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4,799 results on '"The Francis Crick Institute"'

1. Measuring Single Neuron Activity in the Brain (SUNAN)

Author: Francis Crick Institute
Published: 2025

2. Immune Mechanisms of Antipsychotic Treatment Response (IMAT)

Author: South London and Maudsley NHS Foundation Trust, University of Oxford, McPin Foundation, and Francis Crick Institute
Published: 2024

3. Phenotyping Seroconversion Following Vaccination Against COVID-19 in Patients on Haemodialysis Study

Author: Leicester Hospitals Charity and Francis Crick Institute
Published: 2024

4. Nodule IMmunophenotyping Biomarker for Lung Cancer Early Diagnosis Study

Author: Royal Brompton & Harefield NHS Foundation Trust, Royal Marsden Partners West London Cancer Alliance, Imperial College London, University College London Hospitals, Lewisham and Greenwich NHS Trust, Guy's and St Thomas' NHS Foundation Trust, Epsom and St Helier University Hospitals NHS Trust, King's College Hospital NHS Trust, University College London (UCL) Cancer Institute, Institute of Cancer Research, United Kingdom, Francis Crick Institute, and Royal Sussex County Hospital
Published: 2023

5. SARS-CoV-2 (COVID-19) Longitudinal Study: Understanding Susceptibility, Transmission and Disease Severity (Legacy Study)

Author: Francis Crick Institute
Published: 2022

6. TRACERx Renal CAPTURE Sub-study (TRACERxRenal)

Author: Francis Crick Institute
Published: 2020

7. 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

8. 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

9. 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

10. The rates of adult neurogenesis and oligodendrogenesis are linked to cell cycle regulation through p27-dependent gene repression of SOX2

Author: Consejo Superior de Investigaciones Científicas (España), Ministerio de Ciencia e Innovación (España), Agencia Estatal de Investigación (España), Generalitat Valenciana, Francis Crick Institute, Cancer Research UK, Ministerio de Educación, Cultura y Deporte (España), Domingo-Muelas, Ana, Morante-Redolat, Jose Manuel, Moncho-Amor, Verónica, Jordán-Pla, Antonio, Pérez-Villalba, Ana, Carrillo-Barberà, Pau, Belenguer, Germán, Porlan, Eva, Kirstein, Martina, Bachs, Oriol, Ferrón, Sacri R, Lovell-Badge, Robin, Fariñas, Isabel, Consejo Superior de Investigaciones Científicas (España), Ministerio de Ciencia e Innovación (España), Agencia Estatal de Investigación (España), Generalitat Valenciana, Francis Crick Institute, Cancer Research UK, Ministerio de Educación, Cultura y Deporte (España), Domingo-Muelas, Ana, Morante-Redolat, Jose Manuel, Moncho-Amor, Verónica, Jordán-Pla, Antonio, Pérez-Villalba, Ana, Carrillo-Barberà, Pau, Belenguer, Germán, Porlan, Eva, Kirstein, Martina, Bachs, Oriol, Ferrón, Sacri R, Lovell-Badge, Robin, and Fariñas, Isabel
Abstract: Cell differentiation involves profound changes in global gene expression that often has to occur in coordination with cell cycle exit. Because cyclin-dependent kinase inhibitor p27 reportedly regulates proliferation of neural progenitor cells in the subependymal neurogenic niche of the adult mouse brain, but can also have effects on gene expression, we decided to molecularly analyze its role in adult neurogenesis and oligodendrogenesis. At the cell level, we show that p27 restricts residual cyclin-dependent kinase activity after mitogen withdrawal to antagonize cycling, but it is not essential for cell cycle exit. By integrating genome-wide gene expression and chromatin accessibility data, we find that p27 is coincidentally necessary to repress many genes involved in the transit from multipotentiality to differentiation, including those coding for neural progenitor transcription factors SOX2, OLIG2 and ASCL1. Our data reveal both a direct association of p27 with regulatory sequences in the three genes and an additional hierarchical relationship where p27 repression of Sox2 leads to reduced levels of its downstream targets Olig2 and Ascl1. In vivo, p27 is also required for the regulation of the proper level of SOX2 necessary for neuroblasts and oligodendroglial progenitor cells to timely exit cell cycle in a lineage-dependent manner.
Published: 2023

11. 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

12. A Multi-Site Assessment of Anesthetic Overdose, Hypothermic Shock, and Electrical Stunning as Methods of Euthanasia for Zebrafish (Danio rerio) Embryos and Larvae

Author: Francis Crick Institute, Novo Nordisk Foundation, Mocho, Jean-Philippe, Lang, Florian, Valentin, Guillaume, Bedu, Sébastien, McKimm, Robin, Ramos, Juan, Saavedra Torres, Yolanda, Wheatley, Sarah E., Higgins, Joseph, Millington, Mollie E., Lundegaard, Pia Rengtved, Chamorro, Rubén, Jencic, Vlasta, von Krogh, Kristine, Francis Crick Institute, Novo Nordisk Foundation, Mocho, Jean-Philippe, Lang, Florian, Valentin, Guillaume, Bedu, Sébastien, McKimm, Robin, Ramos, Juan, Saavedra Torres, Yolanda, Wheatley, Sarah E., Higgins, Joseph, Millington, Mollie E., Lundegaard, Pia Rengtved, Chamorro, Rubén, Jencic, Vlasta, and von Krogh, Kristine
Abstract: Euthanasia in zebrafish (Danio rerio) younger than 5 days post fertilization (dpf) is poorly described in the literature, and standardized protocols are lacking, most likely because larvae not capable of independent feeding are often not protected under national legislations. We assessed the euthanasia efficacy in laboratories in different countries of a one hour anesthetic overdose immersion with buffered lidocaine hydrochloride (1 g/L, with or without 50 mL/L of ethanol), buffered tricaine (1 g/L), clove oil (0.1%), benzocaine (1 g/L), or 2-phenoxyethanol (3 mL/L), as well as the efficacy of hypothermic shock (one hour immersion) and electrical stunning (for one minute), on zebrafish at <12 h post fertilization (hpf), 24 hpf, and 4 dpf. Based on the survival/recovery rates 24 h after treatment, the most effective methods were clove oil, lidocaine with ethanol, and electrical stunning. For 4 dpf larvae, signs of aversion during treatment demonstrated that all anesthetics, except lidocaine, induced aversive behavior. Therefore, the most suited euthanasic treatment was lidocaine hydrochloride 1 g/L, buffered with 2 g/L of sodium bicarbonate and mixed with 50 mL/L of ethanol, which euthanized both embryos and larvae in an efficient and stress-free manner. Electrical stunning also euthanized embryos and larvae efficiently and without signs of aversion; this method needs further assessment in other laboratories to draw firm conclusions
Published: 2022

