SARM1 dependent diseases? Secondly, to ascertain whether therapies altering SARM1 function may have unintended deleterious impacts on PNS or CNS myelination? Surprisingly, we find that oligodendrocytes express sarm1 mRNA in the zebrafish spinal cord and that SARM1 protein is readily detectable in rodent oligodendrocytes in vitro and in vivo. Furthermore, activation of endogenous SARM1 in cultured oligodendrocytes induces rapid cell death. In contrast, in peripheral glia, SARM1 protein is not detectable in Schwann cells and satellite glia in vivo and sarm1/Sarm1 mRNA is detected at very low levels in Schwann cells, in vivo, in zebrafish and mouse. Application of specific SARM1 activators to cultured mouse Schwann cells does not induce cell death and nicotinamide adenine dinucleotide (NAD) levels remain unaltered suggesting Schwann cells likely contain no functionally relevant levels of SARM1. Finally, we address the question of whether SARM1 is required for myelination or myelin maintenance. In the zebrafish and mouse PNS and CNS, we show that SARM1 is not required for initiation of myelination and myelin sheath maintenance is unaffected in the adult mouse nervous system. Thus, strategies to inhibit SARM1 function to treat neurological disease are unlikely to perturb myelination in humans.
Published: 2023

12. Condensin pinches a short negatively supercoiled DNA loop during each round of ATP usage

Author: Ministerio de Ciencia, Innovación y Universidades (España), Agencia Estatal de Investigación (España), Medical Research Council (UK), Martínez-García, Belén, Dyson, Sílvia, Segura, Joana, Ayats, Alba, Cutts, Erin E., Gutierrez-Escribano, Pilar, Aragón, Luis, Roca, Joaquim, Ministerio de Ciencia, Innovación y Universidades (España), Agencia Estatal de Investigación (España), Medical Research Council (UK), Martínez-García, Belén, Dyson, Sílvia, Segura, Joana, Ayats, Alba, Cutts, Erin E., Gutierrez-Escribano, Pilar, Aragón, Luis, and Roca, Joaquim
Abstract: Condensin, an SMC (structural maintenance of chromosomes) protein complex, extrudes DNA loops using an ATP-dependent mechanism that remains to be elucidated. Here, we show how condensin activity alters the topology of the interacting DNA. High condensin concentrations restrain positive DNA supercoils. However, in experimental conditions of DNA loop extrusion, condensin restrains negative supercoils. Namely, following ATP-mediated loading onto DNA, each condensin complex constrains a DNA linking number difference (∆Lk) of −0.4. This ∆Lk increases to −0.8 during ATP binding and resets to −0.4 upon ATP hydrolysis. These changes in DNA topology do not involve DNA unwinding, do not spread outside the condensin-DNA complex and can occur in the absence of the condensin subunit Ycg1. These findings indicate that during ATP binding, a short DNA domain delimited by condensin is pinched into a negatively supercoiled loop. We propose that this loop is the feeding segment of DNA that is subsequently merged to enlarge an extruding loop. Such a “pinch and merge” mechanism implies that two DNA-binding sites produce the feeding loop, while a third site, plausibly involving Ycg1, might anchor the extruding loop.
Published: 2023

13. Premature termination of transcription is shaped by Rho and translated uORFS in Mycobacterium tuberculosis

Author: Medical Research Council (UK), European Research Council, Newton Fund, Cortes, Teresa [0000-0002-5746-3300], D'Halluin, Alexandre, Polgar, Peter, Kipkorir, Terry, Patel, Zaynah, Cortés, Teresa, Arnvig, Kristine B., Medical Research Council (UK), European Research Council, Newton Fund, Cortes, Teresa [0000-0002-5746-3300], D'Halluin, Alexandre, Polgar, Peter, Kipkorir, Terry, Patel, Zaynah, Cortés, Teresa, and Arnvig, Kristine B.
Abstract: Little is known about the decisions behind transcription elongation versus termination in the human pathogen Mycobacterium tuberculosis (M.TB). By applying Term-seq to M.TB we found that the majority of transcription termination is premature and associated with translated regions, i.e., within previously annotated or newly identified open reading frames. Computational predictions and Term-seq analysis, upon depletion of termination factor Rho, suggests that Rho-dependent transcription termination dominates all transcription termination sites (TTS), including those associated with regulatory 5' leaders. Moreover, our results suggest that tightly coupled translation, in the form of overlapping stop and start codons, may suppress Rho-dependent termination. This study provides detailed insights into novel M.TB cis-regulatory elements, where Rho-dependent, conditional termination of transcription and translational coupling together play major roles in gene expression control. Our findings contribute to a deeper understanding of the fundamental regulatory mechanisms that enable M.TB adaptation to the host environment offering novel potential points of intervention.
Published: 2023

14. The Bacteriophage-Phage-Inducible Chromosomal Island Arms Race Designs an Interkingdom Inhibitor of dUTPases

Author: Ministerio de Economía y Competitividad (España), Ministerio de Ciencia e Innovación (España), Generalitat Valenciana, Medical Research Council (UK), Biotechnology and Biological Sciences Research Council (UK), European Research Council, Marina, Alberto [0000-0002-1334-5273], Sanz-Frasquet, Carla, Ciges-Tomas, J. Rafael, Alite, Christian, Penadés, José R., Marina, Alberto, Ministerio de Economía y Competitividad (España), Ministerio de Ciencia e Innovación (España), Generalitat Valenciana, Medical Research Council (UK), Biotechnology and Biological Sciences Research Council (UK), European Research Council, Marina, Alberto [0000-0002-1334-5273], Sanz-Frasquet, Carla, Ciges-Tomas, J. Rafael, Alite, Christian, Penadés, José R., and Marina, Alberto
Abstract: Stl, the master repressor of the Staphylococcus aureus pathogenicity islands (SaPIs), targets phage-encoded proteins to derepress and synchronize the SaPI and the helper phage life cycles. To activate their cycle, some SaPI Stls target both phage dimeric and phage trimeric dUTPases (Duts) as antirepressors, which are structurally unrelated proteins that perform identical functions for the phage. This intimate link between the SaPI's repressor and the phage inducer has imposed an evolutionary optimization of Stl that allows the interaction with Duts from unrelated organisms. In this work, we structurally characterize this sophisticated mechanism of specialization by solving the structure of the prototypical SaPIbov1 Stl in complex with a prokaryotic and a eukaryotic trimeric Dut. The heterocomplexes with Mycobacterium tuberculosis and Homo sapiens Duts show the molecular strategy of Stl to target trimeric Duts from different kingdoms. Our structural results confirm the participation of the five catalytic motifs of trimeric Duts in Stl binding, including the C-terminal flexible motif V that increases the affinity by embracing Stl. In silico and in vitro analyses with a monomeric Dut support the capacity of Stl to recognize this third family of Duts, confirming this protein as a universal Dut inhibitor in the different kingdoms of life. IMPORTANCE Stl, the Staphylococcus aureus pathogenicity island (SaPI) master repressor, targets phage-encoded proteins to derepress and synchronize the SaPI and the helper phage life cycles. This fascinating phage-SaPI arms race is exemplified by the Stl from SaPIbov1 which targets phage dimeric and trimeric dUTPases (Duts), structurally unrelated proteins with identical functions in the phages. By solving the structure of the Stl in complex with a prokaryotic (M. tuberculosis) and a eukaryotic (human) trimeric Dut, we showed that Stl has developed a sophisticated substrate mimicry strategy to target trimeric Duts. Since all these Duts
Published: 2023

15. The relationship between genetic liability, childhood maltreatment, and IQ: findings from the EU-GEI multicentric case–control study

Author: European Commission, Sao Paulo Research Foundation, Netherlands Organization for Scientific Research, Economic and Social Research Council (UK), Kings College London, Medical Research Council (UK), Ministerio de Ciencia, Innovación y Universidades (España), Ministerio de Ciencia e Innovación (España), Agencia Estatal de Investigación (España), Instituto de Salud Carlos III, Comunidad de Madrid, National Institute of Mental Health (US), Fundación Familia Alonso, Fundación Alicia Koplowitz, Sideli, Lucia, Aas, Monica, Quattrone, Diego, La Barbera, Daniele, La Cascia, Caterina, Ferraro, Laura, Alameda, Luis, Velthorst, Eva, Trotta, Giulia, Tripoli, Giada, Schimmenti, Adriano, Fontana, Andrea, Gayer-Anderson, Charlotte, Stilo, Simona, Seminerio, Fabio, Sartorio, Crocettarachele, Marrazzo, Giovanna, Lasalvia, Antonio, Tosato, Sarah, Tarricone, Ilaria, Berardi, Domenico, D’Andrea, Giuseppe, EU-GEI WP2 Group, Arango, Celso, Arrojo, Manuel, Bernardo, Miguel, Bobes, Julio, Sanjuán, Julio, Santos, José Luis, Rossi Menezes, Paulo, Del-Ben, Cristina Marta, Jongsma, Hannah E., Jones, Peter B., Kirkbride, James B., Llorca, Pierre-Michel, Tortelli, Andrea, Pignon, Baptiste, Haan, Lieuwe de, Selten, Jean-Paul, Os, Jim van, Rutten, Bart P. F., Bentall, Richard, Di Forti, Marta, Murray, Robin M., Morgan, Craig, Fisher, Helen L., European Commission, Sao Paulo Research Foundation, Netherlands Organization for Scientific Research, Economic and Social Research Council (UK), Kings College London, Medical Research Council (UK), Ministerio de Ciencia, Innovación y Universidades (España), Ministerio de Ciencia e Innovación (España), Agencia Estatal de Investigación (España), Instituto de Salud Carlos III, Comunidad de Madrid, National Institute of Mental Health (US), Fundación Familia Alonso, Fundación Alicia Koplowitz, Sideli, Lucia, Aas, Monica, Quattrone, Diego, La Barbera, Daniele, La Cascia, Caterina, Ferraro, Laura, Alameda, Luis, Velthorst, Eva, Trotta, Giulia, Tripoli, Giada, Schimmenti, Adriano, Fontana, Andrea, Gayer-Anderson, Charlotte, Stilo, Simona, Seminerio, Fabio, Sartorio, Crocettarachele, Marrazzo, Giovanna, Lasalvia, Antonio, Tosato, Sarah, Tarricone, Ilaria, Berardi, Domenico, D’Andrea, Giuseppe, EU-GEI WP2 Group, Arango, Celso, Arrojo, Manuel, Bernardo, Miguel, Bobes, Julio, Sanjuán, Julio, Santos, José Luis, Rossi Menezes, Paulo, Del-Ben, Cristina Marta, Jongsma, Hannah E., Jones, Peter B., Kirkbride, James B., Llorca, Pierre-Michel, Tortelli, Andrea, Pignon, Baptiste, Haan, Lieuwe de, Selten, Jean-Paul, Os, Jim van, Rutten, Bart P. F., Bentall, Richard, Di Forti, Marta, Murray, Robin M., Morgan, Craig, and Fisher, Helen L.
Abstract: This study investigated if the association between childhood maltreatment and cognition among psychosis patients and community controls was partially accounted for by genetic liability for psychosis. Patients with first-episode psychosis (N = 755) and unaffected controls (N = 1219) from the EU-GEI study were assessed for childhood maltreatment, intelligence quotient (IQ), family history of psychosis (FH), and polygenic risk score for schizophrenia (SZ-PRS). Controlling for FH and SZ-PRS did not attenuate the association between childhood maltreatment and IQ in cases or controls. Findings suggest that these expressions of genetic liability cannot account for the lower levels of cognition found among adults maltreated in childhood.
Published: 2023

16. GWAS and meta-analysis identifies 49 genetic variants underlying critical COVID-19

Author: Wellcome Trust, Medical Research Council (UK), Roslin Institute, Department of Health & Social Care (UK), Instituto de Salud Carlos III, European Commission, Fundación Amancio Ortega, Banco Santander, Cabildo de Tenerife, Fundación Canaria Instituto de Investigación Sanitaria de Canarias, Pairo-Castineira, Erola, Rawlik, Konrad, Bretherick, Andrew D., Qi, Ting, Wu, Yang, Nassiri, Isar, McConkey, Glenn A., Zechner, Marie, Klaric, Lucija, Griffiths, Fiona, Oosthuyzen, Wilna, Kousathanas, Athanasios, Richmond, Anne, Millar, Jonathan, Russell, Clark D., Malinauskas, Tomas, Thwaites, Ryan, Morrice, Kirstie, Keating, Sean, Maslove, David, Nichol, Alistair, Semple, Malcolm G., Knight, Julian, Shankar-Hari, Manu, Summers, Charlotte, Hinds, Charles, Horby, Peter, Ling, Lowell, McAuley, Danny, Montgomery, Hugh, Openshaw, Peter J. M., Begg, Colin, Walsh, Timothy, Tenesa, Albert, Flores, Carlos, Riancho, José A., Rojas-Martinez, Augusto, Lapunzina, Pablo, Yang, Jian, Ponting, Chris P., Wilson, James F., Vitart, Veronique, Abedalthagafi, Malak, Luchessi, Andre D., Parra, Esteban J., Cruz, Raquel, Carracedo, Ángel, Fawkes, Angie, Murphy, Lee, Rowan, Kathy, Pereira, Alexandre C., Law, Andy, Fairfax, Benjamin, Hendry, Sara Clohisey, Baillie, J. Kenneth, Almeida, Julia, Orfao, Alberto, López-García, Esther, Rodríguez-Artalejo, Fernando, Bustos, Matilde, Rodríguez-Hernández, María A., Wellcome Trust, Medical Research Council (UK), Roslin Institute, Department of Health & Social Care (UK), Instituto de Salud Carlos III, European Commission, Fundación Amancio Ortega, Banco Santander, Cabildo de Tenerife, Fundación Canaria Instituto de Investigación Sanitaria de Canarias, Pairo-Castineira, Erola, Rawlik, Konrad, Bretherick, Andrew D., Qi, Ting, Wu, Yang, Nassiri, Isar, McConkey, Glenn A., Zechner, Marie, Klaric, Lucija, Griffiths, Fiona, Oosthuyzen, Wilna, Kousathanas, Athanasios, Richmond, Anne, Millar, Jonathan, Russell, Clark D., Malinauskas, Tomas, Thwaites, Ryan, Morrice, Kirstie, Keating, Sean, Maslove, David, Nichol, Alistair, Semple, Malcolm G., Knight, Julian, Shankar-Hari, Manu, Summers, Charlotte, Hinds, Charles, Horby, Peter, Ling, Lowell, McAuley, Danny, Montgomery, Hugh, Openshaw, Peter J. M., Begg, Colin, Walsh, Timothy, Tenesa, Albert, Flores, Carlos, Riancho, José A., Rojas-Martinez, Augusto, Lapunzina, Pablo, Yang, Jian, Ponting, Chris P., Wilson, James F., Vitart, Veronique, Abedalthagafi, Malak, Luchessi, Andre D., Parra, Esteban J., Cruz, Raquel, Carracedo, Ángel, Fawkes, Angie, Murphy, Lee, Rowan, Kathy, Pereira, Alexandre C., Law, Andy, Fairfax, Benjamin, Hendry, Sara Clohisey, Baillie, J. Kenneth, Almeida, Julia, Orfao, Alberto, López-García, Esther, Rodríguez-Artalejo, Fernando, Bustos, Matilde, and Rodríguez-Hernández, María A.
Abstract: Critical illness in COVID-19 is an extreme and clinically homogeneous disease phenotype that we have previously shown1 to be highly efficient for discovery of genetic associations2. Despite the advanced stage of illness at presentation, we have shown that host genetics in patients who are critically ill with COVID-19 can identify immunomodulatory therapies with strong beneficial effects in this group3. Here we analyse 24,202 cases of COVID-19 with critical illness comprising a combination of microarray genotype and whole-genome sequencing data from cases of critical illness in the international GenOMICC (11,440 cases) study, combined with other studies recruiting hospitalized patients with a strong focus on severe and critical disease: ISARIC4C (676 cases) and the SCOURGE consortium (5,934 cases). To put these results in the context of existing work, we conduct a meta-analysis of the new GenOMICC genome-wide association study (GWAS) results with previously published data. We find 49 genome-wide significant associations, of which 16 have not been reported previously. To investigate the therapeutic implications of these findings, we infer the structural consequences of protein-coding variants, and combine our GWAS results with gene expression data using a monocyte transcriptome-wide association study (TWAS) model, as well as gene and protein expression using Mendelian randomization. We identify potentially druggable targets in multiple systems, including inflammatory signalling (JAK1), monocyte–macrophage activation and endothelial permeability (PDE4A), immunometabolism (SLC2A5 and AK5), and host factors required for viral entry and replication (TMPRSS2 and RAB2A).
Published: 2023

17. Adipo-glial signaling mediates metabolic adaptation in peripheral nerve regeneration

Author: German Research Foundation, European Commission, European Research Council, Wellcome Trust, Instituto de Salud Carlos III, Medical Research Council (UK), National Institutes of Health (US), Sundaram, Venkat Krishnan, Schütza, Vlad, Schröter, Nele H., Backhaus, Aline, Bilsing, Annika, Joneck, Lisa, Seelbach, Anna, Mutschler, Clara, Gómez-Sánchez, José A., Schäffner, Erik, Ernst Sánchez, Eva, Akkermann, Dagmar, Paul, Christina, Schwagarus, Nancy, Müller, Silvana, Odle, Angela, Childs, Gwen, Ewers, David, Kungl, Theresa, Sitte, Maren, Fledrich, Robert, German Research Foundation, European Commission, European Research Council, Wellcome Trust, Instituto de Salud Carlos III, Medical Research Council (UK), National Institutes of Health (US), Sundaram, Venkat Krishnan, Schütza, Vlad, Schröter, Nele H., Backhaus, Aline, Bilsing, Annika, Joneck, Lisa, Seelbach, Anna, Mutschler, Clara, Gómez-Sánchez, José A., Schäffner, Erik, Ernst Sánchez, Eva, Akkermann, Dagmar, Paul, Christina, Schwagarus, Nancy, Müller, Silvana, Odle, Angela, Childs, Gwen, Ewers, David, Kungl, Theresa, Sitte, Maren, and Fledrich, Robert
Abstract: The peripheral nervous system harbors a remarkable potential to regenerate after acute nerve trauma. Full functional recovery, however, is rare and critically depends on peripheral nerve Schwann cells that orchestrate breakdown and resynthesis of myelin and, at the same time, support axonal regrowth. How Schwann cells meet the high metabolic demand required for nerve repair remains poorly understood. We here report that nerve injury induces adipocyte to glial signaling and identify the adipokine leptin as an upstream regulator of glial metabolic adaptation in regeneration. Signal integration by leptin receptors in Schwann cells ensures efficient peripheral nerve repair by adjusting injury-specific catabolic processes in regenerating nerves, including myelin autophagy and mitochondrial respiration. Our findings propose a model according to which acute nerve injury triggers a therapeutically targetable intercellular crosstalk that modulates glial metabolism to provide sufficient energy for successful nerve repair.
Published: 2023

18. Vitamin C activates young LINE-1 elements in mouse embryonic stem cells via H3K9me3 demethylation

Author: Royal Society (UK), Biotechnology and Biological Sciences Research Council (UK), Medical Research Council (UK), Wellcome Trust, Cheng, Kevin C. L., Frost, Jennifer M., Sánchez-Luque, Francisco J., García-Canãdas, Marta, Taylor, Darren, Yang, Wan R., Irayanar, Branavy, Sampath, Swetha, Patani, Hemalvi, Agger, Karl, Helin, Kristian, Ficz, Gabriella, Burns, Kathleen H., Ewing, Adam D., García-Pérez, José L., Branco, Miguel R., Royal Society (UK), Biotechnology and Biological Sciences Research Council (UK), Medical Research Council (UK), Wellcome Trust, Cheng, Kevin C. L., Frost, Jennifer M., Sánchez-Luque, Francisco J., García-Canãdas, Marta, Taylor, Darren, Yang, Wan R., Irayanar, Branavy, Sampath, Swetha, Patani, Hemalvi, Agger, Karl, Helin, Kristian, Ficz, Gabriella, Burns, Kathleen H., Ewing, Adam D., García-Pérez, José L., and Branco, Miguel R.
Abstract: Background Vitamin C (vitC) enhances the activity of 2-oxoglutarate-dependent dioxygenases, including TET enzymes, which catalyse DNA demethylation, and Jumonji-domain histone demethylases. The epigenetic remodelling promoted by vitC improves the efficiency of induced pluripotent stem cell derivation, and is required to attain a ground-state of pluripotency in embryonic stem cells (ESCs) that closely mimics the inner cell mass of the early blastocyst. However, genome-wide DNA and histone demethylation can lead to upregulation of transposable elements (TEs), and it is not known how vitC addition in culture media affects TE expression in pluripotent stem cells. Results Here we show that vitC increases the expression of several TE families, including evolutionarily young LINE-1 (L1) elements, in mouse ESCs. We find that TET activity is dispensable for L1 upregulation, and that instead it occurs largely as a result of H3K9me3 loss mediated by KDM4A/C histone demethylases. Despite increased L1 levels, we did not detect increased somatic insertion rates in vitC-treated cells. Notably, treatment of human ESCs with vitC also increases L1 protein levels, albeit through a distinct, post-transcriptional mechanism. Conclusion VitC directly modulates the expression of mouse L1s and other TEs through epigenetic mechanisms, with potential for downstream effects related to the multiple emerging roles of L1s in cellular function.
Published: 2023