13. The Golgi as an Assembly Line to the Autophagosome

Author: European Commission, Francis Crick Institute, Cancer Research UK, Medical Research Council (UK), Wellcome Trust, EMBO, Eusko Jaurlaritza, De Tito, Stefano, Hervás, Javier H., Vliet, Alexander R. van, Tooze, Sharon A., European Commission, Francis Crick Institute, Cancer Research UK, Medical Research Council (UK), Wellcome Trust, EMBO, Eusko Jaurlaritza, De Tito, Stefano, Hervás, Javier H., Vliet, Alexander R. van, and Tooze, Sharon A.
Abstract: Autophagy is traditionally depicted as a signaling cascade that culminates in the formation of an autophagosome that degrades cellular cargo. However, recent studies have identified myriad pathways and cellular organelles underlying the autophagy process, be it as signaling platforms or through the contribution of proteins and lipids. The Golgi complex is recognized as being a central transport hub in the cell, with a critical role in endocytic trafficking and endoplasmic reticulum (ER) to plasma membrane (PM) transport. However, the Golgi is also an important site of key autophagy regulators, including the protein autophagy-related (ATG)-9A and the lipid, phosphatidylinositol-4-phosphate [PI(4)P]. In this review, we highlight the central function of this organelle in autophagy as a transport hub supplying various components of autophagosome formation.
Published: 2020

14. High PD-1/PD-L1 Checkpoint Interaction Infers Tumor Selection and Therapeutic Sensitivity to Anti-PD-1/PD-L1 Treatment

Author: Eusko Jaurlaritza, Ministerio de Economía y Competitividad (España), Francis Crick Institute, Cancer Research UK, Medical Research Council (UK), Wellcome Trust, Sánchez-Magraner, Lissete, Miles, James, Baker, Claire L., Applebee, Christopher J., Lee, Dae-Jin, Elsheikh, Somaia, Lashin, Shaimaa, Withers, Katriona, Watts, Andrew G., Parry, Richard, Edmead, Christine, López, Jose Ignacio, Mehta, Raj, Italiano, Antoine, Ward, Stephen G., Parker, Peter J., Larijani, Banafshé, Eusko Jaurlaritza, Ministerio de Economía y Competitividad (España), Francis Crick Institute, Cancer Research UK, Medical Research Council (UK), Wellcome Trust, Sánchez-Magraner, Lissete, Miles, James, Baker, Claire L., Applebee, Christopher J., Lee, Dae-Jin, Elsheikh, Somaia, Lashin, Shaimaa, Withers, Katriona, Watts, Andrew G., Parry, Richard, Edmead, Christine, López, Jose Ignacio, Mehta, Raj, Italiano, Antoine, Ward, Stephen G., Parker, Peter J., and Larijani, Banafshé
Abstract: Many cancers are termed immunoevasive due to expression of immunomodulatory ligands. Programmed death ligand-1 (PD-L1) and cluster of differentiation 80/86 (CD80/86) interact with their receptors, programmed death receptor-1 (PD-1) and cytotoxic T-lymphocyte antigen-4 (CTLA-4), respectively, on tumor-infiltrating leukocytes eliciting immunosuppression. Immunotherapies aimed at blocking these interactions are revolutionizing cancer treatments, albeit in an inadequately described patient subset. To address the issue of patient stratification for immune checkpoint intervention, we quantitatively imaged PD-1/PD-L1 interactions in tumor samples from patients, employing an assay that readily detects these intercellular protein-protein interactions in the less than or equal to 10 nm range. These analyses across multiple patient cohorts demonstrated the intercancer, interpatient, and intratumoral heterogeneity of interacting immune checkpoints. The PD-1/PD-L1 interaction was not correlated with clinical PD-L1 expression scores in malignant melanoma. Crucially, among anti-PD-1-treated patients with metastatic non-small cell lung cancer, those with lower PD-1/PD-L1 interaction had significantly worsened survival. It is surmised that within tumors selecting for an elevated level of PD-1/PD-L1 interaction, there is a greater dependence on this pathway for immune evasion and hence, they exhibit more impressive patient response to intervention. SIGNIFICANCE: Quantitation of immune checkpoint interaction by direct imaging demonstrates that immunotherapy-treated patients with metastatic NSCLC with a low extent of PD-1/PD-L1 interaction show significantly worse outcome.
Published: 2020