19. Randomized Trial of BCG Vaccine to Protect against Covid-19 in Health Care Workers

Author: Bill & Melinda Gates Foundation, Minderoo Foundation, Royal Children's Hospital Foundation, National Health and Medical Research Council (Australia), Swiss National Science Foundation, European Molecular Biology Laboratory, Medical Research Council (UK), Health Services Union New South Wales Branch, Peter Sowerby Foundation, SA Health, Insurance Advisernet Foundation, NAB Foundation, Calvert-Jones Foundation, Modara Pines Charitable Foundation, United Health Foundation, Epworth HealthCare, Victoria State Government, Pittet, Laure F., Messina, Nicole L., Orsini, Francesca, Moore, Cecilia L., Abruzzo, Veronica, Barry, Simone, Bonnici, Rhian, Bonten, Marc, Campbell, John, Croda, Julio, Dalcolmo, Margareth, Gardiner, Kaya, Gell, Grace, Germano, Susie, Gomes-Silva, Adriano, Goodall, Casey, Gwee, Amanda, Jamieson, Tenaya, Jardim, Bruno, Kollmann, Tobias R., Lacerda, Marcus V. G., Lee, Katherine J., Lucas, Michaela, Lynn, David J., Manning, Laurens, Marshall, Helen S., McDonald, Ellie, Munns, Craig F., Nicholson, Suellen, O’Connell, Abby, Oliveira, Roberto D. de, Perlen, Susan, Perrett, Kirsten P., Prat-Aymerich, Cristina, Richmond, Peter C., Rodríguez-Baño, Jesús, Santos, Glauce dos, Silva, Patricia V. da, Teo, Jia Wei, Villanueva, Paola, Warris, Adilia, Wood, Nicholas J., Davidson, Andrew, Curtis, Nigel, BRACE Trial Consortium Group, Bill & Melinda Gates Foundation, Minderoo Foundation, Royal Children's Hospital Foundation, National Health and Medical Research Council (Australia), Swiss National Science Foundation, European Molecular Biology Laboratory, Medical Research Council (UK), Health Services Union New South Wales Branch, Peter Sowerby Foundation, SA Health, Insurance Advisernet Foundation, NAB Foundation, Calvert-Jones Foundation, Modara Pines Charitable Foundation, United Health Foundation, Epworth HealthCare, Victoria State Government, Pittet, Laure F., Messina, Nicole L., Orsini, Francesca, Moore, Cecilia L., Abruzzo, Veronica, Barry, Simone, Bonnici, Rhian, Bonten, Marc, Campbell, John, Croda, Julio, Dalcolmo, Margareth, Gardiner, Kaya, Gell, Grace, Germano, Susie, Gomes-Silva, Adriano, Goodall, Casey, Gwee, Amanda, Jamieson, Tenaya, Jardim, Bruno, Kollmann, Tobias R., Lacerda, Marcus V. G., Lee, Katherine J., Lucas, Michaela, Lynn, David J., Manning, Laurens, Marshall, Helen S., McDonald, Ellie, Munns, Craig F., Nicholson, Suellen, O’Connell, Abby, Oliveira, Roberto D. de, Perlen, Susan, Perrett, Kirsten P., Prat-Aymerich, Cristina, Richmond, Peter C., Rodríguez-Baño, Jesús, Santos, Glauce dos, Silva, Patricia V. da, Teo, Jia Wei, Villanueva, Paola, Warris, Adilia, Wood, Nicholas J., Davidson, Andrew, Curtis, Nigel, and BRACE Trial Consortium Group
Abstract: [BACKGROUND] The bacille Calmette–Guérin (BCG) vaccine has immunomodulatory “off-target” effects that have been hypothesized to protect against coronavirus disease 2019 (Covid-19)., [METHODS] In this international, double-blind, placebo-controlled trial, we randomly assigned health care workers to receive the BCG-Denmark vaccine or saline placebo and followed them for 12 months. Symptomatic Covid-19 and severe Covid-19, the primary outcomes, were assessed at 6 months; the primary analyses involved the modified intention-to-treat population, which was restricted to participants with a negative test for severe acute respiratory syndrome coronavirus 2 at baseline., [RESULTS] A total of 3988 participants underwent randomization; recruitment ceased before the planned sample size was reached owing to the availability of Covid-19 vaccines. The modified intention-to-treat population included 84.9% of the participants who underwent randomization: 1703 in the BCG group and 1683 in the placebo group. The estimated risk of symptomatic Covid-19 by 6 months was 14.7% in the BCG group and 12.3% in the placebo group (risk difference, 2.4 percentage points; 95% confidence interval [CI], −0.7 to 5.5; P=0.13). The risk of severe Covid-19 by 6 months was 7.6% in the BCG group and 6.5% in the placebo group (risk difference, 1.1 percentage points; 95% CI, −1.2 to 3.5; P=0.34); the majority of participants who met the trial definition of severe Covid-19 were not hospitalized but were unable to work for at least 3 consecutive days. In supplementary and sensitivity analyses that used less conservative censoring rules, the risk differences were similar but the confidence intervals were narrower. There were five hospitalizations due to Covid-19 in each group (including one death in the placebo group). The hazard ratio for any Covid-19 episode in the BCG group as compared with the placebo group was 1.23 (95% CI, 0.96 to 1.59). No safety concerns were identified., [CONCLUSIONS] Vaccination with BCG-Denmark did not result in a lower risk of Covid-19 among health care workers than placebo. (Funded by the Bill and Melinda Gates Foundation and others; BRACE ClinicalTrials.gov number, NCT04327206.)
Published: 2023

20. Gain and loss of function variants in EZH1 disrupt neurogenesis and cause dominant and recessive neurodevelopmental disorders

Author: National Institutes of Health (US), Ministerio de Economía y Competitividad (España), Ministerio de Ciencia, Innovación y Universidades (España), Agencia Estatal de Investigación (España), University of Alabama at Birmingham, Ministerio de Ciencia e Innovación (España), Ministerio de Educación y Ciencia (España), Manchester Biomedical Research Centre, European Commission, National Institute for Health Research (UK), Wellcome Trust, Cancer Research UK, Medical Research Council (UK), Wellcome Sanger Institute, Gracia-Díaz, Carolina, Zhou, Yijing, Yang, Qian, Maroofian, Reza, España-Bonilla, Paula, Lee, Chul-Hwan, Zhang, Shuo, Padilla, Natàlia, Fueyo, Raquel, Waxman, Elisa A., Lei, Sunyimeng, Otrimski, Garrett, Li, Dong, Sheppard, Sarah E., Mark, Paul, Harr, Margaret H., Hakonarson, Hakon, Rodan, Lance, Jackson, Adam, Vasudevan, Pradeep, Powel, Corrina, Mohammed, Shehla, Maddirevula, Sateesh, Alzaidan, Hamad, Faqeih, Eissa A., Efthymiou, Stephanie, Turchetti, Valentina, Rahman, Fátima, Maqbool, Shazia, Salpietro, Vincenzo, Ibrahim, Shahnaz H., di Rosa, Gabriella, Houlden, Henry, Alharbi, Maha Nasser, Al-Sannaa, Nouriya Abbas, Bauer, Peter, Zifarelli, Giovanni, Estaras, Conchi, Hurst, Anna C. E., Thompson, Michelle L., Chassevent, Anna, Smith-Hicks, Constance L., Cruz, Xavier de la, Holtz, Alexander M., Elloumi, Houda Zghal, Hajianpour, M. J., Rieubland, Claudine, Braun, Dominique, Banka, Siddharth, French, Deborah L., Heller, Elizabeth A., Saade, Murielle, Song, Hongjun, Ming, Guo-Li, Alkuraya, Fowzan S., Agrawal, Pankaj B., Reinberg, Danny, Bhoj, Elizabeth J., Martínez-Balbás, Marian, Akizu, Naiara, National Institutes of Health (US), Ministerio de Economía y Competitividad (España), Ministerio de Ciencia, Innovación y Universidades (España), Agencia Estatal de Investigación (España), University of Alabama at Birmingham, Ministerio de Ciencia e Innovación (España), Ministerio de Educación y Ciencia (España), Manchester Biomedical Research Centre, European Commission, National Institute for Health Research (UK), Wellcome Trust, Cancer Research UK, Medical Research Council (UK), Wellcome Sanger Institute, Gracia-Díaz, Carolina, Zhou, Yijing, Yang, Qian, Maroofian, Reza, España-Bonilla, Paula, Lee, Chul-Hwan, Zhang, Shuo, Padilla, Natàlia, Fueyo, Raquel, Waxman, Elisa A., Lei, Sunyimeng, Otrimski, Garrett, Li, Dong, Sheppard, Sarah E., Mark, Paul, Harr, Margaret H., Hakonarson, Hakon, Rodan, Lance, Jackson, Adam, Vasudevan, Pradeep, Powel, Corrina, Mohammed, Shehla, Maddirevula, Sateesh, Alzaidan, Hamad, Faqeih, Eissa A., Efthymiou, Stephanie, Turchetti, Valentina, Rahman, Fátima, Maqbool, Shazia, Salpietro, Vincenzo, Ibrahim, Shahnaz H., di Rosa, Gabriella, Houlden, Henry, Alharbi, Maha Nasser, Al-Sannaa, Nouriya Abbas, Bauer, Peter, Zifarelli, Giovanni, Estaras, Conchi, Hurst, Anna C. E., Thompson, Michelle L., Chassevent, Anna, Smith-Hicks, Constance L., Cruz, Xavier de la, Holtz, Alexander M., Elloumi, Houda Zghal, Hajianpour, M. J., Rieubland, Claudine, Braun, Dominique, Banka, Siddharth, French, Deborah L., Heller, Elizabeth A., Saade, Murielle, Song, Hongjun, Ming, Guo-Li, Alkuraya, Fowzan S., Agrawal, Pankaj B., Reinberg, Danny, Bhoj, Elizabeth J., Martínez-Balbás, Marian, and Akizu, Naiara
Abstract: Genetic variants in chromatin regulators are frequently found in neurodevelopmental disorders, but their effect in disease etiology is rarely determined. Here, we uncover and functionally define pathogenic variants in the chromatin modifier EZH1 as the cause of dominant and recessive neurodevelopmental disorders in 19 individuals. EZH1 encodes one of the two alternative histone H3 lysine 27 methyltransferases of the PRC2 complex. Unlike the other PRC2 subunits, which are involved in cancers and developmental syndromes, the implication of EZH1 in human development and disease is largely unknown. Using cellular and biochemical studies, we demonstrate that recessive variants impair EZH1 expression causing loss of function effects, while dominant variants are missense mutations that affect evolutionarily conserved aminoacids, likely impacting EZH1 structure or function. Accordingly, we found increased methyltransferase activity leading to gain of function of two EZH1 missense variants. Furthermore, we show that EZH1 is necessary and sufficient for differentiation of neural progenitor cells in the developing chick embryo neural tube. Finally, using human pluripotent stem cell-derived neural cultures and forebrain organoids, we demonstrate that EZH1 variants perturb cortical neuron differentiation. Overall, our work reveals a critical role of EZH1 in neurogenesis regulation and provides molecular diagnosis for previously undefined neurodevelopmental disorders.
Published: 2023

21. LATE-NC staging in routine neuropathologic diagnosis: an update

Author: National Institutes of Health (US), California Department of Public Health, California Department of Finance, Academy of Finland, Edmond J. Safra Philanthropic Foundation, Rossy Foundation, Nomis Foundation, Alzheimer Forschung Initiative, Medical Research Council (UK), Addenbrooke's Charitable Trust, Life and Health Foundation, Paul G. Allen Family Foundation, Alzheimer's Research UK, Alzheimer Society, National Institute for Health Research (UK), Cambridge Biomedical Research Centre, Research Foundation - Flanders, KU Leuven, BrightFocus Foundation, Instituto de Salud Carlos III, European Commission, Nelson, Peter T., Lee, Edward B., Cykowski, Matthew D., Alafuzoff, Irina, Arfanakis, Konstantinos, Attems, Johannes, Brayne, Carol, Corrada, Maria M., Dugger, Brittany N., Flanagan, Margaret E., Ghetti, Bernardino, Grinberg, Lea T., Grossman, Murray, Grothe, Michel J., Halliday, Glenda M., Hasegawa, Masato, Hokkanen, Suvi R. K., Hunter, Sally, Jellinger, Kurt, Kawas, Claudia H., Keene, C. Dirk, Kouri, Naomi, Kovacs, Gabor G., Leverenz, James B., Latimer, Caitlin S., Mackenzie, Ian R., Mao, Qinwen, McAleese, Kirsty E., Merrick, Richard, Montine, Thomas J., Murray, Melissa E., Myllykangas, Liisa, Nag, Sukriti, Neltner, Janna H., Newell, Kathy L., Rissman, Robert A., Saito, Yuko, Sajjadi, S. Ahmad, Schwetye, Katherine E., Teich, Andrew F., Thal, Dietmar R., Tomé, Sandra O., Troncoso, Juan C., Wang, Shih-Hsiu J., White III, Charles L., Wisniewski, Thomas, Yang, Hyun-Sik, Schneider, Julie A., Dickson, Dennis W., Neumann, Manuela, National Institutes of Health (US), California Department of Public Health, California Department of Finance, Academy of Finland, Edmond J. Safra Philanthropic Foundation, Rossy Foundation, Nomis Foundation, Alzheimer Forschung Initiative, Medical Research Council (UK), Addenbrooke's Charitable Trust, Life and Health Foundation, Paul G. Allen Family Foundation, Alzheimer's Research UK, Alzheimer Society, National Institute for Health Research (UK), Cambridge Biomedical Research Centre, Research Foundation - Flanders, KU Leuven, BrightFocus Foundation, Instituto de Salud Carlos III, European Commission, Nelson, Peter T., Lee, Edward B., Cykowski, Matthew D., Alafuzoff, Irina, Arfanakis, Konstantinos, Attems, Johannes, Brayne, Carol, Corrada, Maria M., Dugger, Brittany N., Flanagan, Margaret E., Ghetti, Bernardino, Grinberg, Lea T., Grossman, Murray, Grothe, Michel J., Halliday, Glenda M., Hasegawa, Masato, Hokkanen, Suvi R. K., Hunter, Sally, Jellinger, Kurt, Kawas, Claudia H., Keene, C. Dirk, Kouri, Naomi, Kovacs, Gabor G., Leverenz, James B., Latimer, Caitlin S., Mackenzie, Ian R., Mao, Qinwen, McAleese, Kirsty E., Merrick, Richard, Montine, Thomas J., Murray, Melissa E., Myllykangas, Liisa, Nag, Sukriti, Neltner, Janna H., Newell, Kathy L., Rissman, Robert A., Saito, Yuko, Sajjadi, S. Ahmad, Schwetye, Katherine E., Teich, Andrew F., Thal, Dietmar R., Tomé, Sandra O., Troncoso, Juan C., Wang, Shih-Hsiu J., White III, Charles L., Wisniewski, Thomas, Yang, Hyun-Sik, Schneider, Julie A., Dickson, Dennis W., and Neumann, Manuela
Abstract: An international consensus report in 2019 recommended a classification system for limbic-predominant age-related TDP-43 encephalopathy neuropathologic changes (LATE-NC). The suggested neuropathologic staging system and nomenclature have proven useful for autopsy practice and dementia research. However, some issues remain unresolved, such as cases with unusual features that do not fit with current diagnostic categories. The goal of this report is to update the neuropathologic criteria for the diagnosis and staging of LATE-NC, based primarily on published data. We provide practical suggestions about how to integrate available genetic information and comorbid pathologies [e.g., Alzheimer’s disease neuropathologic changes (ADNC) and Lewy body disease]. We also describe recent research findings that have enabled more precise guidance on how to differentiate LATE-NC from other subtypes of TDP-43 pathology [e.g., frontotemporal lobar degeneration (FTLD) and amyotrophic lateral sclerosis (ALS)], and how to render diagnoses in unusual situations in which TDP-43 pathology does not follow the staging scheme proposed in 2019. Specific recommendations are also made on when not to apply this diagnostic term based on current knowledge. Neuroanatomical regions of interest in LATE-NC are described in detail and the implications for TDP-43 immunohistochemical results are specified more precisely. We also highlight questions that remain unresolved and areas needing additional study. In summary, the current work lays out a number of recommendations to improve the precision of LATE-NC staging based on published reports and diagnostic experience.
Published: 2023

22. High gamma activity distinguishes frontal cognitive control regions from adjacent cortical networks

Author: Royal Society (UK), Cambridge Commonwealth European and International Trust, Guarantors of Brain, National Institute for Health Research (UK), Brain Tumour Charity, Medical Research Council (UK), Cambridge Biomedical Research Centre, Assem, Moataz, Hart, Michael G., Coelho, Pedro, Romero-García, Rafael, McDonald, Alexa, Woodberry, Emma, Morris, Robert C., Price, Stephen J., Suckling, John, Santarius, Thomas, Duncan, John, Erez, Yaara, Royal Society (UK), Cambridge Commonwealth European and International Trust, Guarantors of Brain, National Institute for Health Research (UK), Brain Tumour Charity, Medical Research Council (UK), Cambridge Biomedical Research Centre, Assem, Moataz, Hart, Michael G., Coelho, Pedro, Romero-García, Rafael, McDonald, Alexa, Woodberry, Emma, Morris, Robert C., Price, Stephen J., Suckling, John, Santarius, Thomas, Duncan, John, and Erez, Yaara
Abstract: Though the lateral frontal cortex is broadly implicated in cognitive control, functional MRI (fMRI) studies suggest fine-grained distinctions within this region. To examine this question electrophysiologically, we placed electrodes on the lateral frontal cortex in patients undergoing awake craniotomy for tumor resection. Patients performed verbal tasks with a manipulation of attentional switching, a canonical control demand. Power in the high gamma range (70–250 Hz) distinguished electrodes based on their location within a high-resolution fMRI network parcellation of the frontal lobe. Electrodes within the canonical fronto-parietal control network showed increased power in the switching condition, a result absent in electrodes within default mode, language and somato-motor networks. High gamma results contrasted with spatially distributed power decreases in the beta range (12–30 Hz). These results confirm the importance of fine-scale functional distinctions within the human frontal lobe, and pave the way for increased precision of functional mapping in tumor surgeries.
Published: 2023

23. Development and validation of the AMMON-OHE model to predict risk of overt hepatic encephalopathy occurrence in outpatients with cirrhosis