15. Prediction of bioconcentration factors in fish and invertebrates using machine learning

Author: Miller, Thomas, Gallidabino, Matteo, MacRae, James, Owen, Stewart, Bury, Nicolas, Barron, Leon, King's College London, Northumbria University, AstraZeneca, The Francis Crick Institute, and University of Suffolk
Subjects: F100, G300, G900, F800
Abstract: The application of machine learning has recently gained interest from ecotoxicological fields for its ability to model and predict chemical and/or biological processes, such as the prediction of bioconcentration. However, comparison of different models and the prediction of bioconcentration in invertebrates has not been previously evaluated. A comparison of 24 linear and machine learning models is presented herein for the prediction of bioconcentration in fish and important factors that influenced accumulation identified. R2 and rootmean square error (RMSE) for the test data (n=110 cases) ranged from 0.23–0.73 and 0.34–1.20, respectively. Model performance was critically assessed with neural networks and tree-based learners showing the best performance. An optimised 4-layer multi-layer perceptron (14 descriptors) was selected for further testing. The model was applied for cross-species prediction of bioconcentration in a freshwater invertebrate, Gammarus pulex. The model for G. pulex showed good performance with R2 of 0.99 and 0.93 for the verification and test data, respectively. Important molecular descriptors determined to influence bioconcentration were molecular mass (MW), octanol-water distribution coefficient (logD), topological polar surface area (TPSA) and number of nitrogen atoms (nN) among others. Modelling of hazard criteria such as PBT, showed potential to replace the need for animal testing. However, the use of machine learning models in the regulatory context has been minimal to date and is critically discussed herein. The movement away from experimental estimations of accumulation to in silico modelling would enable rapid prioritisation of contaminants that may pose a risk to environmental health and the food chain.
Published: 2019

16. A switch from canonical to noncanonical autophagy shapes B cell responses

Author: Francis Crick Institute, Cancer Research UK, Medical Research Council (UK), Wellcome Trust, National Institutes of Health (US), Ragon Institute of MGH, MIT and Harvard, European Commission, Comisión Nacional de Investigación Científica y Tecnológica (Chile), Institut Pasteur, Fondazione Cenci Bolognetti, EMBO, German Research Foundation, Martínez-Martín, Nuria, Maldonado, Paula, Gasparrini, Francesca, Frederico, Bruno, Aggarwal, Shweta, Gaya, Mauro, Tsui, Carlson, Burbage, Marianne, Keppler, Selina Jessica, Montaner, Beatriz, Jefferies, Harold B. J., Nair, Usha, Zhao, Yan G., Domart, Marie-Charlotte, Collinson, Lucy, Bruckbauer, Andreas, Tooze, Sharon A., Batista, Facundo D., Francis Crick Institute, Cancer Research UK, Medical Research Council (UK), Wellcome Trust, National Institutes of Health (US), Ragon Institute of MGH, MIT and Harvard, European Commission, Comisión Nacional de Investigación Científica y Tecnológica (Chile), Institut Pasteur, Fondazione Cenci Bolognetti, EMBO, German Research Foundation, Martínez-Martín, Nuria, Maldonado, Paula, Gasparrini, Francesca, Frederico, Bruno, Aggarwal, Shweta, Gaya, Mauro, Tsui, Carlson, Burbage, Marianne, Keppler, Selina Jessica, Montaner, Beatriz, Jefferies, Harold B. J., Nair, Usha, Zhao, Yan G., Domart, Marie-Charlotte, Collinson, Lucy, Bruckbauer, Andreas, Tooze, Sharon A., and Batista, Facundo D.
Abstract: Autophagy is important in a variety of cellular and pathophysiological situations; however, its role in immune responses remains elusive. Here, we show that among B cells, germinal center (GC) cells exhibited the highest rate of autophagy during viral infection. In contrast to mechanistic target of rapamycin complex 1–dependent canonical autophagy, GC B cell autophagy occurred predominantly through a noncanonical pathway. B cell stimulation was sufficient to down-regulate canonical autophagy transiently while triggering noncanonical autophagy. Genetic ablation of WD repeat domain, phosphoinositide–interacting protein 2 in B cells alone enhanced this noncanonical autophagy, resulting in changes of mitochondrial homeostasis and alterations in GC and antibody-secreting cells. Thus, B cell activation prompts a temporal switch from canonical to noncanonical autophagy that is important in controlling B cell differentiation and fate.
Published: 2017

17. The hippo pathway core cassette regulates asymmetric cell division

Author: Generalitat Valenciana, EMBO, Cancer Research UK, Francis Crick Institute, Ministerio de Ciencia e Innovación (España), European Commission, Ministerio de Economía y Competitividad (España), Keder, Alyona, Rives-Quinto, Noemí, Aerne, Birgit L., Franco, Maribel, Tapon, Nicolas, Carmena, Ana, Generalitat Valenciana, EMBO, Cancer Research UK, Francis Crick Institute, Ministerio de Ciencia e Innovación (España), European Commission, Ministerio de Economía y Competitividad (España), Keder, Alyona, Rives-Quinto, Noemí, Aerne, Birgit L., Franco, Maribel, Tapon, Nicolas, and Carmena, Ana
Abstract: Asymmetric cell division (ACD) is a crucial process during development, homeostasis, and cancer. Stem and progenitor cells divide asymmetrically, giving rise to two daughter cells, one of which retains the parent cell self-renewal capacity, while the other is committed to differentiation. Any imbalance in this process can induce overgrowth or even a cancer-like state. Here, we show that core components of the Hippo signaling pathway, an evolutionarily conserved organ growth regulator, modulate ACD in Drosophila. Hippo pathway inactivation disrupts the asymmetric localization of ACD regulators, leading to aberrant mitotic spindle orientation and defects in the generation of unequal-sized daughter cells. The Hippo pathway downstream kinase Warts, LATS1-2 in mammals, associates with the ACD modulators Inscuteable and Bazooka in vivo and phosphorylates Canoe, the ortholog of Afadin/AF-6, in vitro. Moreover, phosphosite mutant Canoe protein fails to form apical crescents in dividing neuroblasts in vivo, and the lack of Canoe phosphorylation by Warts leads to failures of Discs Large apical localization in metaphase neuroblasts. Given the relevance of ACD in stem cells during tissue homeostasis, and the well-documented role of the Hippo pathway as a tumor suppressor, these results represent a potential route for perturbations in the Hippo signaling to induce tumorigenesis via aberrant stem cell divisions.
Published: 2015

18. Spatial and color hallucinations in a mathematical model of primary visual cortex

Author: Faugeras, Olivier D., Song, Anna, Veltz, Romain, Mathématiques pour les Neurosciences (MATHNEURO), Inria Sophia Antipolis - Méditerranée (CRISAM), Institut National de Recherche en Informatique et en Automatique (Inria)-Institut National de Recherche en Informatique et en Automatique (Inria), Department of Mathematics [Imperial College London], Imperial College London, Haematopoietic Stem Cell Laboratory, The Francis Crick Institute, London, UK, and The Francis Crick Institute [London]
Subjects: Snaking, General Mathematics, [MATH.MATH-DS]Mathematics [math]/Dynamical Systems [math.DS], FOS: Physical sciences, Neural Fields, Dynamical Systems (math.DS), Pattern Formation and Solitons (nlin.PS), [MATH.MATH-FA]Mathematics [math]/Functional Analysis [math.FA], Visual Hallucinations, [NLIN.NLIN-PS]Nonlinear Sciences [physics]/Pattern Formation and Solitons [nlin.PS], Julia programming, FOS: Mathematics, Mathematics - Numerical Analysis, Equivariant Bifurcations, Mathematics - Dynamical Systems, Initial Value Problem, [INFO.INFO-MS]Computer Science [cs]/Mathematical Software [cs.MS], Numerical BifurcationAnalysis, [MATH.MATH-RT]Mathematics [math]/Representation Theory [math.RT], [SCCO.NEUR]Cognitive science/Neuroscience, [SDV.NEU.SC]Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC]/Cognitive Sciences, Numerical Analysis (math.NA), [INFO.INFO-NA]Computer Science [cs]/Numerical Analysis [cs.NA], Nonlinear Sciences - Pattern Formation and Solitons, Integro-partial differential equations, 37L10, 35B06, 35B32, 35G25, 37M20, 45B05, 45K05, 46E35, 47G20, 47H30, 65J15, 65R0, 9208, 9210, 92B20, Quantitative Biology - Neurons and Cognition, FOS: Biological sciences, Equivariant Branching Lemma, Neurons and Cognition (q-bio.NC), Color Perception, OPAL-Meso
Abstract: We study a simplified model of the representation of colors in the primate primary cortical visual area V1. The model is described by an initial value problem related to a Hammerstein equation. The solutions to this problem represent the variation of the activity of populations of neurons in V1 as a function of space and color. The two space variables describe the spatial extent of the cortex while the two color variables describe the hue and the saturation represented at every location in the cortex. We prove the well-posedness of the initial value problem. We focus on its stationary, i.e. independent of time, and periodic in space solutions. We show that the model equation is equivariant with respect to the direct product G of the group of the Euclidean transformations of the planar lattice determined by the spatial periodicity and the group of color transformations, isomorphic to O(2), and study the equivariant bifurcations of its stationary solutions when some parameters in the model vary. Their variations may be caused by the consumption of drugs and the bifurcated solutions may represent visual hallucinations in space and color. Some of the bifurcated solutions can be determined by applying the Equivariant Branching Lemma (EBL) by determining the axial subgroups of G . These define bifurcated solutions which are invariant under the action of the corresponding axial subgroup. We compute analytically these solutions and illustrate them as color images. Using advanced methods of numerical bifurcation analysis we then explore the persistence and stability of these solutions when varying some parameters in the model. We conjecture that we can rely on the EBL to predict the existence of patterns that survive in large parameter domains but not to predict their stability. On our way we discover the existence of spatially localized stable patterns through the phenomenon of "snaking"., Comment: 30 pages, 12 figures
Published: 2022
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19. In vitro cellular reprogramming to model gonad development and its disorders