Author: Instituto de Salud Carlos III, Medical Research Council (UK), Fundación Ramón Areces, Generalitat Valenciana, European Commission, Ballester, María Pilar, Tranah, Thomas H., Balcar, Lorenz, Fiorillo, Alessandra, Ampuero, Javier, Kerbert, Annarein J. C., Thomsen, Karen L., Desamparados Escudero, María, Mandorfer, Mattias, Reiberger, Thomas, Shawcross, Debbie L., Romero-Gómez, Manuel, Montoliu, Carmina, Carbonell-Asins, Juan Antonio, Jalan, Rajiv, Instituto de Salud Carlos III, Medical Research Council (UK), Fundación Ramón Areces, Generalitat Valenciana, European Commission, Ballester, María Pilar, Tranah, Thomas H., Balcar, Lorenz, Fiorillo, Alessandra, Ampuero, Javier, Kerbert, Annarein J. C., Thomsen, Karen L., Desamparados Escudero, María, Mandorfer, Mattias, Reiberger, Thomas, Shawcross, Debbie L., Romero-Gómez, Manuel, Montoliu, Carmina, Carbonell-Asins, Juan Antonio, and Jalan, Rajiv
Abstract: [Background & Aims] Neuropsychological and psychophysical tests are recommended to assess the risk of overt hepatic encephalopathy (OHE), but their accuracy is limited. Hyperammonaemia is central in the pathogenesis of OHE, but its predictive utility is unknown. In this study, we aimed to determine the role of neuropsychological or psychophysical tests and ammonia, and to develop a model (AMMON-OHE) to stratify the risk of subsequent OHE development in outpatients with cirrhosis., [Methods] This observational, prospective study included 426 outpatients without previous OHE from three liver units followed for a median of 2.5 years. Psychometric hepatic encephalopathy score (PHES) <-4 or critical flicker frequency (CFF) <39 was considered abnormal. Ammonia was normalized to upper limit of normal (AMM-ULN) at the respective reference laboratory. Multivariable frailty competing risk and random survival forest analyses were performed to predict future OHE and to develop the AMMON-OHE model. External validation was carried out using 267 and 381 patients from two independent units., [Results] Significant differences were found in time-to-OHE (log-rank p <0.001) according to PHES or CFF and ammonia, with the highest risk in patients with abnormal PHES plus high AMM-ULN (hazard ratio 4.4; 95% CI 2.4-8.1; p <0.001 compared with normal PHES and AMM-ULN). On multivariable analysis, AMM-ULN but not PHES or CFF was an independent predictor of the development of OHE (hazard ratio 1.4; 95% CI 1.1-1.9; p = 0.015). The AMMON-OHE model (sex, diabetes, albumin, creatinine and AMM-ULN) showed a C-index of 0.844 and 0.728 for the prediction of a first episode of OHE in two external validation cohorts., [Conclusions] In this study, we developed and validated the AMMON-OHE model, comprising readily available clinical and biochemical variables that can be used to identify outpatients at the highest risk of developing a first episode of OHE., [Impact and implications] In this study, we aimed to develop a model to predict which patients with cirrhosis are at risk of developing overt hepatic encephalopathy (OHE). Using data from three units and including 426 outpatients with cirrhosis, we developed the AMMON-OHE model – comprising sex, diabetes, albumin, creatinine and ammonia levels – which demonstrated good predictive ability. The AMMON-OHE model performs better than PHES and CFF to predict the first episode of OHE in outpatients with cirrhosis. This model was validated in 267 and 381 patients from two independent liver units. The AMMON-OHE model is available online for clinical use.
Published: 2023

24. Dampened predictable decadal North Atlantic climate fluctuations due to ice melting

Author: Ministerio de Ciencia e Innovación (España), Medical Research Council (UK), 0000-0002-1349-5669, 0000-0001-7245-9863, 0000-0001-7380-4294, 0000-0002-9195-6731, 0000-0002-4607-8685, 0000-0002-9723-3622, 0000-0002-1400-2715, Martin-Puertas, Celia, Hernandez, Armand, Pardo-Igúzquiza, Eulogio, Boyall, Laura, Brierley, Chris, Jiang, Zhiyi, Tjallingii, Rik, Blockley, Simon P.E., Rodríguez-Tovar, Francisco Javier, Ministerio de Ciencia e Innovación (España), Medical Research Council (UK), 0000-0002-1349-5669, 0000-0001-7245-9863, 0000-0001-7380-4294, 0000-0002-9195-6731, 0000-0002-4607-8685, 0000-0002-9723-3622, 0000-0002-1400-2715, Martin-Puertas, Celia, Hernandez, Armand, Pardo-Igúzquiza, Eulogio, Boyall, Laura, Brierley, Chris, Jiang, Zhiyi, Tjallingii, Rik, Blockley, Simon P.E., and Rodríguez-Tovar, Francisco Javier
Abstract: The oscillatory behaviour of the climate system on decadal timescales before the instrumental record is hard to quantify. However, knowledge of this variability is important for putting current changes in context and for supporting reliable future predictions. Here we investigate the recurrent component of Holocene climate variability in the North Atlantic sector from 10,500 to 2,000 years ago by conducting a frequency analysis of both an annually laminated climate record from a lake in England and outputs from a long transient simulation of the Atlantic meridional overturning circulation. We find consistent decadal variability over the past 6,700 years and before 8,500 years before present, probably reflecting predominance of solar and ocean forcings. Between these dates, climate variability was dampened on decadal timescales. Our results suggest that meltwater discharge into the North Atlantic and the subsequent hydrographic changes, from the opening of the Hudson Bay until the final collapse of the Laurentide Ice Sheet, disrupted the decadal cyclic signals for more than a millennium. Given the current acceleration of the Greenland Ice Sheet melting in response to global warming, this study provides long-term evidence of potential challenges predicting future patterns of the climate system.
Published: 2023

25. Structural and functional insights into the delivery of a bacterial Rhs pore-forming toxin to the membrane

Author: Wellcome Trust, Biotechnology and Biological Sciences Research Council (UK), Medical Research Council (UK), Fundación Biofísica Bizkaia, Ministerio de Ciencia e Innovación (España), European Commission, Agencia Estatal de Investigación (España), Eusko Jaurlaritza, Ikerbasque Basque Foundation for Science, Ministerio de Ciencia, Innovación y Universidades (España), Canadian HIV Trials Network Canadian Institutes of Health Research, Universidad Jaime I, Generalitat Valenciana, Burroughs Wellcome Fund, González-Magaña, Amaia [0000-0002-6007-8390], Tascón, Igor [0000-0003-2526-6238], Altuna, Jon [0000-0002-4993-7991], Albesa-Jové, David [0000-0003-2904-8203], González-Magaña, Amaia, Tascón, Igor, Altuna, Jon, Queralt, María, Colautti, Jake, Velázquez, Carmen, Zabala, Maialen, Rojas-Palomino, Jessica, Cárdenas, Marité, Alcaraz, Antonio, Whitney, John C., Ubarretxena, Iban, Albesa-Jové, David, Wellcome Trust, Biotechnology and Biological Sciences Research Council (UK), Medical Research Council (UK), Fundación Biofísica Bizkaia, Ministerio de Ciencia e Innovación (España), European Commission, Agencia Estatal de Investigación (España), Eusko Jaurlaritza, Ikerbasque Basque Foundation for Science, Ministerio de Ciencia, Innovación y Universidades (España), Canadian HIV Trials Network Canadian Institutes of Health Research, Universidad Jaime I, Generalitat Valenciana, Burroughs Wellcome Fund, González-Magaña, Amaia [0000-0002-6007-8390], Tascón, Igor [0000-0003-2526-6238], Altuna, Jon [0000-0002-4993-7991], Albesa-Jové, David [0000-0003-2904-8203], González-Magaña, Amaia, Tascón, Igor, Altuna, Jon, Queralt, María, Colautti, Jake, Velázquez, Carmen, Zabala, Maialen, Rojas-Palomino, Jessica, Cárdenas, Marité, Alcaraz, Antonio, Whitney, John C., Ubarretxena, Iban, and Albesa-Jové, David
Abstract: Bacterial competition is a significant driver of toxin polymorphism, which allows continual compensatory evolution between toxins and the resistance developed to overcome their activity. Bacterial Rearrangement hot spot (Rhs) proteins represent a widespread example of toxin polymorphism. Here, we present the 2.45 Å cryo-electron microscopy structure of Tse5, an Rhs protein central to Pseudomonas aeruginosa type VI secretion system-mediated bacterial competition. This structural insight, coupled with an extensive array of biophysical and genetic investigations, unravels the multifaceted functional mechanisms of Tse5. The data suggest that interfacial Tse5-membrane binding delivers its encapsulated pore-forming toxin fragment to the target bacterial membrane, where it assembles pores that cause cell depolarisation and, ultimately, bacterial death.
Published: 2023

26. Emergent mechanical control of vascular morphogenesis

Author: Wellcome Trust, Leverhulme Trust, Biotechnology and Biological Sciences Research Council (UK), Cancer Research UK, Francis Crick Institute, Medical Research Council (UK), Whisler, Jordan, Shahreza, Somayeh, Schlegelmilch, Karin, Ege, Nil, Javanmardi, Yousef, Malandrino, Andrea, Agrawal, Ayushi, Fantin, Alessandro, Serwinski, Bianca, Azizgolshani, Hesham, Park, Clara, Shone, Victoria, Demuren, Olukunle O., Del Rosario, Amanda, Butty, Vincent L., Holroyd, Natalie, Domart, Marie-Charlotte, Hooper, Steven, Szita, Nicolás, Boyer, Laurie A., Walker-Samuel, Simon, Djordjevic, Boris, Sheridan, Graham K., Collinson, Lucy, Calvo, Fernando, Ruhrberg, Christiana, Sahai, Erik, Kamm, Roger, Moeendarbary, Emad, Wellcome Trust, Leverhulme Trust, Biotechnology and Biological Sciences Research Council (UK), Cancer Research UK, Francis Crick Institute, Medical Research Council (UK), Whisler, Jordan, Shahreza, Somayeh, Schlegelmilch, Karin, Ege, Nil, Javanmardi, Yousef, Malandrino, Andrea, Agrawal, Ayushi, Fantin, Alessandro, Serwinski, Bianca, Azizgolshani, Hesham, Park, Clara, Shone, Victoria, Demuren, Olukunle O., Del Rosario, Amanda, Butty, Vincent L., Holroyd, Natalie, Domart, Marie-Charlotte, Hooper, Steven, Szita, Nicolás, Boyer, Laurie A., Walker-Samuel, Simon, Djordjevic, Boris, Sheridan, Graham K., Collinson, Lucy, Calvo, Fernando, Ruhrberg, Christiana, Sahai, Erik, Kamm, Roger, and Moeendarbary, Emad
Abstract: Vascularization is driven by morphogen signals and mechanical cues that coordinately regulate cellular force generation, migration, and shape change to sculpt the developing vascular network. However, it remains unclear whether developing vasculature actively regulates its own mechanical properties to achieve effective vascularization. We engineered tissue constructs containing endothelial cells and fibroblasts to investigate the mechanics of vascularization. Tissue stiffness increases during vascular morphogenesis resulting from emergent interactions between endothelial cells, fibroblasts, and ECM and correlates with enhanced vascular function. Contractile cellular forces are key to emergent tissue stiffening and synergize with ECM mechanical properties to modulate the mechanics of vascularization. Emergent tissue stiffening and vascular function rely on mechanotransduction signaling within fibroblasts, mediated by YAP1. Mouse embryos lacking YAP1 in fibroblasts exhibit both reduced tissue stiffness and develop lethal vascular defects. Translating our findings through biology-inspired vascular tissue engineering approaches will have substantial implications in regenerative medicine.
Published: 2023

27. Impact of AlphaFold on structure prediction of protein complexes: The CASP15-CAPRI experiment

Author: Francis Crick Institute, Cancer Research UK, Medical Research Council (UK), Wellcome Trust, European Commission, National Science Foundation (US), National Institutes of Health (US), Agencia Estatal de Investigación (España), Ministerio de Ciencia, Innovación y Universidades (España), Johns Hopkins University, National Natural Science Foundation of China, EMBO, Generalitat de Catalunya, Purdue University, National Science Centre (Poland), University of Warsaw, Research Council of Lithuania, Knut and Alice Wallenberg Foundation, Swedish Research Council, Lensink, Marc F., Brysbaert, Guillaume, Raouraoua, Nessim, Bates, Paul A., Giulini, Marco, Honorato, Rodrigo V., van Noort, Charlotte, Teixeira, Joao M. C., Bonvin, Alexandre M. J. J., Kong, Ren, Shi, Hang, Samsonov, Sergey A., Slusarz, Rafal, Zieba, Karolina, Sieradzan, Adam K., Czaplewski, Cezary, Kobayashi, Shinpei, Miyakawa, Yuta, Kiyota, Yasuomi, Takeda-Shitaka, Mayuko, Olechnovic, Kliment, Wallner, Bjorn, Valancauskas, Lukas, Dapkunas, Justas, Venclovas, Ceslovas, Yang, Lin, Hou, Chengyu, He, Xiaodong, Guo, Shuai, Jiang, Shenda, Ma, Xiaoliang, Duan, Rui, Qui, Liming, Xu, Xianjin, Lu, Xufeng, Zou, Xiaoqin, Velankar, Sameer, Wodak, Shoshana J., Chang, Shan, Liu, Jian, Guo, Zhiye, Chen, Xiao, Morehead, Alex, Roy, Raj S., Wu, Tianqi, Giri, Nabin, Quadir, Farhan, Chen, Chen, Cheng, Jianlin, Del Carpio, Carlos A., Ichiishi, Eichiro, Rodríguez-Lumbreras, Luis A., Fernández-Recio, Juan, Harmalkar, Ameya, Chu, Lee-Shin, Canner, Sam, Smanta, Rituparna, Gray, Jeffrey J., Li, Hao, Lin, Peicong, He, Jiahua, Tao, Huanyu, Huang, Sheng-You, Roel-Touris, Jorge, Jimenez-Garcia, Brian, Christoffer, Charles W., Jain, Anika J., Kagaya, Yuki, Kannan, Harini, Nakamura, Tsukasa, Terashi, Genki, Verburgt, Jacob C., Zhang, Yuanyuan, Zhang, Zicong, Fujuta, Hayato, Sekijima, Masakazu, Kihara, Daisuke, Khan, Omeir, Kotelnikov, Sergei, Ghani, Usman, Padhorny, Dzmitry, Beglov, Dmitri, Vajda, Sandor, Kozakov, Dima, Negi, Surendra S., Ricciardelli, Tiziana, Barradas-Bautista, Didier, Cao, Zhen, Chawla, Mohit, Cavallo, Luigi, Oliva, Romina, Yin, Rui, Cheung, Melyssa, Guest, Johnathan D., Lee, Jessica, Pierce, Brian G., Shor, Ben, Cohen, Tomer, Halfon, Matan, Schneidman-Duhovny, Dina, Zhu, Shaowen, Yin, Rujie, Sun, Yuanfei, Shen, Yang, Maszota-Zieleniak, Martyna, Bojarski, Krzysztof K., Lubecka, Emilia A., Marcisz, Mateusz, Danielsson, Annemarie, Dziadek, Lukasz, Gaardlos, Margrethe, Gieldon, Artur, Liwo, Adam, Francis Crick Institute, Cancer Research UK, Medical Research Council (UK), Wellcome Trust, European Commission, National Science Foundation (US), National Institutes of Health (US), Agencia Estatal de Investigación (España), Ministerio de Ciencia, Innovación y Universidades (España), Johns Hopkins University, National Natural Science Foundation of China, EMBO, Generalitat de Catalunya, Purdue University, National Science Centre (Poland), University of Warsaw, Research Council of Lithuania, Knut and Alice Wallenberg Foundation, Swedish Research Council, Lensink, Marc F., Brysbaert, Guillaume, Raouraoua, Nessim, Bates, Paul A., Giulini, Marco, Honorato, Rodrigo V., van Noort, Charlotte, Teixeira, Joao M. C., Bonvin, Alexandre M. J. J., Kong, Ren, Shi, Hang, Samsonov, Sergey A., Slusarz, Rafal, Zieba, Karolina, Sieradzan, Adam K., Czaplewski, Cezary, Kobayashi, Shinpei, Miyakawa, Yuta, Kiyota, Yasuomi, Takeda-Shitaka, Mayuko, Olechnovic, Kliment, Wallner, Bjorn, Valancauskas, Lukas, Dapkunas, Justas, Venclovas, Ceslovas, Yang, Lin, Hou, Chengyu, He, Xiaodong, Guo, Shuai, Jiang, Shenda, Ma, Xiaoliang, Duan, Rui, Qui, Liming, Xu, Xianjin, Lu, Xufeng, Zou, Xiaoqin, Velankar, Sameer, Wodak, Shoshana J., Chang, Shan, Liu, Jian, Guo, Zhiye, Chen, Xiao, Morehead, Alex, Roy, Raj S., Wu, Tianqi, Giri, Nabin, Quadir, Farhan, Chen, Chen, Cheng, Jianlin, Del Carpio, Carlos A., Ichiishi, Eichiro, Rodríguez-Lumbreras, Luis A., Fernández-Recio, Juan, Harmalkar, Ameya, Chu, Lee-Shin, Canner, Sam, Smanta, Rituparna, Gray, Jeffrey J., Li, Hao, Lin, Peicong, He, Jiahua, Tao, Huanyu, Huang, Sheng-You, Roel-Touris, Jorge, Jimenez-Garcia, Brian, Christoffer, Charles W., Jain, Anika J., Kagaya, Yuki, Kannan, Harini, Nakamura, Tsukasa, Terashi, Genki, Verburgt, Jacob C., Zhang, Yuanyuan, Zhang, Zicong, Fujuta, Hayato, Sekijima, Masakazu, Kihara, Daisuke, Khan, Omeir, Kotelnikov, Sergei, Ghani, Usman, Padhorny, Dzmitry, Beglov, Dmitri, Vajda, Sandor, Kozakov, Dima, Negi, Surendra S., Ricciardelli, Tiziana, Barradas-Bautista, Didier, Cao, Zhen, Chawla, Mohit, Cavallo, Luigi, Oliva, Romina, Yin, Rui, Cheung, Melyssa, Guest, Johnathan D., Lee, Jessica, Pierce, Brian G., Shor, Ben, Cohen, Tomer, Halfon, Matan, Schneidman-Duhovny, Dina, Zhu, Shaowen, Yin, Rujie, Sun, Yuanfei, Shen, Yang, Maszota-Zieleniak, Martyna, Bojarski, Krzysztof K., Lubecka, Emilia A., Marcisz, Mateusz, Danielsson, Annemarie, Dziadek, Lukasz, Gaardlos, Margrethe, Gieldon, Artur, and Liwo, Adam
Abstract: We present the results for CAPRI Round 54, the 5th joint CASP-CAPRI protein assembly prediction challenge. The Round offered 37 targets, including 14 homodimers, 3 homo-trimers, 13 heterodimers including 3 antibody-antigen complexes, and 7 large assemblies. On average ~70 CASP and CAPRI predictor groups, including more than 20 automatics servers, submitted models for each target. A total of 21 941 models submitted by these groups and by 15 CAPRI scorer groups were evaluated using the CAPRI model quality measures and the DockQ score consolidating these measures. The prediction performance was quantified by a weighted score based on the number of models of acceptable quality or higher submitted by each group among their five best models. Results show substantial progress achieved across a significant fraction of the 60+ participating groups. High-quality models were produced for about 40% of the targets compared to 8% two years earlier. This remarkable improvement is due to the wide use of the AlphaFold2 and AlphaFold2-Multimer software and the confidence metrics they provide. Notably, expanded sampling of candidate solutions by manipulating these deep learning inference engines, enriching multiple sequence alignments, or integration of advanced modeling tools, enabled top performing groups to exceed the performance of a standard AlphaFold2-Multimer version used as a yard stick. This notwithstanding, performance remained poor for complexes with antibodies and nanobodies, where evolutionary relationships between the binding partners are lacking, and for complexes featuring conformational flexibility, clearly indicating that the prediction of protein complexes remains a challenging problem.
Published: 2023

28. Genetically encoded imaging tools for investigating cell dynamics at a glance

Author: Cancer Research UK, UK Research and Innovation, Biotechnology and Biological Sciences Research Council (UK), Medical Research Council (UK), Human Frontier Science Program, Sittewelle, Méghane, Ferrándiz, Nuria, Fesenko, Mary, Royle, Stephen J., Cancer Research UK, UK Research and Innovation, Biotechnology and Biological Sciences Research Council (UK), Medical Research Council (UK), Human Frontier Science Program, Sittewelle, Méghane, Ferrándiz, Nuria, Fesenko, Mary, and Royle, Stephen J.
Abstract: The biology of a cell is the sum of many highly dynamic processes, each orchestrated by a plethora of proteins and other molecules. Microscopy is an invaluable approach to spatially and temporally dissect the molecular details of these processes. Hundreds of genetically encoded imaging tools have been developed that allow cell scientists to determine the function of a protein of interest in the context of these dynamic processes. Broadly, these tools fall into three strategies: observation, inhibition and activation. Using examples for each strategy, in this Cell Science at a Glance and the accompanying poster, we provide a guide to using these tools to dissect protein function in a given cellular process. Our focus here is on tools that allow rapid modification of proteins of interest and how observing the resulting changes in cell states is key to unlocking dynamic cell processes. The aim is to inspire the reader's next set of imaging experiments.
Published: 2023