Author: Gonen, Nitzan, Eozenou, Caroline, Mitter, Richard, Elzaiat, Maëva, Stévant, Isabelle, Aviram, Rona, Bernardo, Andreia Sofia, Chervova, Almira, Wankanit, Somboon, Frachon, Emmanuel, Commere, Pierre-Henri, Brailly-Tabard, Sylvie, Valon, Léo, Barrio Cano, Laura, Levayer, Romain, Mazen, Inas, Gobaa, Samy, Smith, James C., McElreavey, Kenneth, Lovell-Badge, Robin, Bashamboo, Anu, Bar-Ilan University [Israël], The Francis Crick Institute [London], Génétique du Développement humain - Human developmental genetics, Institut Pasteur [Paris] (IP)-Centre National de la Recherche Scientifique (CNRS)-Université Paris Cité (UPCité), Imperial College London, Département de Biologie du Développement et Cellules souches - Department of Developmental and Stem Cell Biology, Institut Pasteur [Paris] (IP), Biomatériaux et Microfluidiques (plateforme) - Biomaterials and Microfluidics (platform), Cytometrie et Biomarqueurs – Cytometry and Biomarkers (UTechS CB), AP-HP Hôpital Bicêtre (Le Kremlin-Bicêtre), Mort cellulaire et homéostasie des épithéliums / Cell death and epithelial homeostasis, National Research Center [Caire, Egypte], This work is funded in part by a research grant (40000767) from the European Society of Pediatric Endocrinology (to A.B.) and by the Agence Nationale de la Recherche (ANR, ANR-10-LABX-73 REVIVE, ANR-17-CE14-0038-01, and ANR 20CE14 0007 to K.M., and ANR-19-CE14-0022 and ANR-19-CE14-0012 to A.B.). N.G., A.S.B., R.M., J.C.S., and R.L.-B. were funded by the Francis Crick Institute. The Francis Crick Institute receives its core funding from Cancer Research UK (CC2116), the UK Medical Research Council (CC2116), and the Wellcome Trust (CC2116). For the purpose of Open Access, the author has applied a CC BY public copyright licence to any Author Accepted Manuscript version arising from this submission. . N.G., I.S., and R.A. are funded by the ERC Starting Grant EnhanceSex (101039928). A.S.B. was also funded by the British Heart Foundation (BHF-FS/12/37/29516) and the Wellcome Trust (210987/Z/18/Z)., ANR-10-LABX-0073,REVIVE,Stem Cells in Regenerative Biology and Medicine(2010), ANR-17-CE14-0038,MGonDev,Etude des mécanismes du développement des gonades chez l'homme(2017), ANR-20-CE14-0007,Goldilocks,Analyse intégrée du rôle du facteur de transcription SF-1 / NR5A1 et de ses gènes cibles dépendants du dosage dans la fonction gonadique et les troubles du développement sexuel (DSD)(2020), ANR-19-CE14-0022,SexDiff,Régulation de la détermination du sexe et de la différenciation ovarienne : implications dans les troubles du développement sexuel(2019), and ANR-19-CE14-0012,RNA-SEX,Fonction de l'ARN hélicase dans la détermination du sexe chez les vertébrés et les troubles du développement du sexe chez l'homme (DSD)(2019)
Subjects: Model organisms, Chemical Biology & High Throughput, Multidisciplinary, MESH: Humans, FOS: Clinical medicine, Stem Cells, [SDV]Life Sciences [q-bio], Genome Integrity & Repair, Neurosciences, Gene Expression, MESH: Gonadal Dysgenesis, 46,XY, Tumour Biology, MESH: Induced Pluripotent Stem Cells, MESH: Cellular Reprogramming, MESH: Male, Signalling & Oncogenes, MESH: Gonads, MESH: Animals, Genetics & Genomics, MESH: Mice, MESH: Female, Developmental Biology, Computational & Systems Biology
Abstract: During embryonic development, mutually antagonistic signaling cascades determine gonadal fate toward a testicular or ovarian identity. Errors in this process result in disorders of sex development (DSDs), characterized by discordance between chromosomal, gonadal, and anatomical sex. The absence of an appropriate, accessible in vitro system is a major obstacle in understanding mechanisms of sex-determination/DSDs. Here, we describe protocols for differentiation of mouse and human pluripotent cells toward gonadal progenitors. Transcriptomic analysis reveals that the in vitro–derived murine gonadal cells are equivalent to embryonic day 11.5 in vivo progenitors. Using similar conditions, Sertoli-like cells derived from 46,XY human induced pluripotent stem cells (hiPSCs) exhibit sustained expression of testis-specific genes, secrete anti-Müllerian hormone, migrate, and form tubular structures. Cells derived from 46,XY DSD female hiPSCs, carrying an NR5A1 variant, show aberrant gene expression and absence of tubule formation. CRISPR-Cas9–mediated variant correction rescued the phenotype. This is a robust tool to understand mechanisms of sex determination and model DSDs.
Published: 2023
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20. Informing a target product profile for rapid tests to identify HBV-infected pregnant women with high viral loads: a discrete choice experiment with African healthcare workers

Author: Isa, Yasir Shitu, Sicsic, Jonathan, Njuguna, Henry, Ward, John, Chakroun, Mohamed, El-Kassas, Mohamed, Ramanampamonjy, Rado, Chalal, Salim, Vincent, Jeanne Perpétue, Andersson, Monique, Desalegn, Hailemichael, Fall, Fatou, Johannessen, Asgeir, Matthews, Philippa C, Ndow, Gibril, Okeke, Edith, Riches, Nicholas, Seydi, Moussa, Sinkala, Edford, Spearman, C Wendy, Stockdale, Alexander, Vinikoor, Michael J, Wandeler, Gilles, Sombié, Roger, Lemoine, Maud, Mueller, Judith E, Shimakawa, Yusuke, Epidémiologie des Maladies Emergentes - Emerging Diseases Epidemiology, Université Paris Cité (UPCité)-Pasteur-Cnam Risques infectieux et émergents (PACRI), Institut Pasteur [Paris] (IP)-Conservatoire National des Arts et Métiers [CNAM] (CNAM), HESAM Université - Communauté d'universités et d'établissements Hautes écoles Sorbonne Arts et métiers université (HESAM)-HESAM Université - Communauté d'universités et d'établissements Hautes écoles Sorbonne Arts et métiers université (HESAM)-Université Paris Cité (UPCité)-Institut Pasteur [Paris] (IP)-Conservatoire National des Arts et Métiers [CNAM] (CNAM), HESAM Université - Communauté d'universités et d'établissements Hautes écoles Sorbonne Arts et métiers université (HESAM)-HESAM Université - Communauté d'universités et d'établissements Hautes écoles Sorbonne Arts et métiers université (HESAM), École des Hautes Études en Santé Publique [EHESP] (EHESP), Laboratoire Interdisciplinaire de Recherche Appliquée en Economie de la Santé (LIRAES (URP_ 4470)), Université Paris Cité (UPCité), Fattouma Bourguiba University Hospital, Helwan University [Caire], Hôpital Joseph Raseta Befelatanana, CHU d’Antananarivo, Data Management (Plate-forme) - Data Management Core Facility (Platform), Institut Pasteur [Paris] (IP)-Université Paris Cité (UPCité), Stellenbosch University, University of Oxford, Hôpital Principal de Dakar, University of Oslo (UiO), Vestfold Hospital [Tønsberg, Norway], The Francis Crick Institute [London], University College of London [London] (UCL), London School of Hygiene & Tropical Medicine [Fajara, The Gambia], Imperial College London, University of Jos [Nigeria], Liverpool School of Tropical Medicine (LSTM), Centre Hospitalier National et Universitaire de Fann-Dakar, University of Zambia [Lusaka] (UNZA), University of Cape Town, University of Liverpool, University of Alabama at Birmingham [ Birmingham] (UAB), University of Bern, Centre Hospitalier Universitaire Yalgado Ouédraogo (CHUYO), PCM receives funding from Wellcome (ref. 110110/Z/15/Z), University College London Hospital NIHR Biomedical Research Centre and the Francis Crick Institute., and We thank the leadership and communication team at the Coalition for Global Hepatitis Elimination (CGHE) and colleagues of the Hepatitis in Sub-Saharan Africa network (HEPSANET
Subjects: Elimination, Mother-to-child transmission, FOS: Clinical medicine, Immunology, 610 Medicine & health, Infectious Disease, Rapid diagnostic test, Hepatitis B, Discrete choice experiment, Preferences, Target product profile, Africa, [SDV.SPEE]Life Sciences [q-bio]/Santé publique et épidémiologie, Genetics & Genomics
Abstract: Background Elimination of mother-to-child transmission of hepatitis B virus (HBV) requires infant immunoprophylaxis and antiviral prophylaxis for pregnant women with high viral loads. Since real-time polymerase chain reaction (RT-PCR), a gold standard for assessing antiviral eligibility, is neither accessible nor affordable for women living in low-income and middle-income countries (LMICs), rapid diagnostic tests (RDTs) detecting alternative HBV markers may be needed. To inform future development of the target product profile (TPP) for RDTs to identify highly viremic women, we used a discrete choice experiment (DCE) and elicited preference and trade-off of healthcare workers (HCW) in Africa between the following four attributes of fictional RDTs: price, time-to-result, diagnostic sensitivity, and specificity. Methods Through an online questionnaire survey, we asked participants to indicate their preferred test from a set of two RDTs in seven choice tasks with varying levels of the four attributes. We used mixed multinomial logit models to quantify the utility gain or loss generated by each attribute. We attempted to define minimal and optimal criteria for test attributes that can satisfy ≥ 70% and ≥ 90% of HCWs, respectively, as an alternative to RT-PCR. Results A total of 555 HCWs from 41 African countries participated. Increases in sensitivity and specificity generated significant utility and increases in cost and time-to-result generated significant disutility. The size of the coefficients for the highest attribute levels relative to the reference levels were in the following order: sensitivity (β = 3.749), cost (β = -2.550), specificity (β = 1.134), and time-to-result (β = -0.284). Doctors cared most about test sensitivity, while public health practitioners cared about cost and midwives about time-to-result. For an RDT with 95% specificity, costing 1 US$, and yielding results in 20 min, the minimally acceptable test sensitivity would be 82.5% and the optimally acceptable sensitivity would be 87.5%. Conclusions African HCWs would prefer an RDT with the following order of priority: higher sensitivity, lower cost, higher specificity, and shorter time-to-result. The development and optimization of RDTs that can meet the criteria are urgently needed to scale up the prevention of HBV mother-to-child transmission in LMICs.
Published: 2023
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21. Grey wolf genomic history reveals a dual ancestry of dogs