29. The CCP4 suite: integrative software for macromolecular crystallography

Author: Royal Society (UK), Engineering and Physical Sciences Research Council (UK), European Commission, Medical Research Council (UK), Federal Ministry of Education and Research (Germany), German Research Foundation, Institute of Geology of the Czech Academy of Sciences, Netherlands Organization for Scientific Research, Dutch Cancer Society, Wellcome Trust, Ministerio de Ciencia e Innovación (España), Agencia Estatal de Investigación (España), Agirre, Jon, Atanasova, Mihaela, Bagdonas, Haroldas, Ballard, Charles B., Basle, A., Beilsten-Edmands, James, Borges, Rafael J., Brown, D. G., Burgos-Mármol, J. Javier, Berrisford, J., Bond, Paul S., Caballero, Iracema, Catapano, Lucrezia, Chojnowski, G., Cook, Atlanta G., Cowtan, K., Croll, Tristan I., Debreczeny, Judith E., Devenish, Nicholas E., Dodson, Eleanor J., Drevon, Tarik R., Emsley, Paul, Evans, Gwyndaf, Evans, Phil R., Fando, M., Foadi, James, Fuentes-Montero, Luis, Garman, Elspeth F., Gerstel, Markus, Gildea, Richard J., Hatti, Kaushik, Hekkelman, Maarten L., Heuser, Philipp, Wen Hoh, Soon, Hough, Michael A., Jenkins, Huw T., Jiménez, Elisabet, Joosten, Robbie P., Keegan, R. M., Keep, Nicholas, Krissinel, E., Kolenko, Petr, Kovalevskiy, O., Lamzin, V., Lawson, David M., Lebedev, Andrey, Leslie, A. G. W., Lohkamp, B., Long, Fei, Maly, Martin, McCoy, Airlie J., McNicholas, S., Medina, Ana, Millán, Claudia, Murray, James W., Murshudov, Garib, Nicholls, R. A., Noble, Martin E. M., Oeffner, Robert D., Pannu, Navraj S., Parkhurst, James M., Pearce, Nicholas, Pereira, Joana, Perrakis, Anastassis, Powell, Harold R., Read, Randy J., Rigden, D. J., Rochira, William, Sammito, Massimo, Sánchez Rodríguez, Filomeno, Sheldrick, George M., Shelley, Kathryn L., Simkovic, Felix, Simpkin, A. J., Skubák, P., Sobolev, Egor, Steiner, Roberto A., Stevenson, Kyle, Tews, I., Thomas, J. M. H., Thorn, Andrea, Triviño, Josep, Uski, V., Usón, Isabel, Vagin, Alexei, Velankar, Sameer, Vollmar, Melanie, Walden, Helen, Waterman, David, Wilson, Keith S., Winn, Martyn D., Winter, Graeme, Wojdyr, M., Yamashita, Keitaro, Royal Society (UK), Engineering and Physical Sciences Research Council (UK), European Commission, Medical Research Council (UK), Federal Ministry of Education and Research (Germany), German Research Foundation, Institute of Geology of the Czech Academy of Sciences, Netherlands Organization for Scientific Research, Dutch Cancer Society, Wellcome Trust, Ministerio de Ciencia e Innovación (España), Agencia Estatal de Investigación (España), Agirre, Jon, Atanasova, Mihaela, Bagdonas, Haroldas, Ballard, Charles B., Basle, A., Beilsten-Edmands, James, Borges, Rafael J., Brown, D. G., Burgos-Mármol, J. Javier, Berrisford, J., Bond, Paul S., Caballero, Iracema, Catapano, Lucrezia, Chojnowski, G., Cook, Atlanta G., Cowtan, K., Croll, Tristan I., Debreczeny, Judith E., Devenish, Nicholas E., Dodson, Eleanor J., Drevon, Tarik R., Emsley, Paul, Evans, Gwyndaf, Evans, Phil R., Fando, M., Foadi, James, Fuentes-Montero, Luis, Garman, Elspeth F., Gerstel, Markus, Gildea, Richard J., Hatti, Kaushik, Hekkelman, Maarten L., Heuser, Philipp, Wen Hoh, Soon, Hough, Michael A., Jenkins, Huw T., Jiménez, Elisabet, Joosten, Robbie P., Keegan, R. M., Keep, Nicholas, Krissinel, E., Kolenko, Petr, Kovalevskiy, O., Lamzin, V., Lawson, David M., Lebedev, Andrey, Leslie, A. G. W., Lohkamp, B., Long, Fei, Maly, Martin, McCoy, Airlie J., McNicholas, S., Medina, Ana, Millán, Claudia, Murray, James W., Murshudov, Garib, Nicholls, R. A., Noble, Martin E. M., Oeffner, Robert D., Pannu, Navraj S., Parkhurst, James M., Pearce, Nicholas, Pereira, Joana, Perrakis, Anastassis, Powell, Harold R., Read, Randy J., Rigden, D. J., Rochira, William, Sammito, Massimo, Sánchez Rodríguez, Filomeno, Sheldrick, George M., Shelley, Kathryn L., Simkovic, Felix, Simpkin, A. J., Skubák, P., Sobolev, Egor, Steiner, Roberto A., Stevenson, Kyle, Tews, I., Thomas, J. M. H., Thorn, Andrea, Triviño, Josep, Uski, V., Usón, Isabel, Vagin, Alexei, Velankar, Sameer, Vollmar, Melanie, Walden, Helen, Waterman, David, Wilson, Keith S., Winn, Martyn D., Winter, Graeme, Wojdyr, M., and Yamashita, Keitaro
Abstract: The Collaborative Computational Project No. 4 (CCP4) is a UK-led international collective with a mission to develop, test, distribute and promote software for macromolecular crystallography. The CCP4 suite is a multiplatform collection of programs brought together by familiar execution routines, a set of common libraries and graphical interfaces. The CCP4 suite has experienced several considerable changes since its last reference article, involving new infrastructure, original programs and graphical interfaces. This article, which is intended as a general literature citation for the use of the CCP4 software suite in structure determination, will guide the reader through such transformations, offering a general overview of the new features and outlining future developments. As such, it aims to highlight the individual programs that comprise the suite and to provide the latest references to them for perusal by crystallographers around the world.
Published: 2023

30. Roadmap for optical tweezers

Author: NASA Innovative Advanced Concepts, Australian Research Council, Japan Society for the Promotion of Science, Boğaziçi Üniversity, Novo Nordisk UK Research Foundation, Knut and Alice Wallenberg Foundation, Ministerio de Ciencia, Innovación y Universidades (España), Agencia Estatal de Investigación (España), Universidad Autónoma de Madrid, Conselho Nacional de Desenvolvimento Científico e Tecnológico (Brasil), Universidade Federal do Ceará, Agenzia Spaziale Italiana, Istituto Nazionale di Astrofisica, Agence Nationale de la Recherche (France), Wellcome Trust, Austrian Science Fund, Universidad Nacional Autónoma de México, European Commission, European Research Council, German Research Foundation, Natural Sciences and Engineering Research Council of Canada, Swedish Research Council, Engineering and Physical Sciences Research Council (UK), Office of Naval Research (US), National Science Foundation (US), Institute of Geology of the Czech Academy of Sciences, Czech Science Foundation, Generalitat de Catalunya, University of Münster, Department of Science and Technology (India), Human Frontier Science Program, Biotechnology and Biological Sciences Research Council (UK), Medical Research Council (UK), Danish National Research Foundation, Independent Research Fund Denmark, Beckman Institute, Associazione Italiana per la Ricerca sul Cancro, Volpe, Giovanni [0000-0001-5057-1846], Maragò, Onofrio M. [0000-0002-7220-8527], Rubinsztein-Dunlop, Halina [0000-0002-8332-2309], Stilgoe, Alexander B. [0000-0002-9299-5695], Volpe, Giorgio [0000-0001-9993-5348], Truong, Viet Giang [0000-0003-3589-7850], Chormaic, Síle Nic [0000-0003-4276-2014], Elahi, Parviz [0000-0003-3545-8436], Käll, Mikael [0000-0002-1163-0345], Callegari, Agnese [0000-0002-4488-4106], Neves, Antonio A. R. [0000-0002-2615-8573], Eismann, Jörg S. [0000-0002-2495-4613], Banzer, Peter [0000-0002-6336-6953], Roy, Basudev [0000-0003-0737-2889], Thalhammer-Thurner, Gregor [0000-0002-3948-8045], Ritsch-Marte, Monika [0000-0002-5945-546X], Pérez Castillo, Isaac0000-0001-7622-9440, Muenker, Till M. [0000-0003-3225-8746], Vos, Bart E. [0000-0002-4325-6298], Betz, Timo [0000-0002-1548-0655], Reece, Peter J. [0000-0003-4852-3735], McGloin, David [0000-0002-0075-4481], Gordon, Reuven [0000-0002-1485-6067], Bruce, Graham D. [0000-0003-3403-0614], Dholakia, Kishan [0000-0001-6534-9009], Roichman, Yael [0000-0003-1927-4506], Bobkova, Valeriia [0000-0003-4080-9069], Wittkowski, Raphael [0000-0003-4881-9173], Denz, Cornelia [0000-0002-7292-2499], Pavan Kumar, G. V. [0000-0002-4036-7187], Foti, Antonino [0000-0002-9824-3099], Donato, Maria Grazia [0000-0002-7580-3137], Gucciardi, Pietro G. [0000-0003-1826-9174], Gardini, Lucia [0000-0003-0923-9221], Kashchuk, Anatolii V. [0000-0002-2364-9393], Capitanio, Marco [0000-0002-9799-9353], Paterson, Lynn [0000-0003-0493-5041], Jones, Philip H. [0000-0002-0860-631X], Berg-Sørensen, Kirstine [0000-0002-9977-3980], Oddershede, Lene B. [0000-0003-2923-2844], Magazzù, Alessandro [0000-0003-1247-2702], Bronte Ciriza, David [0000-0002-5874-6601], Iatì, Maria Antonia [0000-0002-3576-8656], Swartzlander, Grover A. [0000-0003-3513-2225], Volpe, Giovanni, Maragò, Onofrio M., Rubinsztein-Dunlop, Halina, Pesce, Giuseppe, Stilgoe, Alexander B., Volpe, Giorgio, Tkachenko, Georgiy, Truong, Viet Giang, Chormaic, Síle Nic, Kalantarifard, Fatemeh, Elahi, Parviz, Käll, Mikael, Callegari, Agnese, Marqués, Manuel I., Neves, Antonio A. R., Moreira, Wendel L., Fontes, Adriana, César, Carlos L., Saija, Rosalba, Saidi, Abir, Beck, Paul, Eismann, Jörg S., Banzer, Peter, Fernandes, Thales F. D., Pedaci, Francesco, Bowen, Warwick P., Vaippully, Rahul, Lokesh, Muruga, Roy, Basudev, Thalhammer-Thurner, Gregor, Ritsch-Marte, Monika, Pérez García, Laura, Arzola, Alejandro V., Pérez Castillo, Isaac, Argun, Aykut, Muenker, Till M., Vos, Bart E., Betz, Timo, Cristiani, Ilaria, Minzioni, Paolo, Reece, Peter J., Wang, Fan, McGloin, David, Ndukaife, Justus C., Quidant, Romain, Roberts, Reece P., Laplane, Cyril, Volz, Thomas, Gordon, Reuven, Hanstorp, Dag, Tello Marmolejo, Javier, Bruce, Graham D., Dholakia, Kishan, Li, Tongcang, Brzobohatý, Oto, Simpson, Stephen H., Zemánek, Pavel, Ritort, Félix, Roichman, Yael, Bobkova, Valeriia, Wittkowski, Raphael, Denz, Cornelia, Pavan Kumar, G. V., Foti, Antonino, Donato, Maria Grazia, Gucciardi, Pietro G., Gardini, Lucia, Bianchi, Giulio, Kashchuk, Anatolii V., Capitanio, Marco, Paterson, Lynn, Jones, Philip H., Berg-Sørensen, Kirstine, Barooji, Younes F., Oddershede, Lene B., Pouladian, Pegah, Preece, Daryl, Adiels, Caroline Beck, De Luca, Anna Chiara, Magazzù, Alessandro, Bronte Ciriza, David, Iatì, Maria Antonia, Swartzlander, Grover A., NASA Innovative Advanced Concepts, Australian Research Council, Japan Society for the Promotion of Science, Boğaziçi Üniversity, Novo Nordisk UK Research Foundation, Knut and Alice Wallenberg Foundation, Ministerio de Ciencia, Innovación y Universidades (España), Agencia Estatal de Investigación (España), Universidad Autónoma de Madrid, Conselho Nacional de Desenvolvimento Científico e Tecnológico (Brasil), Universidade Federal do Ceará, Agenzia Spaziale Italiana, Istituto Nazionale di Astrofisica, Agence Nationale de la Recherche (France), Wellcome Trust, Austrian Science Fund, Universidad Nacional Autónoma de México, European Commission, European Research Council, German Research Foundation, Natural Sciences and Engineering Research Council of Canada, Swedish Research Council, Engineering and Physical Sciences Research Council (UK), Office of Naval Research (US), National Science Foundation (US), Institute of Geology of the Czech Academy of Sciences, Czech Science Foundation, Generalitat de Catalunya, University of Münster, Department of Science and Technology (India), Human Frontier Science Program, Biotechnology and Biological Sciences Research Council (UK), Medical Research Council (UK), Danish National Research Foundation, Independent Research Fund Denmark, Beckman Institute, Associazione Italiana per la Ricerca sul Cancro, Volpe, Giovanni [0000-0001-5057-1846], Maragò, Onofrio M. [0000-0002-7220-8527], Rubinsztein-Dunlop, Halina [0000-0002-8332-2309], Stilgoe, Alexander B. [0000-0002-9299-5695], Volpe, Giorgio [0000-0001-9993-5348], Truong, Viet Giang [0000-0003-3589-7850], Chormaic, Síle Nic [0000-0003-4276-2014], Elahi, Parviz [0000-0003-3545-8436], Käll, Mikael [0000-0002-1163-0345], Callegari, Agnese [0000-0002-4488-4106], Neves, Antonio A. R. [0000-0002-2615-8573], Eismann, Jörg S. [0000-0002-2495-4613], Banzer, Peter [0000-0002-6336-6953], Roy, Basudev [0000-0003-0737-2889], Thalhammer-Thurner, Gregor [0000-0002-3948-8045], Ritsch-Marte, Monika [0000-0002-5945-546X], Pérez Castillo, Isaac0000-0001-7622-9440, Muenker, Till M. [0000-0003-3225-8746], Vos, Bart E. [0000-0002-4325-6298], Betz, Timo [0000-0002-1548-0655], Reece, Peter J. [0000-0003-4852-3735], McGloin, David [0000-0002-0075-4481], Gordon, Reuven [0000-0002-1485-6067], Bruce, Graham D. [0000-0003-3403-0614], Dholakia, Kishan [0000-0001-6534-9009], Roichman, Yael [0000-0003-1927-4506], Bobkova, Valeriia [0000-0003-4080-9069], Wittkowski, Raphael [0000-0003-4881-9173], Denz, Cornelia [0000-0002-7292-2499], Pavan Kumar, G. V. [0000-0002-4036-7187], Foti, Antonino [0000-0002-9824-3099], Donato, Maria Grazia [0000-0002-7580-3137], Gucciardi, Pietro G. [0000-0003-1826-9174], Gardini, Lucia [0000-0003-0923-9221], Kashchuk, Anatolii V. [0000-0002-2364-9393], Capitanio, Marco [0000-0002-9799-9353], Paterson, Lynn [0000-0003-0493-5041], Jones, Philip H. [0000-0002-0860-631X], Berg-Sørensen, Kirstine [0000-0002-9977-3980], Oddershede, Lene B. [0000-0003-2923-2844], Magazzù, Alessandro [0000-0003-1247-2702], Bronte Ciriza, David [0000-0002-5874-6601], Iatì, Maria Antonia [0000-0002-3576-8656], Swartzlander, Grover A. [0000-0003-3513-2225], Volpe, Giovanni, Maragò, Onofrio M., Rubinsztein-Dunlop, Halina, Pesce, Giuseppe, Stilgoe, Alexander B., Volpe, Giorgio, Tkachenko, Georgiy, Truong, Viet Giang, Chormaic, Síle Nic, Kalantarifard, Fatemeh, Elahi, Parviz, Käll, Mikael, Callegari, Agnese, Marqués, Manuel I., Neves, Antonio A. R., Moreira, Wendel L., Fontes, Adriana, César, Carlos L., Saija, Rosalba, Saidi, Abir, Beck, Paul, Eismann, Jörg S., Banzer, Peter, Fernandes, Thales F. D., Pedaci, Francesco, Bowen, Warwick P., Vaippully, Rahul, Lokesh, Muruga, Roy, Basudev, Thalhammer-Thurner, Gregor, Ritsch-Marte, Monika, Pérez García, Laura, Arzola, Alejandro V., Pérez Castillo, Isaac, Argun, Aykut, Muenker, Till M., Vos, Bart E., Betz, Timo, Cristiani, Ilaria, Minzioni, Paolo, Reece, Peter J., Wang, Fan, McGloin, David, Ndukaife, Justus C., Quidant, Romain, Roberts, Reece P., Laplane, Cyril, Volz, Thomas, Gordon, Reuven, Hanstorp, Dag, Tello Marmolejo, Javier, Bruce, Graham D., Dholakia, Kishan, Li, Tongcang, Brzobohatý, Oto, Simpson, Stephen H., Zemánek, Pavel, Ritort, Félix, Roichman, Yael, Bobkova, Valeriia, Wittkowski, Raphael, Denz, Cornelia, Pavan Kumar, G. V., Foti, Antonino, Donato, Maria Grazia, Gucciardi, Pietro G., Gardini, Lucia, Bianchi, Giulio, Kashchuk, Anatolii V., Capitanio, Marco, Paterson, Lynn, Jones, Philip H., Berg-Sørensen, Kirstine, Barooji, Younes F., Oddershede, Lene B., Pouladian, Pegah, Preece, Daryl, Adiels, Caroline Beck, De Luca, Anna Chiara, Magazzù, Alessandro, Bronte Ciriza, David, Iatì, Maria Antonia, and Swartzlander, Grover A.
Abstract: Optical tweezers are tools made of light that enable contactless pushing, trapping, and manipulation of objects, ranging from atoms to space light sails. Since the pioneering work by Arthur Ashkin in the 1970s, optical tweezers have evolved into sophisticated instruments and have been employed in a broad range of applications in the life sciences, physics, and engineering. These include accurate force and torque measurement at the femtonewton level, microrheology of complex fluids, single micro- and nano-particle spectroscopy, single-cell analysis, and statistical-physics experiments. This roadmap provides insights into current investigations involving optical forces and optical tweezers from their theoretical foundations to designs and setups. It also offers perspectives for applications to a wide range of research fields, from biophysics to space exploration.
Published: 2023

31. Current Progress and Challenges in Large-Scale 3D Mitochondria Instance Segmentation

Author: National Science Foundation (US), National Institutes of Health (US), Universidad del País Vasco, Ministerio de Ciencia e Innovación (España), Agencia Estatal de Investigación (España), Francis Crick Institute, Cancer Research UK, Medical Research Council (UK), Wellcome Trust, Frederick National Laboratory for Cancer Research (US), Franco-Barranco, Daniel, Lin, Zudi, Jang, Won-Dong, Wang, Xueying, Shen, Qijia, Yin, Wenjie, Fan, Yutian, Li, Mingxing, Chen, Chang, Xiong, Zhiwei, Xin, Rui, Liu, Hao, Chen, Huai, Li, Zhili, Zhao, Jie, Chen, Xuejin, Pape, Constantin, Conrad, Ryan, Nightingale, Luke, Folter, Joost de, Jones, Martin L., Liu, Yanling, Ziaei, Dorsa, Huschauer, Stephan, Arganda-Carreras, Ignacio, Pfister, Hanspeter, Wei, Donglai, National Science Foundation (US), National Institutes of Health (US), Universidad del País Vasco, Ministerio de Ciencia e Innovación (España), Agencia Estatal de Investigación (España), Francis Crick Institute, Cancer Research UK, Medical Research Council (UK), Wellcome Trust, Frederick National Laboratory for Cancer Research (US), Franco-Barranco, Daniel, Lin, Zudi, Jang, Won-Dong, Wang, Xueying, Shen, Qijia, Yin, Wenjie, Fan, Yutian, Li, Mingxing, Chen, Chang, Xiong, Zhiwei, Xin, Rui, Liu, Hao, Chen, Huai, Li, Zhili, Zhao, Jie, Chen, Xuejin, Pape, Constantin, Conrad, Ryan, Nightingale, Luke, Folter, Joost de, Jones, Martin L., Liu, Yanling, Ziaei, Dorsa, Huschauer, Stephan, Arganda-Carreras, Ignacio, Pfister, Hanspeter, and Wei, Donglai
Abstract: In this paper, we present the results of the MitoEM challenge on mitochondria 3D instance segmentation from electron microscopy images, organized in conjunction with the IEEE-ISBI 2021 conference. Our benchmark dataset consists of two large-scale 3D volumes, one from human and one from rat cortex tissue, which are 1,986 times larger than previously used datasets. At the time of paper submission, 257 participants had registered for the challenge, 14 teams had submitted their results, and six teams participated in the challenge workshop. Here, we present eight top-performing approaches from the challenge participants, along with our own baseline strategies. Posterior to the challenge, annotation errors in the ground truth were corrected without altering the final ranking. Additionally, we present a retrospective evaluation of the scoring system which revealed that: 1) challenge metric was permissive with the false positive predictions; and 2) size-based grouping of instances did not correctly categorize mitochondria of interest. Thus, we propose a new scoring system that better reflects the correctness of the segmentation results. Although several of the top methods are compared favorably to our own baselines, substantial errors remain unsolved for mitochondria with challenging morphologies. Thus, the challenge remains open for submission and automatic evaluation, with all volumes available for download.
Published: 2023