Author: Anders Bergström, David W. G. Stanton, Ulrike H. Taron, Laurent Frantz, Mikkel-Holger S. Sinding, Erik Ersmark, Saskia Pfrengle, Molly Cassatt-Johnstone, Ophélie Lebrasseur, Linus Girdland-Flink, Daniel M. Fernandes, Morgane Ollivier, Leo Speidel, Shyam Gopalakrishnan, Michael V. Westbury, Jazmin Ramos-Madrigal, Tatiana R. Feuerborn, Ella Reiter, Joscha Gretzinger, Susanne C. Münzel, Pooja Swali, Nicholas J. Conard, Christian Carøe, James Haile, Anna Linderholm, Semyon Androsov, Ian Barnes, Chris Baumann, Norbert Benecke, Hervé Bocherens, Selina Brace, Ruth F. Carden, Dorothée G. Drucker, Sergey Fedorov, Mihály Gasparik, Mietje Germonpré, Semyon Grigoriev, Pam Groves, Stefan T. Hertwig, Varvara V. Ivanova, Luc Janssens, Richard P. Jennings, Aleksei K. Kasparov, Irina V. Kirillova, Islam Kurmaniyazov, Yaroslav V. Kuzmin, Pavel A. Kosintsev, Martina Lázničková-Galetová, Charlotte Leduc, Pavel Nikolskiy, Marc Nussbaumer, Cóilín O’Drisceoil, Ludovic Orlando, Alan Outram, Elena Y. Pavlova, Angela R. Perri, Małgorzata Pilot, Vladimir V. Pitulko, Valerii V. Plotnikov, Albert V. Protopopov, André Rehazek, Mikhail Sablin, Andaine Seguin-Orlando, Jan Storå, Christian Verjux, Victor F. Zaibert, Grant Zazula, Philippe Crombé, Anders J. Hansen, Eske Willerslev, Jennifer A. Leonard, Anders Götherström, Ron Pinhasi, Verena J. Schuenemann, Michael Hofreiter, M. Thomas P. Gilbert, Beth Shapiro, Greger Larson, Johannes Krause, Love Dalén, Pontus Skoglund, Bergström, Anders [0000-0002-4096-9268], Frantz, Laurent [0000-0001-8030-3885], Sinding, Mikkel-Holger S [0000-0003-1371-219X], Lebrasseur, Ophélie [0000-0003-0687-8538], Fernandes, Daniel M [0000-0002-7434-6552], Ollivier, Morgane [0000-0002-8361-4221], Westbury, Michael V [0000-0003-0478-3930], Ramos-Madrigal, Jazmin [0000-0002-1661-7991], Feuerborn, Tatiana R [0000-0003-1610-3402], Conard, Nicholas J [0000-0002-4633-0385], Haile, James [0000-0002-8521-8337], Linderholm, Anna [0000-0002-1613-9926], Barnes, Ian [0000-0001-8322-6918], Baumann, Chris [0000-0002-1001-8621], Bocherens, Hervé [0000-0002-0494-0126], Brace, Selina [0000-0003-2126-6732], Drucker, Dorothée G [0000-0003-0854-4371], Germonpré, Mietje [0000-0001-8865-0937], Jennings, Richard P [0000-0001-9996-7518], Kuzmin, Yaroslav V [0000-0002-4512-2269], Orlando, Ludovic [0000-0003-3936-1850], Outram, Alan [0000-0003-3360-089X], Perri, Angela R [0000-0002-4349-1060], Plotnikov, Valerii V [0000-0002-4870-3499], Sablin, Mikhail [0000-0002-2773-7454], Crombé, Philippe [0000-0002-4198-8057], Hansen, Anders J [0000-0002-1890-2702], Willerslev, Eske [0000-0002-7081-6748], Leonard, Jennifer A [0000-0003-0291-7819], Pinhasi, Ron [0000-0003-1629-8131], Shapiro, Beth [0000-0002-2733-7776], Larson, Greger [0000-0002-4092-0392], Krause, Johannes [0000-0001-9144-3920], Dalén, Love [0000-0001-8270-7613], Skoglund, Pontus [0000-0002-3021-5913], Apollo - University of Cambridge Repository, The Francis Crick Institute [London], Swedish Museum of Natural History (NRM), Ludwig Maximilian University [Munich] (LMU), University of Copenhagen = Københavns Universitet (UCPH), Trinity College Dublin, University of Greenland, University of Tübingen, University of Oxford, Ecosystèmes, biodiversité, évolution [Rennes] (ECOBIO), Université de Rennes (UR)-Institut Ecologie et Environnement (INEE), Centre National de la Recherche Scientifique (CNRS)-Centre National de la Recherche Scientifique (CNRS)-Observatoire des Sciences de l'Univers de Rennes (OSUR), Université de Rennes (UR)-Institut national des sciences de l'Univers (INSU - CNRS)-Université de Rennes 2 (UR2)-Centre National de la Recherche Scientifique (CNRS)-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE)-Institut national des sciences de l'Univers (INSU - CNRS)-Université de Rennes 2 (UR2)-Centre National de la Recherche Scientifique (CNRS)-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE)-Centre National de la Recherche Scientifique (CNRS), University College of London [London] (UCL), IT University of Copenhagen (ITU), Max Planck Institute for the Science of Human History (MPI-SHH), Max-Planck-Gesellschaft, Eberhard Karls Universität Tübingen = Eberhard Karls University of Tuebingen, Globe Institute, Faculty of Health and Medical Sciences, University of Copenhagen = Københavns Universitet (UCPH)-University of Copenhagen = Københavns Universitet (UCPH), Texas A&M University System, Stockholm University, Natural History Museum [Oslo], University of Oslo (UiO), German Archaeological Institute (DAI), The Natural History Museum [London] (NHM), UCD School of Biology and Environmental Science, UCD, Royal Belgian Institute of Natural Sciences (RBINS), North-Eastern Federal University, School of Archaeology, Histoire naturelle de l'Homme préhistorique (HNHP), Muséum national d'Histoire naturelle (MNHN)-Université de Perpignan Via Domitia (UPVD)-Centre National de la Recherche Scientifique (CNRS), Centre d'anthropologie et de génomique de Toulouse (CAGT), Université Toulouse III - Paul Sabatier (UT3), Université de Toulouse (UT)-Université de Toulouse (UT)-Centre National de la Recherche Scientifique (CNRS), University of Vienna [Vienna], Max Planck Institute for Evolutionary Anthropology [Leipzig], This work was supported by grants to P. Skoglund from the European Research Council (grant no. 852558), the Erik Philip Sörensen Foundation and the Science for Life Laboratory, Swedish Biodiversity Program, made available by support from the Knut and Alice Wallenberg Foundation. A.B., L.S., P. Swali and P. Skoglund were supported by Francis Crick Institute core funding (FC001595) from Cancer Research UK, the UK Medical Research Council and the Wellcome Trust. P. Skoglund was also supported by the Vallee Foundation, the European Molecular Biology Organisation and the Wellcome Trust (217223/Z/19/Z). Computations were supported by SNIC-UPPMAX. We also acknowledge support from Science for Life Laboratory, the Knut and Alice Wallenberg Foundation, the National Genomics Infrastructure funded by the Swedish Research Council and the Uppsala Multidisciplinary Center for Advanced Computational Science for assistance with massively parallel sequencing and access to the UPPMAX computational infrastructure. We thank the Yukon gold mining community and First Nations, including the Tr’ondëk Hwëch’in, for continued support of our palaeontology research in the Yukon Territories, Canada. We thank the Danish National High-Throughput Sequencing Centre and BGI-Europe for assistance in sequencing data generation and the Danish National Supercomputer for Life Sciences–Computerome (https://computerome.dtu.dk) for computational resources. We thank National Museum Wales for continued sampling support. M. Germonpré acknowledges support from the Brain.be 2.0 ICHIE project (BELSPO B2/191/P2/ICHIE). M.T.P.G. was supported by the European Research Council (grant no. 681396). M.