32. Pseudotyping Bacteriophage P2 Tail Fibers to Extend the Host Range for Biomedical Applications

Author: British Columbia Knowledge Development Fund, Medical Research Council (UK), Ministerio de Ciencia, Innovación y Universidades (España), Agencia Estatal de Investigación (España), Biotechnology and Biological Sciences Research Council (UK), University of Warwick, Engineering and Physical Sciences Research Council (UK), European Commission, Cunliffe, Tabitha G., Parker, Alan L., Jaramillo, Alfonso, British Columbia Knowledge Development Fund, Medical Research Council (UK), Ministerio de Ciencia, Innovación y Universidades (España), Agencia Estatal de Investigación (España), Biotechnology and Biological Sciences Research Council (UK), University of Warwick, Engineering and Physical Sciences Research Council (UK), European Commission, Cunliffe, Tabitha G., Parker, Alan L., and Jaramillo, Alfonso
Abstract: Bacteriophages (phages) represent powerful potential treatments against antibiotic-resistant bacterial infections. Antibiotic-resistant bacteria represent a significant threat to global health, with an estimated 70% of infection-causing bacteria being resistant to one or more antibiotics. Developing novel antibiotics against the limited number of cellular targets is expensive and time-consuming, and bacteria can rapidly develop resistance. While bacterial resistance to phage can evolve, bacterial resistance to phage does not appear to spread through lateral gene transfer, and phage may similarly adapt through mutation to recover infectivity. Phages have been identified for all known bacteria, allowing the strain-selective killing of pathogenic bacteria. Here, we re-engineered the Escherichia coli phage P2 to alter its tropism toward pathogenic bacteria. Chimeric tail fibers formed between P2 and S16 genes were designed and generated through two approaches: homology- and literature-based. By presenting chimeric P2:S16 fibers on the P2 particle, our data suggests that the resultant phages were effectively detargeted from the native P2 cellular target, lipopolysaccharide, and were instead able to infect via the proteinaceous receptor, OmpC, the natural S16 receptor. Our work provides evidence that pseudotyping P2 is feasible and can be used to extend the host range of P2 to alternative receptors. Extension of this work could produce alternative chimeric tail fibers to target pathogenic bacterial threats. Our engineering of P2 allows adsorption through a heterologous outer-membrane protein without culturing in its native host, thus providing a potential means of engineering designer phages against pathogenic bacteria from knowledge of their surface proteome.
Published: 2022

33. CCP4 Cloud for structure determination and project management in macromolecular crystallography

Author: Biotechnology and Biological Sciences Research Council (UK), Medical Research Council (UK), Krissinel, E., Lebedev, Andrey, Uski, V., Ballard, Charles B., Keegan, R. M., Kovalevskiy, O., Nicholls, R. A., Pannu, Navraj S., Skubák, P., Berrisford, J., Fando, M., Lohkamp, B., Wojdyr, M., Simpkin, A. J., Thomas, J. M. H., Oliver, C., Vonrhein, C., Chojnowski, G., Basle, A., Purkiss, A., Isupov, M. N., McNicholas, S., Lowe, E., Triviño, Josep, Cowtan, K., Agirre, Jon, Rigden, D. J., Usón, Isabel, Lamzin, V., Tews, I., Bricogne, G., Leslie, A. G. W., Brown, D. G., Biotechnology and Biological Sciences Research Council (UK), Medical Research Council (UK), Krissinel, E., Lebedev, Andrey, Uski, V., Ballard, Charles B., Keegan, R. M., Kovalevskiy, O., Nicholls, R. A., Pannu, Navraj S., Skubák, P., Berrisford, J., Fando, M., Lohkamp, B., Wojdyr, M., Simpkin, A. J., Thomas, J. M. H., Oliver, C., Vonrhein, C., Chojnowski, G., Basle, A., Purkiss, A., Isupov, M. N., McNicholas, S., Lowe, E., Triviño, Josep, Cowtan, K., Agirre, Jon, Rigden, D. J., Usón, Isabel, Lamzin, V., Tews, I., Bricogne, G., Leslie, A. G. W., and Brown, D. G.
Abstract: Nowadays, progress in the determination of three-dimensional macromolecular structures from diffraction images is achieved partly at the cost of increasing data volumes. This is due to the deployment of modern high-speed, high-resolution detectors, the increased complexity and variety of crystallographic software, the use of extensive databases and high-performance computing. This limits what can be accomplished with personal, offline, computing equipment in terms of both productivity and maintainability. There is also an issue of long-term data maintenance and availability of structure-solution projects as the links between experimental observations and the final results deposited in the PDB. In this article, CCP4 Cloud, a new front-end of the CCP4 software suite, is presented which mitigates these effects by providing an online, cloud-based environment for crystallographic computation. CCP4 Cloud was developed for the efficient delivery of computing power, database services and seamless integration with web resources. It provides a rich graphical user interface that allows project sharing and long-term storage for structure-solution projects, and can be linked to data-producing facilities. The system is distributed with the CCP4 software suite version 7.1 and higher, and an online publicly available instance of CCP4 Cloud is provided by CCP4.
Published: 2022

34. Standardized annotation of translated open reading frames

Author: Wellcome Trust, National Human Genome Research Institute (US), European Molecular Biology Laboratory, National Institutes of Health (US), State Secretariat for Education, Research and Innovation (Switzerland), Stowers Institute for Medical Research, Cancer Prevention and Research Institute of Texas, Howard Hughes Medical Institute, Russian Science Foundation, European Research Council, European Commission, Fondation Leducq, Canadian Institutes of Health Research, Canada Research Chairs, National Science Foundation (US), Medical Research Council (UK), Fonds de Recherche du Québec, Mudge, Jonathan M., Ruiz-Orera, Jorge, Prensner, John R., Brunet, Marie A., Calvet, Ferriol, Jungreis, Irwin, González, José Manuel, Magrane, Michele, Martinez, Thomas F., Felicitas Schulz, Jana, Yang, Yucheng T., Albà, M. Mar, Aspden, Julie Louise, Baranov, Pavel V., Bazzini, Ariel A., Bruford, Elspeth, Martín, María Jesús, Calviello, Lorenzo, Chen, Jin, Couso, Juan Pablo, Deutsch, Eric W., Flicek, Paul, Frankish, Adam, Gerstein, Mark, Hubner, Norbert, Ingolia, Nicholas T., Kellis, Manolis, Menschaert, Gerben, Moritz, Robert L., Ohler, Uwe, Roucou, Xavier, Saghatelian, Alan, Weissman, Jonathan S., Heesch, Sebastiaan van, Wellcome Trust, National Human Genome Research Institute (US), European Molecular Biology Laboratory, National Institutes of Health (US), State Secretariat for Education, Research and Innovation (Switzerland), Stowers Institute for Medical Research, Cancer Prevention and Research Institute of Texas, Howard Hughes Medical Institute, Russian Science Foundation, European Research Council, European Commission, Fondation Leducq, Canadian Institutes of Health Research, Canada Research Chairs, National Science Foundation (US), Medical Research Council (UK), Fonds de Recherche du Québec, Mudge, Jonathan M., Ruiz-Orera, Jorge, Prensner, John R., Brunet, Marie A., Calvet, Ferriol, Jungreis, Irwin, González, José Manuel, Magrane, Michele, Martinez, Thomas F., Felicitas Schulz, Jana, Yang, Yucheng T., Albà, M. Mar, Aspden, Julie Louise, Baranov, Pavel V., Bazzini, Ariel A., Bruford, Elspeth, Martín, María Jesús, Calviello, Lorenzo, Chen, Jin, Couso, Juan Pablo, Deutsch, Eric W., Flicek, Paul, Frankish, Adam, Gerstein, Mark, Hubner, Norbert, Ingolia, Nicholas T., Kellis, Manolis, Menschaert, Gerben, Moritz, Robert L., Ohler, Uwe, Roucou, Xavier, Saghatelian, Alan, Weissman, Jonathan S., and Heesch, Sebastiaan van
Abstract: Ribosome profiling (Ribo-seq) has extended our understanding of the translational ‘vocabulary’ of the human genome, uncovering thousands of open reading frames (ORFs) within long noncoding RNAs (lncRNAs) and presumed untranslated regions (UTRs) of protein-coding genes. However, reference gene annotation projects have been circumspect in their incorporation of these ORFs because of uncertainties about their experimental reproducibility and physiological roles. Yet, it is clear that certain ‘Ribo-seq ORFs’ make stable proteins, others mediate gene regulation, and many have medical implications. Ultimately, the absence of standardized ORF annotation has created a circular problem: while Ribo-seq ORFs remain unrecognized by reference annotation databases, this lack of recognition will thwart studies examining their roles. Here, we outline a community-led effort involving Ensembl/GENCODE, the HUGO Gene Nomenclature Committee (HGNC), UniProtKB, HUPO/HPP and PeptideAtlas to produce a standardized catalog of 7,264 human Ribo-seq ORFs; a path to bring protein-level evidence for Ribo-seq ORFs into reference annotation databases; and a roadmap to facilitate research in the global community.
Published: 2022

35. Dipeptide repeat pathology in C9orf72-ALS is associated with redox, mitochondrial and NRF2 pathway imbalance

Author: Ministerio de Ciencia, Innovación y Universidades (España), Agencia Estatal de Investigación (España), Fundación Tatiana Pérez de Guzmán el Bueno, Medical Research Council (UK), Instituto de Salud Carlos III, Universidad Autónoma de Madrid, Motor Neuron Disease Association, National Institute for Health and Care Research (US), European Cooperation in Science and Technology, Jiménez-Villegas, José, Kirby, Janine, Mata, Ana M., Cadenas, Susana, Turner, Martin R., Malaspina, Andrea, Shaw, Pamela J., Cuadrado, Antonio, Rojo, Ana I., Ministerio de Ciencia, Innovación y Universidades (España), Agencia Estatal de Investigación (España), Fundación Tatiana Pérez de Guzmán el Bueno, Medical Research Council (UK), Instituto de Salud Carlos III, Universidad Autónoma de Madrid, Motor Neuron Disease Association, National Institute for Health and Care Research (US), European Cooperation in Science and Technology, Jiménez-Villegas, José, Kirby, Janine, Mata, Ana M., Cadenas, Susana, Turner, Martin R., Malaspina, Andrea, Shaw, Pamela J., Cuadrado, Antonio, and Rojo, Ana I.
Abstract: The hexanucleotide expansion of the C9orf72 gene is found in 40% of familial amyotrophic lateral sclerosis (ALS) patients. This genetic alteration has been connected with impaired management of reactive oxygen species. In this study, we conducted targeted transcriptional profiling in leukocytes from C9orf72 patients and control subjects by examining the mRNA levels of 84 redox-related genes. The expression of ten redox genes was altered in samples from C9orf72 ALS patients compared to healthy controls. Considering that Nuclear factor erythroid 2-Related Factor 2 (NRF2) modulates the expression of a wide range of redox genes, we further investigated its status on an in vitro model of dipeptide repeat (DPR) toxicity. This model mimics the gain of function, toxic mechanisms attributed to C9orf72 pathology. We found that exposure to DPRs increased superoxide levels and reduced mitochondrial potential as well as cell survival. Importantly, cells overexpressing DPRs exhibited reduced protein levels of NRF2 and its target genes upon inhibition of the proteasome or its canonical repressor, the E3 ligase adapter KEAP1. However, NRF2 activation was sufficient to recover cell viability and redox homeostasis. This study identifies NRF2 as a putative target in precision medicine for the therapy of ALS patients harboring C9orf72 expansion repeats.
Published: 2022

36. A deep graph neural network architecture for modelling spatio-temporal dynamics in resting-state functional MRI data

Author: W. D. Armstrong Trust Fund, University of Cambridge, British Academy, Autism Research Trust, Guarantors of Brain, Medical Research Council (UK), Azevedo, Tiago, Campbell, Alexander, Romero García, Rafael, Passamonti, Luca, Bethlehem, Richard A. I., Liò, Pietro, Toschi, Nicola, W. D. Armstrong Trust Fund, University of Cambridge, British Academy, Autism Research Trust, Guarantors of Brain, Medical Research Council (UK), Azevedo, Tiago, Campbell, Alexander, Romero García, Rafael, Passamonti, Luca, Bethlehem, Richard A. I., Liò, Pietro, and Toschi, Nicola
Abstract: Resting-state functional magnetic resonance imaging (rs-fMRI) has been successfully employed to understand the organisation of the human brain. Typically, the brain is parcellated into regions of interest (ROIs) and modelled as a graph where each ROI represents a node and association measures between ROI-specific blood-oxygen-level-dependent (BOLD) time series are edges. Recently, graph neural networks (GNNs) have seen a surge in popularity due to their success in modelling unstructured relational data. The latest developments with GNNs, however, have not yet been fully exploited for the analysis of rs-fMRI data, particularly with regards to its spatio-temporal dynamics. In this paper, we present a novel deep neural network architecture which combines both GNNs and temporal convolutional networks (TCNs) in order to learn from both the spatial and temporal components of rs-fMRI data in an end-to-end fashion. In particular, this corresponds to intra-feature learning (i.e., learning temporal dynamics with TCNs) as well as inter-feature learning (i.e., leveraging interactions between ROI-wise dynamics with GNNs). We evaluate our model with an ablation study using 35,159 samples from the UK Biobank rs-fMRI database, as well as in the smaller Human Connectome Project (HCP) dataset, both in a unimodal and in a multimodal fashion. We also demonstrate that out architecture contains explainability-related features which easily map to realistic neurobiological insights. We suggest that this model could lay the groundwork for future deep learning architectures focused on leveraging the inherently and inextricably spatio-temporal nature of rs-fMRI data.
Published: 2022

37. Assessing the digenic model in rare disorders using population sequencing data

Author: Ministerio de Ciencia e Innovación (España), Agencia Estatal de Investigación (España), European Commission, Generalitat de Catalunya, Department of Health & Social Care (UK), National Institute for Health Research (UK), National Health Service (UK), Wellcome Trust, Medical Research Council (UK), Moreno-Ruiz, Nerea [0000-0002-9636-0179], Lao, Oscar [0000-0002-8525-9649], Arostegui, Juan Ignacio [0000-0003-4757-504X], Laayouni, Hafid [0000-0003-1297-5078], Casals, Ferran [0000-0002-8941-0369], Moreno-Ruiz, Nerea, Lao, Oscar, Arostegui, Juan Ignacio, Laayouni, Hafid, Casals, Ferran, Genomics England Research Consortium, Ministerio de Ciencia e Innovación (España), Agencia Estatal de Investigación (España), European Commission, Generalitat de Catalunya, Department of Health & Social Care (UK), National Institute for Health Research (UK), National Health Service (UK), Wellcome Trust, Medical Research Council (UK), Moreno-Ruiz, Nerea [0000-0002-9636-0179], Lao, Oscar [0000-0002-8525-9649], Arostegui, Juan Ignacio [0000-0003-4757-504X], Laayouni, Hafid [0000-0003-1297-5078], Casals, Ferran [0000-0002-8941-0369], Moreno-Ruiz, Nerea, Lao, Oscar, Arostegui, Juan Ignacio, Laayouni, Hafid, Casals, Ferran, and Genomics England Research Consortium
Abstract: An important fraction of patients with rare disorders remains with no clear genetic diagnostic, even after whole-exome or whole-genome sequencing, posing a difficulty in giving adequate treatment and genetic counseling. The analysis of genomic data in rare disorders mostly considers the presence of single gene variants in coding regions that follow a concrete monogenic mode of inheritance. A digenic inheritance, with variants in two functionally-related genes in the same individual, is a plausible alternative that might explain the genetic basis of the disease in some cases. In this case, digenic disease combinations should be absent or underrepresented in healthy individuals. We develop a framework to evaluate the significance of digenic combinations and test its statistical power in different scenarios. We suggest that this approach will be relevant with the advent of new sequencing efforts including hundreds of thousands of samples.
Published: 2022

38. Whole-genome sequencing reveals host factors underlying critical COVID-19

Author: Department of Health & Social Care (UK), Medical Research Council (UK), Roslin Institute, Pérez-Tur, Jordi [0000-0002-9111-1712], Kousathanas, Athanasios, Pairo-Castineira, Erola, Rawlik, Konrad, Stuckey, Alex, Odhams, Christopher A., Walker, Susan, Russell, Clark D., Malinauskas, Tomas, Wu, Yang, Millar, Jonathan, Shen, Xia, Elliott, Katherine S., Griffiths, Fiona, Oosthuyzen, Wilna, Morrice, Kirstie, Keating, Sean, Wang, Bo, Rhodes, Daniel, Klaric, Lucija, Zechner, Marie, Parkinson, Nick, Siddiq, Afshan, Goddard, Peter, Donovan, Sally, Maslove, David, Nichol, Alistair, Semple, Malcolm G., Zainy, Tala, Maleady-Crowe, Fiona, Todd, Linda, Salehi, Shahla, Knight, Julian, Elgar, Greg, Chan, Georgia, Arumugam, Prabhu, Patch, Christine, Rendon, Augusto, Bentley, David, Kingsley, Clare, Kosmicki, Jack A., Horowitz, Julie E., Baras, Aris, Abecasis, Goncalo R., Ferreira, Manuel A. R., Justice, Anne, Mirshahi, Tooraj, Oetjens, Matthew, Rader, Daniel J., Ritchie, Marylyn D., Verma, Anurag, Fowler, Tom A., Shankar-Hari, Manu, Summers, Charlotte, Hinds, Charles, Horby, Peter, Ling, Lowell, McAuley, Danny, Montgomery, Hugh, Openshaw, Peter J. M., Elliott, Paul, Walsh, Timothy, Tenesa, Albert, Fawkes, Angie, Murphy, Lee, Rowan, Kathy, Ponting, Chris P., Vitart, Veronique, Wilson, James F., Yang, Jian, Bretherick, Andrew D., Scott, Richard H., Hendry, Sara Clohisey, Moutsianas, Loukas, Law, Andy, Caulfield, Mark J., Pérez-Tur, Jordi, Llucià-Carol, Laia, DeDiego, Marta L., Lloret Iglesias, Lara, Planas, Anna M., Márquez, Leonardo, Bernardo, David, Domínguez-Mayoral, Ana, Montaner, Joan, Menéndez-Valladares, Paloma, Baillie, J Kenneth, Department of Health & Social Care (UK), Medical Research Council (UK), Roslin Institute, Pérez-Tur, Jordi [0000-0002-9111-1712], Kousathanas, Athanasios, Pairo-Castineira, Erola, Rawlik, Konrad, Stuckey, Alex, Odhams, Christopher A., Walker, Susan, Russell, Clark D., Malinauskas, Tomas, Wu, Yang, Millar, Jonathan, Shen, Xia, Elliott, Katherine S., Griffiths, Fiona, Oosthuyzen, Wilna, Morrice, Kirstie, Keating, Sean, Wang, Bo, Rhodes, Daniel, Klaric, Lucija, Zechner, Marie, Parkinson, Nick, Siddiq, Afshan, Goddard, Peter, Donovan, Sally, Maslove, David, Nichol, Alistair, Semple, Malcolm G., Zainy, Tala, Maleady-Crowe, Fiona, Todd, Linda, Salehi, Shahla, Knight, Julian, Elgar, Greg, Chan, Georgia, Arumugam, Prabhu, Patch, Christine, Rendon, Augusto, Bentley, David, Kingsley, Clare, Kosmicki, Jack A., Horowitz, Julie E., Baras, Aris, Abecasis, Goncalo R., Ferreira, Manuel A. R., Justice, Anne, Mirshahi, Tooraj, Oetjens, Matthew, Rader, Daniel J., Ritchie, Marylyn D., Verma, Anurag, Fowler, Tom A., Shankar-Hari, Manu, Summers, Charlotte, Hinds, Charles, Horby, Peter, Ling, Lowell, McAuley, Danny, Montgomery, Hugh, Openshaw, Peter J. M., Elliott, Paul, Walsh, Timothy, Tenesa, Albert, Fawkes, Angie, Murphy, Lee, Rowan, Kathy, Ponting, Chris P., Vitart, Veronique, Wilson, James F., Yang, Jian, Bretherick, Andrew D., Scott, Richard H., Hendry, Sara Clohisey, Moutsianas, Loukas, Law, Andy, Caulfield, Mark J., Pérez-Tur, Jordi, Llucià-Carol, Laia, DeDiego, Marta L., Lloret Iglesias, Lara, Planas, Anna M., Márquez, Leonardo, Bernardo, David, Domínguez-Mayoral, Ana, Montaner, Joan, Menéndez-Valladares, Paloma, and Baillie, J Kenneth
Abstract: Critical COVID-19 is caused by immune-mediated inflammatory lung injury. Host genetic variation influences the development of illness requiring critical care1 or hospitalization2-4 after infection with SARS-CoV-2. The GenOMICC (Genetics of Mortality in Critical Care) study enables the comparison of genomes from individuals who are critically ill with those of population controls to find underlying disease mechanisms. Here we use whole-genome sequencing in 7,491 critically ill individuals compared with 48,400 controls to discover and replicate 23 independent variants that significantly predispose to critical COVID-19. We identify 16 new independent associations, including variants within genes that are involved in interferon signalling (IL10RB and PLSCR1), leucocyte differentiation (BCL11A) and blood-type antigen secretor status (FUT2). Using transcriptome-wide association and colocalization to infer the effect of gene expression on disease severity, we find evidence that implicates multiple genes-including reduced expression of a membrane flippase (ATP11A), and increased expression of a mucin (MUC1)-in critical disease. Mendelian randomization provides evidence in support of causal roles for myeloid cell adhesion molecules (SELE, ICAM5 and CD209) and the coagulation factor F8, all of which are potentially druggable targets. Our results are broadly consistent with a multi-component model of COVID-19 pathophysiology, in which at least two distinct mechanisms can predispose to life-threatening disease: failure to control viral replication; or an enhanced tendency towards pulmonary inflammation and intravascular coagulation. We show that comparison between cases of critical illness and population controls is highly efficient for the detection of therapeutically relevant mechanisms of disease.
Published: 2022

39. Fluorogenic Granzyme A substrates enable real-time imaging of adaptive immune cell activity

Author: Gobierno de Aragón, Ministerio de Ciencia e Innovación (España), Agencia Estatal de Investigación (España), Centro de Investigación Biomédica en Red de Enfermedades Infecciosas (España), Instituto de Salud Carlos III, European Commission, Ministerio de Ciencia, Innovación y Universidades (España), Medical Research Council (UK), Cancer Research UK, European Research Council, Mendive-Tapia, Lorena [0000-0002-3406-5203], Kitamura, Takanori [0000-0003-2032-3918], Samarakoon, Youhani [0000-0002-9845-4232], Roberts, Edward W. [0000-0002-8229-1715], Arias, Maykel [0000-0002-9730-2210], Pardo, Julián [0000-0003-0154-0730], Gálvez Buerba, Eva Mª [0000-0001-6928-5516], Cheng, Zhiming, Thompson, Emily J., Mendive-Tapia, Lorena, Scott, Jamie I., Benson, Sam, Kitamura, Takanori, Senán Salinas, Ana, Samarakoon, Youhani, Roberts, Edward W., Arias, Maykel, Pardo, Julián, Gálvez Buerba, Eva Mª, Gobierno de Aragón, Ministerio de Ciencia e Innovación (España), Agencia Estatal de Investigación (España), Centro de Investigación Biomédica en Red de Enfermedades Infecciosas (España), Instituto de Salud Carlos III, European Commission, Ministerio de Ciencia, Innovación y Universidades (España), Medical Research Council (UK), Cancer Research UK, European Research Council, Mendive-Tapia, Lorena [0000-0002-3406-5203], Kitamura, Takanori [0000-0003-2032-3918], Samarakoon, Youhani [0000-0002-9845-4232], Roberts, Edward W. [0000-0002-8229-1715], Arias, Maykel [0000-0002-9730-2210], Pardo, Julián [0000-0003-0154-0730], Gálvez Buerba, Eva Mª [0000-0001-6928-5516], Cheng, Zhiming, Thompson, Emily J., Mendive-Tapia, Lorena, Scott, Jamie I., Benson, Sam, Kitamura, Takanori, Senán Salinas, Ana, Samarakoon, Youhani, Roberts, Edward W., Arias, Maykel, Pardo, Julián, and Gálvez Buerba, Eva Mª
Abstract: Cytotoxic immune cells, including T lymphocytes (CTLs) and natural killer (NK) cells, are essential components of the host response against tumors. CTLs and NK cells secrete granzyme A (GzmA) upon recognition of cancer cells; however, there are very few tools that can detect physiological levels of active GzmA with high spatiotemporal resolution. Herein, we report the rational design of the near-infrared fluorogenic substrates for human GzmA and mouse GzmA. These activity-based probes display very high catalytic efficiency and selectivity over other granzymes, as shown in tissue lysates from wild-type and GzmA knock-out mice. Furthermore, we demonstrate that the probes can image how adaptive immune cells respond to antigen-driven recognition of cancer cells in real time.
Published: 2022

40. Regenerative neurology and regenerative cardiology: Shared hurdles and achievements

Author: Croatian Science Foundation, European Commission, Università degli Studi del Piemonte Orientale “A. Avogadro”, Ministry of Education, Science and Technological Development (Serbia), Medical Research Council (UK), National Innovation Office (Hungary), Ministerio de Ciencia, Innovación y Universidades (España), Agencia Estatal de Investigación (España), Instituto de Salud Carlos III, National Science Centre (Poland), Mitrečić, Dinko, Hribljan, Valentina, Jagečić, Denis, Isaković, Jasmina, Lamberto, Federica, Horánszky, Alex, Zana, Melinda, Foldes, Gabor, Zavan, Barbara, Pivoriūnas, Augustas, Martínez, Salvador, Mazzini, Letizia, Radenovic, Lidija, Milasin, Jelena, Chachques, Juan Carlos, Buzanska, Leonora, Song, Min Suk, Dinnyés, András, Croatian Science Foundation, European Commission, Università degli Studi del Piemonte Orientale “A. Avogadro”, Ministry of Education, Science and Technological Development (Serbia), Medical Research Council (UK), National Innovation Office (Hungary), Ministerio de Ciencia, Innovación y Universidades (España), Agencia Estatal de Investigación (España), Instituto de Salud Carlos III, National Science Centre (Poland), Mitrečić, Dinko, Hribljan, Valentina, Jagečić, Denis, Isaković, Jasmina, Lamberto, Federica, Horánszky, Alex, Zana, Melinda, Foldes, Gabor, Zavan, Barbara, Pivoriūnas, Augustas, Martínez, Salvador, Mazzini, Letizia, Radenovic, Lidija, Milasin, Jelena, Chachques, Juan Carlos, Buzanska, Leonora, Song, Min Suk, and Dinnyés, András
Abstract: From the first success in cultivation of cells in vitro, it became clear that developing cell and/or tissue specific cultures would open a myriad of new opportunities for medical research. Expertise in various in vitro models has been developing over decades, so nowadays we benefit from highly specific in vitro systems imitating every organ of the human body. Moreover, obtaining sufficient number of standardized cells allows for cell transplantation approach with the goal of improving the regeneration of injured/disease affected tissue. However, different cell types bring different needs and place various types of hurdles on the path of regenerative neurology and regenerative cardiology. In this review, written by European experts gathered in Cost European action dedicated to neurology and cardiology-Bioneca, we present the experience acquired by working on two rather different organs: the brain and the heart. When taken into account that diseases of these two organs, mostly ischemic in their nature (stroke and heart infarction), bring by far the largest burden of the medical systems around Europe, it is not surprising that in vitro models of nervous and heart muscle tissue were in the focus of biomedical research in the last decades. In this review we describe and discuss hurdles which still impair further progress of regenerative neurology and cardiology and we detect those ones which are common to both fields and some, which are field-specific. With the goal to elucidate strategies which might be shared between regenerative neurology and cardiology we discuss methodological solutions which can help each of the fields to accelerate their development.
Published: 2022

41. Epithelial and sensory mechanisms of nasal hyperreactivity

Author: Medical Research Council (UK), KU Leuven, Research Foundation - Flanders, Agencia Estatal de Investigación (España), Ministerio de Ciencia, Innovación y Universidades (España), Generalitat Valenciana, Velasco, Enrique, Delicado-Miralles, Miguel, Hellings, Peter W., Gallar, Juana, Gerven, Laura van, Talavera, Karel, Medical Research Council (UK), KU Leuven, Research Foundation - Flanders, Agencia Estatal de Investigación (España), Ministerio de Ciencia, Innovación y Universidades (España), Generalitat Valenciana, Velasco, Enrique, Delicado-Miralles, Miguel, Hellings, Peter W., Gallar, Juana, Gerven, Laura van, and Talavera, Karel
Abstract: “Nasal hyperreactivity” is a key feature in various phenotypes of upper airway diseases, whereby reactions of the nasal epithelium to diverse chemical and physical stimuli are exacerbated. In this review, we illustrate how nasal hyperreactivity can result from at least three types of mechanisms: (1) impaired barrier function, (2) hypersensitivity to external and endogenous stimuli, and (3) potentiation of efferent systems. We describe the known molecular basis of hyperreactivity related to the functional impairment of epithelial cells and somatosensory innervation, and indicate that the thermal, chemical, and mechanical sensors determining hyperreactivity in humans remain to be identified. We delineate research directions that may provide new insights into nasal hyperreactivity associated with rhinitis/rhinosinusitis pathophysiology and therapeutics. The elucidation of the molecular mechanisms underlying nasal hyperreactivity is essential for the treatment of rhinitis according to the precepts of precision medicine.
Published: 2022

42. Emerging role of HDACs in regeneration and ageing in the peripheral nervous system: Repair Schwann cells as pivotal targets

Author: Ministerio de Economía y Competitividad (España), Agencia Estatal de Investigación (España), Ministerio de Ciencia, Innovación y Universidades (España), Generalitat Valenciana, Medical Research Council (UK), Gómez-Sánchez, José A., Patel, Nikiben, Martirena, Fernanda, Fazal, Shaline V., Mutschler, Clara, Cabedo, Hugo, Ministerio de Economía y Competitividad (España), Agencia Estatal de Investigación (España), Ministerio de Ciencia, Innovación y Universidades (España), Generalitat Valenciana, Medical Research Council (UK), Gómez-Sánchez, José A., Patel, Nikiben, Martirena, Fernanda, Fazal, Shaline V., Mutschler, Clara, and Cabedo, Hugo
Abstract: The peripheral nervous system (PNS) has a remarkable regenerative capacity in comparison to the central nervous system (CNS), a phenomenon that is impaired during ageing. The ability of PNS axons to regenerate after injury is due to Schwann cells (SC) being reprogrammed into a repair phenotype called Repair Schwann cells. These repair SCs are crucial for supporting axonal growth after injury, myelin degradation in a process known as myelinophagy, neurotropic factor secretion, and axonal growth guidance through the formation of Büngner bands. After regeneration, repair SCs can remyelinate newly regenerated axons and support nonmyelinated axons. Increasing evidence points to an epigenetic component in the regulation of repair SC gene expression changes, which is necessary for SC reprogramming and regeneration. One of these epigenetic regulations is histone acetylation by histone acetyl transferases (HATs) or histone deacetylation by histone deacetylases (HDACs). In this review, we have focused particularly on three HDAC classes (I, II, and IV) that are Zn2+-dependent deacetylases. These HDACs are important in repair SC biology and remyelination after PNS injury. Another key aspect explored in this review is HDAC genetic compensation in SCs and novel HDAC inhibitors that are being studied to improve nerve regeneration.
Published: 2022

43. Plasma ammonia levels predict hospitalisation with liver-related complications and mortality in clinically stable outpatients with cirrhosis

Author: Medical Research Council (UK), Instituto de Salud Carlos III, Fundación Ramón Areces, Generalitat Valenciana, European Commission, Tranah, Thomas H. [0000-0001-9290-3044], Montoliu, Carmina [0000-0002-4740-4788], Jalan, Rajiv [0000-0002-7747-4015], Shawcross, Debbie L. [0000-0001-6133-4619], Tranah, Thomas H., Ballester, María Pilar, Carbonell-Asins, Juan Antonio, Ampuero, Javier, Alexandrino, Gonçalo, Caracostea, Andra, Sánchez-Torrijos, Yolanda, Thomsen, Karen L., Kerbert, Annarein J. C., Capilla-Lozano, María, Romero-Gómez, Manuel, Escudero, Desamparados, Montoliu, Carmina, Jalan, Rajiv, Shawcross, Debbie L., Medical Research Council (UK), Instituto de Salud Carlos III, Fundación Ramón Areces, Generalitat Valenciana, European Commission, Tranah, Thomas H. [0000-0001-9290-3044], Montoliu, Carmina [0000-0002-4740-4788], Jalan, Rajiv [0000-0002-7747-4015], Shawcross, Debbie L. [0000-0001-6133-4619], Tranah, Thomas H., Ballester, María Pilar, Carbonell-Asins, Juan Antonio, Ampuero, Javier, Alexandrino, Gonçalo, Caracostea, Andra, Sánchez-Torrijos, Yolanda, Thomsen, Karen L., Kerbert, Annarein J. C., Capilla-Lozano, María, Romero-Gómez, Manuel, Escudero, Desamparados, Montoliu, Carmina, Jalan, Rajiv, and Shawcross, Debbie L.
Abstract: [Background & Aims] Hyperammonaemia is central in the pathogenesis of hepatic encephalopathy. It also has pleiotropic deleterious effects on several organ systems, such as immune function, sarcopenia, energy metabolism and portal hypertension. This study was performed to test the hypothesis that severity of hyperammonaemia is a risk factor for liver-related complications in clinically stable outpatients with cirrhosis., [Methods] We studied 754 clinically stable outpatients with cirrhosis from 3 independent liver units. Baseline ammonia levels were corrected to the upper limit of normal (AMM-ULN) for the reference laboratory. The primary endpoint was hospitalisation with liver-related complications (a composite endpoint of bacterial infection, variceal bleeding, overt hepatic encephalopathy, or new onset or worsening of ascites). Multivariable competing risk frailty analyses using fast unified random forests were performed to predict complications and mortality. External validation was carried out using prospective data from 130 patients with cirrhosis in an independent tertiary liver centre., [Results] Overall, 260 (35%) patients were hospitalised with liver-related complications. On multivariable analysis, AMM-ULN was an independent predictor of both liver-related complications (hazard ratio 2.13; 95% CI 1.89–2.40; p <0.001) and mortality (hazard ratio 1.45; 95% CI 1.20–1.76; p <0.001). The AUROC of AMM-ULN was 77.9% for 1-year liver-related complications, which is higher than traditional severity scores. Statistical differences in survival were found between high and low levels of AMM-ULN both for complications and mortality (p <0.001) using 1.4 as the optimal cut-off from the training set. AMM-ULN remained a key variable for the prediction of complications within the random forests model in the derivation cohort and upon external validation., [Conclusion] Ammonia is an independent predictor of hospitalisation with liver-related complications and mortality in clinically stable outpatients with cirrhosis and performs better than traditional prognostic scores in predicting complications.
Published: 2022

44. Virtual ontogeny of cortical growth preceding mental illness

Author: German Research Foundation, University of Münster, National Health and Medical Research Council (Australia), University of Cape Town, National Research Foundation (South Africa), Swinburne University of Technology, Jack Brockhoff Foundation, University of Melbourne, Barbara Dicker Brain Sciences Foundation, Rebecca L. Cooper Medical Research Foundation, Society for Mental Health Research (Australia), Swedish Research Council, Swedish Foundation for Strategic Research, Swedish Brain Foundation, Health Research Board (Ireland), Russian Foundation for Basic Research, University of Zurich, Pratt Foundation, Ramsay Health Care, Viertel Charitable Foundation, Schizophrenia Research Institute (Australia), European Commission, Australian Research Council, Instituto de Salud Carlos III, National Institute for Health and Care Research (US), National Institute for Health Research (UK), Ministry of Health of the Czech Republic, Bill & Melinda Gates Foundation, South African Medical Research Council, Carnegie Corporation of New York, Wellcome Trust, Medical Research Council (UK), Medical Research Scotland, Netherlands Organization for Scientific Research, Ambrogi, Sonia [0000-0002-2897-358X], Banaschewski, Tobias [0000-0003-4595-1144], Bandeira, Cibele Edom [0000-0003-0681-1309], Cupertino, Renata [0000-0002-3452-0632], Calderoni, Sara [0000-0002-6250-5739], Cannon, Dara [0000-0001-7378-3411], Carr, Vaughan [0000-0002-8907-5804], Chew, Qian Hui [0000-0003-0969-7994], Coghill, David [0000-0003-3017-9737], Cullen, Kathryn [0000-0001-9631-3770], Dahl, Andreas [0000-0002-8097-2082], Epstein, Jeffery [0000-0003-3464-5256], Foran, William [0000-0001-7491-9798], Fortea, Lydia [0000-0001-6778-2316], Fuentes-Claramonte, Paola [0000-0002-1428-7976], Fullerton, Janice M. [0000-0003-4014-4490], Furlong, Lisa [0000-0001-6196-4565], Gallagher, Louise [0000-0001-9462-2836], Gao, Si [0000-0002-4473-1142], Gotlib, Ian [0000-0002-3622-3199], Haavik, Jan [0000-0001-7865-2808], Henskens, Frans [0000-0003-2358-5630], Hilland, Eva [0000-0002-7102-8372], Hoekstra, Pieter J [0000-0001-7260-4119], Howells, Fleur M [0000-0001-9759-2556], Ipser, Jonathan [0000-0003-1272-0032], Jørgensen, Jes Kristian [0000-0001-9133-1670], Karantonis, James A. [0000-0003-2281-0912], Lawrie, Stephen [0000-0002-2444-5675], Patel, Yash, Shin, Jean, Abé, Christoph, Agartz, Ingrid, Alloza, Clara, Alnæs, Dag, Ambrogi, Sonia, Antonucci, Linda A., Arango, Celso, Arolt, Volker, Auzias, Guillaume, Gruber, Oliver, Haavik, Jan, McDonald, Colm, Hahn, Tim, Harrison, Ben J., Heindel, Walter, Henskens, Frans, Heslenfeld, Dirk J., Hilland, Eva, King, Joseph A., Vernooij, Meike W., Hoekstra, Pieter J., Hohmann, Sarah, Holz, Nathalie, Howells, Fleur M., McIntosh, Andrew, Ipser, Jonathan C., Meinert, Susanne, Hoogman, Martine, Kircher, Tilo, Kochunov, Peter, Vieta, Eduard, Koopowitz, Sheri-Michelle, Landén, Mikael, Landrø, Nils Inge, Lawrie, Stephen, Michie, Patricia T., Ayesa Arriola, Rosa, Mitchell, Philip, Moreno-Alcázar, Ana, Franke, Barbara, Mowry, Bryan, Bau, Claiton H. D., Muratori, Filippo, Nabulsi, Leila, Nenadić, Igor, O'Gorman Tuura, Ruth, Oosterlaan, Jaap, Overs, Bronwyn, Pantelis, Christos, Banaj, Nerisa, Parellada, Mara, van Rooij, Daan, Vilarroya, Oscar, Pariente, Jose C., Pauli, Paul, Pergola, Giulio, Piarulli, Francesco Maria, Picon, Felipe, Piras, Fabrizio, Pomarol-Clotet, Edith, Pretus, Clara, Quidé, Yann, Banaschewski, Tobias, Weickert, Cynthia, Buitelaar, Jan, Radua, Joaquim, Ramos-Quiroga, J. Antoni, Rasser, Paul E., Reif, Andreas, Retico, Alessandra, Roberts, Gloria, Rossell, Susan, Rovaris, Diego Luiz, Rubia, Katya, Weickert, Thomas, Sacchet, Matthew, Ching, Christopher R. K., Bandeira, Cibele, Salavert, Josep, Salvador, Raymond, Sarró, Salvador, Sawa, Akira, Schall, Ulrich, Scott, Rodney, Selvaggi, Pierluigi, Westlye, Lars T., Silk, Tim, Sim, Kang, Andreassen, Ole A., Skoch, Antonin, Başgöze, Zeynep, Spalletta, Gianfranco, Spaniel, Filip, Stein, Dan J., Steinsträter, Olaf, Stolicyn, Aleks, Whalley, Heather, Takayanagi, Yoichiro, Tamm, Leanne, Tavares, Maria, Pozzi, Elena, Teumer, Alexander, Thiel, Katharina, Cupertino, Renata Basso, Thomopoulos, Sophia I., Tomecek, David, Tomyshev, Alexander S., Willinger, David, Tordesillas-Gutiérrez, Diana, Tosetti, Michela, Uhlmann, Anne, Van Rheenen, Tamsyn, Veltman, Dick, Vázquez-Bourgon, Javier, Schmaal, Lianne, Jahanshad, Neda, Winter, Alexandra, Wittfeld, Katharina, Yang, Tony T., Yoncheva, Yuliya, Bauer, Jochen, Zijlmans, Jendé L., Baumeister, Sarah, Lebedeva, Irina, van Erp, Theo G. M., Turner, Jessica, Jakobi, Babette, Castellanos, F. Xavier, Pausova, Zdenka, Thompson, Paul, Paus, Tomas, Bernardoni, Fabio, Bertolino, Alessandro, Bonnin, Caterina Del Mar, Brandeis, Daniel, Luna, Beatriz, Brem, Silvia, Jansen, Andreas, Bruggemann, Jason, Bülow, Robin, Bustillo, Juan R., Calderoni, Sara, Calvo, Rosa, Canales-Rodríguez, Erick J., Cannon, Dara M., Carmona, Susanna, Carr, Vaughan J., Lundervold, Astri J., Janssen, Joost, Catts, Stanley V., Chenji, Sneha, Chew, Qian Hui, Coghill, David, Connolly, Colm G., Conzelmann, Annette, Craven, Alexander R., Crespo-Facorro, Benedicto, Cullen, Kathryn, Dahl, Andreas, Jonassen, Rune, MacMaster, Frank P., Dannlowski, Udo, Davey, Christopher G., Deruelle, Christine, Díaz-Caneja, Covadonga M., Dohm, Katharina, Ehrlich, Stefan, Epstein, Jeffery, Erwin-Grabner, Tracy, Eyler, Lisa T., Kaiser, Anna, Fedor, Jennifer, Maglanoc, Luigi A., Fitzgerald, Jacqueline, Foran, William, Ford, Judith M., Fortea, Lydia, Fuentes-Claramonte, Paola, Fullerton, Janice, Furlong, Lisa, Gallagher, Louise, Kaleda, Vasiliy, Gao, Bingchen, Gao, Si, Mathalon, Daniel H., Goikolea, Jose M., Gotlib, Ian, Goya-Maldonado, Roberto, Grabe, Hans J., Green, Melissa, Grevet, Eugenio H., Groenewold, Nynke A., Karantonis, James, Grotegerd, Dominik., German Research Foundation, University of Münster, National Health and Medical Research Council (Australia), University of Cape Town, National Research Foundation (South Africa), Swinburne University of Technology, Jack Brockhoff Foundation, University of Melbourne, Barbara Dicker Brain Sciences Foundation, Rebecca L. Cooper Medical Research Foundation, Society for Mental Health Research (Australia), Swedish Research Council, Swedish Foundation for Strategic Research, Swedish Brain Foundation, Health Research Board (Ireland), Russian Foundation for Basic Research, University of Zurich, Pratt Foundation, Ramsay Health Care, Viertel Charitable Foundation, Schizophrenia Research Institute (Australia), European Commission, Australian Research Council, Instituto de Salud Carlos III, National Institute for Health and Care Research (US), National Institute for Health Research (UK), Ministry of Health of the Czech Republic, Bill & Melinda Gates Foundation, South African Medical Research Council, Carnegie Corporation of New York, Wellcome Trust, Medical Research Council (UK), Medical Research Scotland, Netherlands Organization for Scientific Research, Ambrogi, Sonia [0000-0002-2897-358X], Banaschewski, Tobias [0000-0003-4595-1144], Bandeira, Cibele Edom [0000-0003-0681-1309], Cupertino, Renata [0000-0002-3452-0632], Calderoni, Sara [0000-0002-6250-5739], Cannon, Dara [0000-0001-7378-3411], Carr, Vaughan [0000-0002-8907-5804], Chew, Qian Hui [0000-0003-0969-7994], Coghill, David [0000-0003-3017-9737], Cullen, Kathryn [0000-0001-9631-3770], Dahl, Andreas [0000-0002-8097-2082], Epstein, Jeffery [0000-0003-3464-5256], Foran, William [0000-0001-7491-9798], Fortea, Lydia [0000-0001-6778-2316], Fuentes-Claramonte, Paola [0000-0002-1428-7976], Fullerton, Janice M. [0000-0003-4014-4490], Furlong, Lisa [0000-0001-6196-4565], Gallagher, Louise [0000-0001-9462-2836], Gao, Si [0000-0002-4473-1142], Gotlib, Ian [0000-0002-3622-3199], Haavik, Jan [0000-0001-7865-2808], Henskens, Frans [0000-0003-2358-5630], Hilland, Eva [0000-0002-7102-8372], Hoekstra, Pieter J [0000-0001-7260-4119], Howells, Fleur M [0000-0001-9759-2556], Ipser, Jonathan [0000-0003-1272-0032], Jørgensen, Jes Kristian [0000-0001-9133-1670], Karantonis, James A. [0000-0003-2281-0912], Lawrie, Stephen [0000-0002-2444-5675], Patel, Yash, Shin, Jean, Abé, Christoph, Agartz, Ingrid, Alloza, Clara, Alnæs, Dag, Ambrogi, Sonia, Antonucci, Linda A., Arango, Celso, Arolt, Volker, Auzias, Guillaume, Gruber, Oliver, Haavik, Jan, McDonald, Colm, Hahn, Tim, Harrison, Ben J., Heindel, Walter, Henskens, Frans, Heslenfeld, Dirk J., Hilland, Eva, King, Joseph A., Vernooij, Meike W., Hoekstra, Pieter J., Hohmann, Sarah, Holz, Nathalie, Howells, Fleur M., McIntosh, Andrew, Ipser, Jonathan C., Meinert, Susanne, Hoogman, Martine, Kircher, Tilo, Kochunov, Peter, Vieta, Eduard, Koopowitz, Sheri-Michelle, Landén, Mikael, Landrø, Nils Inge, Lawrie, Stephen, Michie, Patricia T., Ayesa Arriola, Rosa, Mitchell, Philip, Moreno-Alcázar, Ana, Franke, Barbara, Mowry, Bryan, Bau, Claiton H. D., Muratori, Filippo, Nabulsi, Leila, Nenadić, Igor, O'Gorman Tuura, Ruth, Oosterlaan, Jaap, Overs, Bronwyn, Pantelis, Christos, Banaj, Nerisa, Parellada, Mara, van Rooij, Daan, Vilarroya, Oscar, Pariente, Jose C., Pauli, Paul, Pergola, Giulio, Piarulli, Francesco Maria, Picon, Felipe, Piras, Fabrizio, Pomarol-Clotet, Edith, Pretus, Clara, Quidé, Yann, Banaschewski, Tobias, Weickert, Cynthia, Buitelaar, Jan, Radua, Joaquim, Ramos-Quiroga, J. Antoni, Rasser, Paul E., Reif, Andreas, Retico, Alessandra, Roberts, Gloria, Rossell, Susan, Rovaris, Diego Luiz, Rubia, Katya, Weickert, Thomas, Sacchet, Matthew, Ching, Christopher R. K., Bandeira, Cibele, Salavert, Josep, Salvador, Raymond, Sarró, Salvador, Sawa, Akira, Schall, Ulrich, Scott, Rodney, Selvaggi, Pierluigi, Westlye, Lars T., Silk, Tim, Sim, Kang, Andreassen, Ole A., Skoch, Antonin, Başgöze, Zeynep, Spalletta, Gianfranco, Spaniel, Filip, Stein, Dan J., Steinsträter, Olaf, Stolicyn, Aleks, Whalley, Heather, Takayanagi, Yoichiro, Tamm, Leanne, Tavares, Maria, Pozzi, Elena, Teumer, Alexander, Thiel, Katharina, Cupertino, Renata Basso, Thomopoulos, Sophia I., Tomecek, David, Tomyshev, Alexander S., Willinger, David, Tordesillas-Gutiérrez, Diana, Tosetti, Michela, Uhlmann, Anne, Van Rheenen, Tamsyn, Veltman, Dick, Vázquez-Bourgon, Javier, Schmaal, Lianne, Jahanshad, Neda, Winter, Alexandra, Wittfeld, Katharina, Yang, Tony T., Yoncheva, Yuliya, Bauer, Jochen, Zijlmans, Jendé L., Baumeister, Sarah, Lebedeva, Irina, van Erp, Theo G. M., Turner, Jessica, Jakobi, Babette, Castellanos, F. Xavier, Pausova, Zdenka, Thompson, Paul, Paus, Tomas, Bernardoni, Fabio, Bertolino, Alessandro, Bonnin, Caterina Del Mar, Brandeis, Daniel, Luna, Beatriz, Brem, Silvia, Jansen, Andreas, Bruggemann, Jason, Bülow, Robin, Bustillo, Juan R., Calderoni, Sara, Calvo, Rosa, Canales-Rodríguez, Erick J., Cannon, Dara M., Carmona, Susanna, Carr, Vaughan J., Lundervold, Astri J., Janssen, Joost, Catts, Stanley V., Chenji, Sneha, Chew, Qian Hui, Coghill, David, Connolly, Colm G., Conzelmann, Annette, Craven, Alexander R., Crespo-Facorro, Benedicto, Cullen, Kathryn, Dahl, Andreas, Jonassen, Rune, MacMaster, Frank P., Dannlowski, Udo, Davey, Christopher G., Deruelle, Christine, Díaz-Caneja, Covadonga M., Dohm, Katharina, Ehrlich, Stefan, Epstein, Jeffery, Erwin-Grabner, Tracy, Eyler, Lisa T., Kaiser, Anna, Fedor, Jennifer, Maglanoc, Luigi A., Fitzgerald, Jacqueline, Foran, William, Ford, Judith M., Fortea, Lydia, Fuentes-Claramonte, Paola, Fullerton, Janice, Furlong, Lisa, Gallagher, Louise, Kaleda, Vasiliy, Gao, Bingchen, Gao, Si, Mathalon, Daniel H., Goikolea, Jose M., Gotlib, Ian, Goya-Maldonado, Roberto, Grabe, Hans J., Green, Melissa, Grevet, Eugenio H., Groenewold, Nynke A., Karantonis, James, and Grotegerd, Dominik.
Abstract: [Background]: Morphology of the human cerebral cortex differs across psychiatric disorders, with neurobiology and developmental origins mostly undetermined. Deviations in the tangential growth of the cerebral cortex during pre/perinatal periods may be reflected in individual variations in cortical surface area later in life., [Methods]: Interregional profiles of group differences in surface area between cases and controls were generated using T1-weighted magnetic resonance imaging from 27,359 individuals including those with attention-deficit/hyperactivity disorder, autism spectrum disorder, bipolar disorder, major depressive disorder, schizophrenia, and high general psychopathology (through the Child Behavior Checklist). Similarity of interregional profiles of group differences in surface area and prenatal cell-specific gene expression was assessed., [Results]: Across the 11 cortical regions, group differences in cortical area for attention-deficit/hyperactivity disorder, schizophrenia, and Child Behavior Checklist were dominant in multimodal association cortices. The same interregional profiles were also associated with interregional profiles of (prenatal) gene expression specific to proliferative cells, namely radial glia and intermediate progenitor cells (greater expression, larger difference), as well as differentiated cells, namely excitatory neurons and endothelial and mural cells (greater expression, smaller difference). Finally, these cell types were implicated in known pre/perinatal risk factors for psychosis. Genes coexpressed with radial glia were enriched with genes implicated in congenital abnormalities, birth weight, hypoxia, and starvation. Genes coexpressed with endothelial and mural genes were enriched with genes associated with maternal hypertension and preterm birth., [Conclusions]: Our findings support a neurodevelopmental model of vulnerability to mental illness whereby prenatal risk factors acting through cell-specific processes lead to deviations from typical brain development during pregnancy.
Published: 2022

45. Can epigenetics shine a light on the biological pathways underlying major mental disorders?

Author: Swiss National Science Foundation, Economic and Social Research Council (UK), Biotechnology and Biological Sciences Research Council (UK), Medical Research Council (UK), Alameda, Luis, Trotta, Giulia, Quigley, Harriet, Rodríguez, Victoria, Gadelrab, Romayne, Dwir, Daniella, Dempster, Emma, Wong, Chloe C. Y., Di Forti, Marta, Swiss National Science Foundation, Economic and Social Research Council (UK), Biotechnology and Biological Sciences Research Council (UK), Medical Research Council (UK), Alameda, Luis, Trotta, Giulia, Quigley, Harriet, Rodríguez, Victoria, Gadelrab, Romayne, Dwir, Daniella, Dempster, Emma, Wong, Chloe C. Y., and Di Forti, Marta
Abstract: A significant proportion of the global burden of disease can be attributed to mental illness. Despite important advances in identifying risk factors for mental health conditions, the biological processing underlying causal pathways to disease onset remain poorly understood. This represents a limitation to implement effective prevention and the development of novel pharmacological treatments. Epigenetic mechanisms have emerged as mediators of environmental and genetic risk factors which might play a role in disease onset, including childhood adversity (CA) and cannabis use (CU). Particularly, human research exploring DNA methylation has provided new and promising insights into the role of biological pathways implicated in the aetio-pathogenesis of psychiatric conditions, including: monoaminergic (Serotonin and Dopamine), GABAergic, glutamatergic, neurogenesis, inflammatory and immune response and oxidative stress. While these epigenetic changes have been often studied as disease-specific, similarly to the investigation of environmental risk factors, they are often transdiagnostic. Therefore, we aim to review the existing literature on DNA methylation from human studies of psychiatric diseases (i) to identify epigenetic modifications mapping onto biological pathways either transdiagnostically or specifically related to psychiatric diseases such as Eating Disorders, Post-traumatic Stress Disorder, Bipolar and Psychotic Disorder, Depression, Autism Spectrum Disorder and Anxiety Disorder, and (ii) to investigate a convergence between some of these epigenetic modifications and the exposure to known risk factors for psychiatric disorders such as CA and CU, as well as to other epigenetic confounders in psychiatry research.
Published: 2022

46. Interaction Testing and Polygenic Risk Scoring to Estimate the Association of Common Genetic Variants With Treatment Resistance in Schizophrenia

Author: Medical Research Council (UK), Cardiff University, Welsh Government, Health and Care Research Wales, European Commission, Academy of Medical Sciences (UK), Research Council of Norway, K. G. Jebsen Centres for Medical Research, National Institute for Health Research (UK), University College London, Government of Canada, University of Manitoba, Swedish Research Council, National Institute of Mental Health (US), Kings College London, Public Health Agency (Northern Ireland), The Psychiatry Research Trust, Maudsley Charity, Swiss National Science Foundation, Fondation Alamaya, Ministry of Health of the Czech Republic, Instituto de Salud Carlos III, Plan Nacional sobre Drogas (España), Fundació Seny, Fundación Marques de Valdecilla, Ministerio de Economía y Competitividad (España), Wellcome Trust, Pardiñas, Antonio F., Smart, Sophie E., Willcocks, Isabella R., Holmans, Peter A., Dennison, Charlotte A., Lynham, Amy, Legge, Sophie E., Baune, Bernhard T., Bigdeli, Tim B., Cairns, Murray J., Corvin, Aiden, Fanous, Ayman H., Frank, Josef, Kelly, Brian, McQuillin, Andrew, Melle, Ingrid, Mortensen, Preben B., Mowry, Bryan J., Pato, Carlos N., Periyasamy, Sathish, Rietschel, Marcella, Rujescu, Dan, Simonsen, Carmen, St Clair, David, Tooney, Paul, Wu, Jing Qin, Andreassen, Ole A., Kowalec, Kaarina, Sullivan, Patrick F., Murray, Robin M., Owen, Michael J., MacCabe, James H., O'Donovan, Michael C., Walters, James T. R., Genetics Workstream of the Schizophrenia Treatment Resistance and Therapeutic Advances (STRATA), Consortium and the Schizophrenia Working Group of the Psychiatric Genomics Consortium (PGC), Medical Research Council (UK), Cardiff University, Welsh Government, Health and Care Research Wales, European Commission, Academy of Medical Sciences (UK), Research Council of Norway, K. G. Jebsen Centres for Medical Research, National Institute for Health Research (UK), University College London, Government of Canada, University of Manitoba, Swedish Research Council, National Institute of Mental Health (US), Kings College London, Public Health Agency (Northern Ireland), The Psychiatry Research Trust, Maudsley Charity, Swiss National Science Foundation, Fondation Alamaya, Ministry of Health of the Czech Republic, Instituto de Salud Carlos III, Plan Nacional sobre Drogas (España), Fundació Seny, Fundación Marques de Valdecilla, Ministerio de Economía y Competitividad (España), Wellcome Trust, Pardiñas, Antonio F., Smart, Sophie E., Willcocks, Isabella R., Holmans, Peter A., Dennison, Charlotte A., Lynham, Amy, Legge, Sophie E., Baune, Bernhard T., Bigdeli, Tim B., Cairns, Murray J., Corvin, Aiden, Fanous, Ayman H., Frank, Josef, Kelly, Brian, McQuillin, Andrew, Melle, Ingrid, Mortensen, Preben B., Mowry, Bryan J., Pato, Carlos N., Periyasamy, Sathish, Rietschel, Marcella, Rujescu, Dan, Simonsen, Carmen, St Clair, David, Tooney, Paul, Wu, Jing Qin, Andreassen, Ole A., Kowalec, Kaarina, Sullivan, Patrick F., Murray, Robin M., Owen, Michael J., MacCabe, James H., O'Donovan, Michael C., Walters, James T. R., Genetics Workstream of the Schizophrenia Treatment Resistance and Therapeutic Advances (STRATA), and Consortium and the Schizophrenia Working Group of the Psychiatric Genomics Consortium (PGC)
Abstract: [Importance] About 20% to 30% of people with schizophrenia have psychotic symptoms that do not respond adequately to first-line antipsychotic treatment. This clinical presentation, chronic and highly disabling, is known as treatment-resistant schizophrenia (TRS). The causes of treatment resistance and their relationships with causes underlying schizophrenia are largely unknown. Adequately powered genetic studies of TRS are scarce because of the difficulty in collecting data from well-characterized TRS cohorts., [Objective] To examine the genetic architecture of TRS through the reassessment of genetic data from schizophrenia studies and its validation in carefully ascertained clinical samples., [Design, Setting, and Participants] Two case-control genome-wide association studies (GWASs) of schizophrenia were performed in which the case samples were defined as individuals with TRS (n = 10 501) and individuals with non-TRS (n = 20 325). The differences in effect sizes for allelic associations were then determined between both studies, the reasoning being such differences reflect treatment resistance instead of schizophrenia. Genotype data were retrieved from the CLOZUK and Psychiatric Genomics Consortium (PGC) schizophrenia studies. The output was validated using polygenic risk score (PRS) profiling of 2 independent schizophrenia cohorts with TRS and non-TRS: a prevalence sample with 817 individuals (Cardiff Cognition in Schizophrenia [CardiffCOGS]) and an incidence sample with 563 individuals (Genetics Workstream of the Schizophrenia Treatment Resistance and Therapeutic Advances [STRATA-G])., [Main Outcomes and Measures] GWAS of treatment resistance in schizophrenia. The results of the GWAS were compared with complex polygenic traits through a genetic correlation approach and were used for PRS analysis on the independent validation cohorts using the same TRS definition., [Results] The study included a total of 85 490 participants (48 635 [56.9%] male) in its GWAS stage and 1380 participants (859 [62.2%] male) in its PRS validation stage. Treatment resistance in schizophrenia emerged as a polygenic trait with detectable heritability (1% to 4%), and several traits related to intelligence and cognition were found to be genetically correlated with it (genetic correlation, 0.41-0.69). PRS analysis in the CardiffCOGS prevalence sample showed a positive association between TRS and a history of taking clozapine (r2 = 2.03%; P = .001), which was replicated in the STRATA-G incidence sample (r2 = 1.09%; P = .04)., [Conclusions and Relevance] In this GWAS, common genetic variants were differentially associated with TRS, and these associations may have been obscured through the amalgamation of large GWAS samples in previous studies of broadly defined schizophrenia. Findings of this study suggest the validity of meta-analytic approaches for studies on patient outcomes, including treatment resistance.
Published: 2022

47. ISARIC-COVID-19 dataset: A Prospective, Standardized, Global Dataset of Patients Hospitalized with COVID-19

Author: Bill & Melinda Gates Foundation, Minderoo Foundation, Commonwealth Foundation, Wellcome Trust, National Institute for Health Research (UK), Medical Research Council (UK), University of Liverpool, Imperial College London, Canadian Institutes of Health Research, Sunnybrook Research Institute, Health Research Board (Ireland), European Commission, All India Institute of Medical Sciences, University of Cape Town, University of Oxford, Research Council of Norway, Innovative Medicines Initiative, Governo Italiano, University of Queensland, Australian Research Council, Prince Charles Hospital Foundation, Instituto de Salud Carlos III, Institut National de la Santé et de la Recherche Médicale (France), Conselho Nacional de Desenvolvimento Científico e Tecnológico (Brasil), ISARIC Clinical Characterization Group, García-Gallo, Esteban, Merson, Laura, Kennon, Kalynn, Kelly, Sadie, Citarella, Barbara Wanjiru, Fryer, Daniel Vidali, Shrapnel, Sally, Lee, James, Duque, Sara, Fuentes, Yuli V., Balan, Valeria, Smith, Sue, Wei, Jia, Gonçalves, Bronner P., Russell, Clark D., Sigfrid, Louise, Dagens, Andrew, Olliaro, Piero L., Baruch, Joaquín, Kartsonaki, Christiana, Dunning, Jake, Rojek, Amanda, Rashan, Aasiyah, Beane, Abi, Murthy, Srinivas, Reyes, Luis Felipe, Bill & Melinda Gates Foundation, Minderoo Foundation, Commonwealth Foundation, Wellcome Trust, National Institute for Health Research (UK), Medical Research Council (UK), University of Liverpool, Imperial College London, Canadian Institutes of Health Research, Sunnybrook Research Institute, Health Research Board (Ireland), European Commission, All India Institute of Medical Sciences, University of Cape Town, University of Oxford, Research Council of Norway, Innovative Medicines Initiative, Governo Italiano, University of Queensland, Australian Research Council, Prince Charles Hospital Foundation, Instituto de Salud Carlos III, Institut National de la Santé et de la Recherche Médicale (France), Conselho Nacional de Desenvolvimento Científico e Tecnológico (Brasil), ISARIC Clinical Characterization Group, García-Gallo, Esteban, Merson, Laura, Kennon, Kalynn, Kelly, Sadie, Citarella, Barbara Wanjiru, Fryer, Daniel Vidali, Shrapnel, Sally, Lee, James, Duque, Sara, Fuentes, Yuli V., Balan, Valeria, Smith, Sue, Wei, Jia, Gonçalves, Bronner P., Russell, Clark D., Sigfrid, Louise, Dagens, Andrew, Olliaro, Piero L., Baruch, Joaquín, Kartsonaki, Christiana, Dunning, Jake, Rojek, Amanda, Rashan, Aasiyah, Beane, Abi, Murthy, Srinivas, and Reyes, Luis Felipe
Abstract: The International Severe Acute Respiratory and Emerging Infection Consortium (ISARIC) COVID-19 dataset is one of the largest international databases of prospectively collected clinical data on people hospitalized with COVID-19. This dataset was compiled during the COVID-19 pandemic by a network of hospitals that collect data using the ISARIC-World Health Organization Clinical Characterization Protocol and data tools. The database includes data from more than 705,000 patients, collected in more than 60 countries and 1,500 centres worldwide. Patient data are available from acute hospital admissions with COVID-19 and outpatient follow-ups. The data include signs and symptoms, pre-existing comorbidities, vital signs, chronic and acute treatments, complications, dates of hospitalization and discharge, mortality, viral strains, vaccination status, and other data. Here, we present the dataset characteristics, explain its architecture and how to gain access, and provide tools to facilitate its use.
Published: 2022

48. Epigenetic and post-transcriptional regulation of somatostatin receptor subtype 5 (SST5 ) in pituitary and pancreatic neuroendocrine tumors

Author: Junta de Andalucía, Ministerio de Economía y Competitividad (España), Ministerio de Ciencia, Innovación y Universidades (España), Agencia Estatal de Investigación (España), Instituto de Salud Carlos III, European Commission, Ministerio de Educación, Cultura y Deporte (España), EMBO, Grupo Español de Tumores Neuroendocrinos y Endocrinos, Fundación Eugenio Rodríguez Pascual, Medical Research Council (UK), Centro de Investigación Biomédica en Red Fisiopatología de la Obesidad y Nutrición (España), Ibáñez-Costa, Alejandro [0000-0003-4649-0095], Gahete, Manuel D. [0000-0002-4578-2179], Castaño, Justo P. [0000-0002-3145-7287], Pedraza-Arévalo, Sergio, Ibáñez-Costa, Alejandro, Blázquez-Encinas, Ricardo, Branco, Miguel R., Vázquez-Borrego, Mari C., Herrera-Martínez, Aura D., Venegas Moreno, Eva, Serrano-Blanch, Raquel, Arjona-Sánchez, Álvaro, Gálvez-Moreno, María Ángeles, Korbonits, Marta, Soto-Moreno, Alfonso, Gahete, Manuel D., Charalambous, Marika, Luque, Raúl M., Castaño, Justo P., Junta de Andalucía, Ministerio de Economía y Competitividad (España), Ministerio de Ciencia, Innovación y Universidades (España), Agencia Estatal de Investigación (España), Instituto de Salud Carlos III, European Commission, Ministerio de Educación, Cultura y Deporte (España), EMBO, Grupo Español de Tumores Neuroendocrinos y Endocrinos, Fundación Eugenio Rodríguez Pascual, Medical Research Council (UK), Centro de Investigación Biomédica en Red Fisiopatología de la Obesidad y Nutrición (España), Ibáñez-Costa, Alejandro [0000-0003-4649-0095], Gahete, Manuel D. [0000-0002-4578-2179], Castaño, Justo P. [0000-0002-3145-7287], Pedraza-Arévalo, Sergio, Ibáñez-Costa, Alejandro, Blázquez-Encinas, Ricardo, Branco, Miguel R., Vázquez-Borrego, Mari C., Herrera-Martínez, Aura D., Venegas Moreno, Eva, Serrano-Blanch, Raquel, Arjona-Sánchez, Álvaro, Gálvez-Moreno, María Ángeles, Korbonits, Marta, Soto-Moreno, Alfonso, Gahete, Manuel D., Charalambous, Marika, Luque, Raúl M., and Castaño, Justo P.
Abstract: Somatostatin receptor subtype 5 (SST5 ) is an emerging biomarker and actionable target in pituitary (PitNETs) and pancreatic (PanNETs) neuroendocrine tumors. Transcriptional and epigenetic regulation of SSTR5 gene expression and mRNA biogenesis is poorly understood. Recently, an overlapping natural antisense transcript, SSTR5-AS1, potentially regulating SSTR5 expression, was identified. We aimed to elucidate whether epigenetic processes contribute to the regulation of SSTR5 expression in PitNETs (somatotropinomas) and PanNETs. We analyzed the SSTR5/SSTR5-AS1 human locus in silico to identify CpG islands. SSTR5 and SSTR5-AS1 expression was assessed by quantitative real-time PCR (qPCR) in 27 somatotropinomas, 11 normal pituitaries (NPs), and 15 PanNETs/paired adjacent (control) samples. We evaluated methylation grade in four CpG islands in the SSTR5/SSTR5-AS1 genes. Results revealed that SSTR5 and SSTR5-AS1 were directly correlated in NP, somatotropinoma, and PanNET samples. Interestingly, selected CpG islands were differentially methylated in somatotropinomas compared with NPs. In PanNETs cell lines, SSTR5-AS1 silencing downregulated SSTR5 expression, altered aggressiveness features, and influenced pasireotide response. These results provide evidence that SSTR5 expression in PitNETs and PanNETs can be epigenetically regulated by the SSTR5-AS1 antisense transcript and, indirectly, by DNA methylation, which may thereby impact tumor behavior and treatment response.
Published: 2022

49. Brain charts for the human lifespan

Author: British Academy, Autism Research Trust, National Institute of Mental Health (US), UK Research and Innovation, Medical Research Council (UK), National Institute for Health and Care Research (US), Wellcome Trust, University of Cambridge, Cambridge Biomedical Research Centre, Bethlehem, Richard A. I., Seidlitz, J., White, S. R., Vogel, Jacob W., Anderson, K. M., Adamson, C., Adler, S., Alexopoulos, G. S., Anagnostou, E., Areces-González, A., Astle, D. E., Auyeung, Bonnie, Ayub, Muhammad, Bae, J., Ball, G, Baron-Cohen, Simon, Beare, R., Bedford, S. A., Benegal, V., Beyer, Frauke, Blangero, John, Blesa Cábez, M., Boardman, J. P., Borzage, M., Bosch-Bayard, J. F., Bourke, N., Calhoun, V. D., Chakravarty, M. M., Chen, C., Chertavian, C., Chetelat, G., Chong, Y. S., Cole, J. H., Corvin, Aiden, Costantino, M., Courchesne, E., Crivello, Fabrice, Cropley, V. L., Crosbie, J., Crossley, N., Delarue, M., Delorme, R., Desrivieres, Sylvane, Devenyi, G. A., Di Biase, M. A., Dolan, R., Donald, K. A., Donohoe, Gary, Dunlop, K., Edwards, A. D., Elison, J. T., Ellis, C. T., Elman, J. A., Eyler, L., Fair, D. A., Feczko, E., Fletcher, P. C., Fonagy, P., Franz, C. E., Galán-García, L., Gholipour, A., Giedd, J., Gilmore, J. H., Glahn, David C., Goodyer, I. M., Grant, P. E., Groenewold, Nynke A., Gunning, F. M., Gur, Rachel E., Gur, Ruben C., Hammill, C. F., Hansson, Oskar, Hedden, T., Heinz, Andreas, Henson, R. N., Heuer, K., Hoare, J., Holla, B., Holmes, Avram J., Holt, Rosemary, Huang, Hailiang, Im, K., Ipser, J., Jack, C. R., Jackowski, A. P., Jia, T., Johnson, K. A., Jones, P. B., Jones, David T. W., Kahn, René S., Karlsson, H., Karlsson, L., Kawashima, R., Kelley, E. A., Kern, Silke, Kim, K. W., Kitzbichler, M. G., Kremen, W. S., Lalonde, F., Landeau, B., Lee, S., Lerch, J., Lewis, J. D., Li, J., Liao, W., Liston, C., Lombardo, Michael, V., Lv, J., Lynch, Christopher D., Mallard, T. T., Marcelis, Machteld, Markello, R. D., Mathias, Samuel R., Mazoyer, Bernard, McGuire, Philip, Meaney, M. J., Mechelli, Andrea, Medic, N., Misic, B., Morgan, S. E., Mothersill, David O., Nigg, J., Ong, M. Q. W., Ortinau, C., Ossenkoppele, Rik, Ouyang, M., Palaniyappan, L., Paly, L., Pan, P. M., Pantelis, Christos, Park, M. M., Paus, Tomas, Pausova, Zdenka, Paz-Linares, D., Pichler, Alexander, Pierce, K., Qian, X., Qiu, Jing, Qiu, A., Raznahan, A., Rittman, T., Rodrigue, A., Rollins, C. K., Romero García, Rafael, Ronan, L., Rosenberg, M. D., Rowitch, D. H., Salum, G. A., Satterthwaite, Theodore D., Schaare, H. L., Schachar, R. J., Schultz, A. P., Schumann, Gunter, Schöll, Michael, Sharp, D., Shinohara, R. T., Skoog, Ingmar, Smyser, C. D., Sperling, R. A., Stein, Dan J., Stolicyn, A., Suckling, John, Sullivan, G., Taki, Y., Thyreau, B., Toro, Raquel del, Traut, N., Tsvetanov, K. A., Turk-Browne, N. B., Tuulari, J. J., Tzourio, C., Vachon-Presseau, É., Valdes-Sosa, M. J., Valdes-Sosa, P. A., Valk, Sofie L., van Amelsvoort, Therese, Vandekar, S. N., Vasung, L., Victoria, L. W., Villeneuve, S., Villringer, Arno, Vértes, P. E., Wagstyl, K., Wang, Y. S., Warfield, S. K., Warrier, V., Westman, Eric, Westwater, M. L., Whalley, Heather, Witte, A. Veronica, Yang, N., Yeo, B., Yun, H., Zalesky, A., Zar, H. J., Zettergren, Anna, Zhou, J. H., Ziauddeen, H., Zugman, A., Zuo, X. N., Bullmore, E. T., Alexander-Bloch, A. F., British Academy, Autism Research Trust, National Institute of Mental Health (US), UK Research and Innovation, Medical Research Council (UK), National Institute for Health and Care Research (US), Wellcome Trust, University of Cambridge, Cambridge Biomedical Research Centre, Bethlehem, Richard A. I., Seidlitz, J., White, S. R., Vogel, Jacob W., Anderson, K. M., Adamson, C., Adler, S., Alexopoulos, G. S., Anagnostou, E., Areces-González, A., Astle, D. E., Auyeung, Bonnie, Ayub, Muhammad, Bae, J., Ball, G, Baron-Cohen, Simon, Beare, R., Bedford, S. A., Benegal, V., Beyer, Frauke, Blangero, John, Blesa Cábez, M., Boardman, J. P., Borzage, M., Bosch-Bayard, J. F., Bourke, N., Calhoun, V. D., Chakravarty, M. M., Chen, C., Chertavian, C., Chetelat, G., Chong, Y. S., Cole, J. H., Corvin, Aiden, Costantino, M., Courchesne, E., Crivello, Fabrice, Cropley, V. L., Crosbie, J., Crossley, N., Delarue, M., Delorme, R., Desrivieres, Sylvane, Devenyi, G. A., Di Biase, M. A., Dolan, R., Donald, K. A., Donohoe, Gary, Dunlop, K., Edwards, A. D., Elison, J. T., Ellis, C. T., Elman, J. A., Eyler, L., Fair, D. A., Feczko, E., Fletcher, P. C., Fonagy, P., Franz, C. E., Galán-García, L., Gholipour, A., Giedd, J., Gilmore, J. H., Glahn, David C., Goodyer, I. M., Grant, P. E., Groenewold, Nynke A., Gunning, F. M., Gur, Rachel E., Gur, Ruben C., Hammill, C. F., Hansson, Oskar, Hedden, T., Heinz, Andreas, Henson, R. N., Heuer, K., Hoare, J., Holla, B., Holmes, Avram J., Holt, Rosemary, Huang, Hailiang, Im, K., Ipser, J., Jack, C. R., Jackowski, A. P., Jia, T., Johnson, K. A., Jones, P. B., Jones, David T. W., Kahn, René S., Karlsson, H., Karlsson, L., Kawashima, R., Kelley, E. A., Kern, Silke, Kim, K. W., Kitzbichler, M. G., Kremen, W. S., Lalonde, F., Landeau, B., Lee, S., Lerch, J., Lewis, J. D., Li, J., Liao, W., Liston, C., Lombardo, Michael, V., Lv, J., Lynch, Christopher D., Mallard, T. T., Marcelis, Machteld, Markello, R. D., Mathias, Samuel R., Mazoyer, Bernard, McGuire, Philip, Meaney, M. J., Mechelli, Andrea, Medic, N., Misic, B., Morgan, S. E., Mothersill, David O., Nigg, J., Ong, M. Q. W., Ortinau, C., Ossenkoppele, Rik, Ouyang, M., Palaniyappan, L., Paly, L., Pan, P. M., Pantelis, Christos, Park, M. M., Paus, Tomas, Pausova, Zdenka, Paz-Linares, D., Pichler, Alexander, Pierce, K., Qian, X., Qiu, Jing, Qiu, A., Raznahan, A., Rittman, T., Rodrigue, A., Rollins, C. K., Romero García, Rafael, Ronan, L., Rosenberg, M. D., Rowitch, D. H., Salum, G. A., Satterthwaite, Theodore D., Schaare, H. L., Schachar, R. J., Schultz, A. P., Schumann, Gunter, Schöll, Michael, Sharp, D., Shinohara, R. T., Skoog, Ingmar, Smyser, C. D., Sperling, R. A., Stein, Dan J., Stolicyn, A., Suckling, John, Sullivan, G., Taki, Y., Thyreau, B., Toro, Raquel del, Traut, N., Tsvetanov, K. A., Turk-Browne, N. B., Tuulari, J. J., Tzourio, C., Vachon-Presseau, É., Valdes-Sosa, M. J., Valdes-Sosa, P. A., Valk, Sofie L., van Amelsvoort, Therese, Vandekar, S. N., Vasung, L., Victoria, L. W., Villeneuve, S., Villringer, Arno, Vértes, P. E., Wagstyl, K., Wang, Y. S., Warfield, S. K., Warrier, V., Westman, Eric, Westwater, M. L., Whalley, Heather, Witte, A. Veronica, Yang, N., Yeo, B., Yun, H., Zalesky, A., Zar, H. J., Zettergren, Anna, Zhou, J. H., Ziauddeen, H., Zugman, A., Zuo, X. N., Bullmore, E. T., and Alexander-Bloch, A. F.
Abstract: Over the past few decades, neuroimaging has become a ubiquitous tool in basic research and clinical studies of the human brain. However, no reference standards currently exist to quantify individual differences in neuroimaging metrics over time, in contrast to growth charts for anthropometric traits such as height and weight1. Here we assemble an interactive open resource to benchmark brain morphology derived from any current or future sample of MRI data ( http://www.brainchart.io/ ). With the goal of basing these reference charts on the largest and most inclusive dataset available, acknowledging limitations due to known biases of MRI studies relative to the diversity of the global population, we aggregated 123,984 MRI scans, across more than 100 primary studies, from 101,457 human participants between 115 days post-conception to 100 years of age. MRI metrics were quantified by centile scores, relative to non-linear trajectories2 of brain structural changes, and rates of change, over the lifespan. Brain charts identified previously unreported neurodevelopmental milestones3, showed high stability of individuals across longitudinal assessments, and demonstrated robustness to technical and methodological differences between primary studies. Centile scores showed increased heritability compared with non-centiled MRI phenotypes, and provided a standardized measure of atypical brain structure that revealed patterns of neuroanatomical variation across neurological and psychiatric disorders. In summary, brain charts are an essential step towards robust quantification of individual variation benchmarked to normative trajectories in multiple, commonly used neuroimaging phenotypes.
Published: 2022

50. Parallel evolution of a splicing program controlling neuronal excitability in flies and mammals

Author: European Commission, European Research Council, Ministerio de Ciencia, Innovación y Universidades (España), Agencia Estatal de Investigación (España), Cancer Research UK, Medical Research Council (UK), Wellcome Trust, Boehringer Ingelheim Fonds, Torres-Méndez, Antonio, Pop, Sinziana, Bonnal, Sophie, Almudi, Isabel, Avola, Alida, Roberts, Ruairí J. V., Paolantoni, Chiara, Alcaina-Caro, Ana, Martín-Anduaga, Ane, Haussmann, Irmgard U., Morin, Violeta, Casares, Fernando, Soller, Matthias, Kadener, Sebastian, Roignant, Jean-Yves, Prieto-Godino, Lucía, Irimia, Manuel, European Commission, European Research Council, Ministerio de Ciencia, Innovación y Universidades (España), Agencia Estatal de Investigación (España), Cancer Research UK, Medical Research Council (UK), Wellcome Trust, Boehringer Ingelheim Fonds, Torres-Méndez, Antonio, Pop, Sinziana, Bonnal, Sophie, Almudi, Isabel, Avola, Alida, Roberts, Ruairí J. V., Paolantoni, Chiara, Alcaina-Caro, Ana, Martín-Anduaga, Ane, Haussmann, Irmgard U., Morin, Violeta, Casares, Fernando, Soller, Matthias, Kadener, Sebastian, Roignant, Jean-Yves, Prieto-Godino, Lucía, and Irimia, Manuel
Abstract: Alternative splicing increases neuronal transcriptomic complexity throughout animal phylogeny. To delve into the mechanisms controlling the assembly and evolution of this regulatory layer, we characterized the neuronal microexon program in Drosophila and compared it with that of mammals. In nonvertebrate bilaterians, this splicing program is restricted to neurons by the posttranscriptional processing of the enhancer of microexons (eMIC) domain in Srrm234. In Drosophila, this processing is dependent on regulation by Elav/Fne. eMIC deficiency or misexpression leads to widespread neurological alterations largely emerging from impaired neuronal activity, as revealed by a combination of neuronal imaging experiments and cell type–specific rescues. These defects are associated with the genome-wide skipping of short neural exons, which are strongly enriched in ion channels. We found no overlap of eMIC-regulated exons between flies and mice, illustrating how ancient posttranscriptional programs can evolve independently in different phyla to affect distinct cellular modules while maintaining cell-type specificity.
Published: 2022

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