-H.S.S. was supported by the Velux Foundations through the Qimmeq Project, the Aage og Johanne Louis-Hansens Fond and the Independent Research Fund Denmark (8028-00005B). L.D. acknowledges support from FORMAS (2018-01640). D.W.G.S. received funding for this project from the European Union’s Horizon 2020 research and innovation programme under Marie Skłodowska-Curie grant agreement no. 796877. M.P. was supported by the Polish National Agency for Academic Exchange–NAWA (grant no. PPN/PPO/2018/1/00037). V.J.S. was supported by the University of Zurich’s University Research Priority Program ‘Evolution in Action: From Genomes to Ecosystems’. This research was done with the participation of ZIN RAS (grant no. 075-15-2021-1069). We are grateful to the museum of the Institute of Plant and Animal Ecology UB RAS (Ekaterinburg, Russia) for provision of samples. R.P.J. and C.O’D. were supported by the Standing Committee for Archaeology of the Royal Irish Academy through the Archaeological Excavation Research Grant Scheme. E.Y.P., P.N. and V.V.P. are supported by the Russian Science Foundation (grant no. 16-18-10265-RNF and 21-18-00457-RNF). Y.V.K. was supported by the Russian Science Foundation (grant no. 20-17-00033). M.H. was supported by the European Research Council (consolidator grant GeneFlow no. 310763). M.L.-G. was supported by the Czech Science Foundation GAČR (grant no. 15-06446S) and institutional financing of the Moravian Museum from the Czech Ministry of Culture (IP DKRVO 2019-2023, MK000094862). L.S. is supported by the Sir Henry Wellcome fellowship (220457/Z/20/Z). We thank Staatliches Museum für Naturkunde Stuttgart for sample access. L.F. and G.L. were supported by European Research Council grants (ERC-2013-StG-337574-UNDEAD and ERC-2019-StG-853272-PALAEOFARM) and Natural Environmental Research Council grants (NE/K005243/1, NE/K003259/1, NE/S007067/1 and NE/S00078X/1). L.F. was also supported by the Wellcome Trust (210119/Z/18/Z). This research was funded in whole, or in part, by the Wellcome Trust (FC001595). For the purpose of open access, the author has applied a CC-BY public copyright licence to any author accepted manuscript version arising from this submission., Université de Rennes 1 (UR1), Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES)-Institut Ecologie et Environnement (INEE), Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES)-Institut national des sciences de l'Univers (INSU - CNRS)-Université de Rennes 2 (UR2), Université de Rennes (UNIV-RENNES)-Centre National de la Recherche Scientifique (CNRS)-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE)-Institut national des sciences de l'Univers (INSU - CNRS)-Université de Rennes 2 (UR2), Université de Rennes (UNIV-RENNES)-Centre National de la Recherche Scientifique (CNRS)-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE)-Centre National de la Recherche Scientifique (CNRS), Department of Geosciences and Geography, and Faculty of Science
Subjects: History, RUSSIAN FEDERATION, 631/158/2464, CANIS LUPUS, ANIMAL EXPERIMENT, Domestication, Ecology,Evolution & Ethology, MIDDLE EAST, DOG, History, Ancient, Phylogeny, CANID, WOLF, Multidisciplinary, Genome, ORIGIN, article, 45/77, Genomics, CC, ADMIXTURE, CONTAMINATION, Europe, GENOME, EXTINCTION, DOGS, COMPLETE MITOCHONDRIAL GENOME, Genetics & Genomics, NATURAL SELECTION, 1171 Geosciences, AFRICA, EUROPE, NORTH AMERICA, GENETICS, SIBERIA, General Science & Technology, PHYLOGENY, PLEISTOCENE, LIBRARY PREPARATION, 45/23, Infectious Disease, ANCESTRY, SEQUENCE, EURASIA, Ancient, TIME SERIES ANALYSIS, 631/181/27, Middle East, QH301, Dogs, UPPER PLEISTOCENE, Genetic, EVOLUTIONARY HISTORY, WOLVES, GENE MUTATION, ANCIENT DNA, Animals, NONHUMAN, 631/181/457, DNA, Ancient, Selection, Genetic, ARTICLE, Selection, QH426, QL, Wolves, History and Archaeology, Tumor Suppressor Proteins, ANIMALS, Biology and Life Sciences, DNA, ANIMAL, GENE, Siberia, CONTROLLED STUDY, DOMESTICATION, 631/181/2474, Africa, Mutation, North America, 570 Life sciences, biology, [SDE.BE]Environmental Sciences/Biodiversity and Ecology, GENOMICS
Abstract: The grey wolf (Canis lupus) was the first species to give rise to a domestic population, and they remained widespread throughout the last Ice Age when many other large mammal species went extinct. Little is known, however, about the history and possible extinction of past wolf populations or when and where the wolf progenitors of the present-day dog lineage (Canis familiaris) lived1–8. Here we analysed 72 ancient wolf genomes spanning the last 100,000 years from Europe, Siberia and North America. We found that wolf populations were highly connected throughout the Late Pleistocene, with levels of differentiation an order of magnitude lower than they are today. This population connectivity allowed us to detect natural selection across the time series, including rapid fixation of mutations in the gene IFT88 40,000–30,000 years ago. We show that dogs are overall more closely related to ancient wolves from eastern Eurasia than to those from western Eurasia, suggesting a domestication process in the east. However, we also found that dogs in the Near East and Africa derive up to half of their ancestry from a distinct population related to modern southwest Eurasian wolves, reflecting either an independent domestication process or admixture from local wolves. None of the analysed ancient wolf genomes is a direct match for either of these dog ancestries, meaning that the exact progenitor populations remain to be located. © 2022, The Author(s). 8028-00005B; IP DKRVO 2019-2023, MK000094862; 220457/Z/20/Z, ERC-2013-StG-337574-UNDEAD, ERC-2019-StG-853272-PALAEOFARM; 075-15-2021-1069; European Molecular Biology Organization, EMBO: 217223/Z/19/Z; Vallee Foundation; Velux Fonden; Wellcome Trust, WT; Francis Crick Institute, FCI: FC001595; Horizon 2020 Framework Programme, H2020: 796877; Medical Research Council, MRC; Natural Environment Research Council, NERC: 210119/Z/18/Z, NE/K003259/1, NE/K005243/1, NE/S00078X/1, NE/S007067/1; Cancer Research UK, CRUK; European Research Council, ERC: 852558; Grantová Agentura České Republiky, GA ČR: 15-06446S; Svenska Forskningsrådet Formas: 2018-01640; Knut och Alice Wallenbergs Stiftelse; Vetenskapsrådet, VR: 681396, BELSPO B2/191/P2/ICHIE; Russian Science Foundation, RSF: 16-18-10265-RNF, 20-17-00033, 21-18-00457-RNF, 310763; Science for Life Laboratory, SciLifeLab; Narodowa Agencja Wymiany Akademickiej, NAWA: PPN/PPO/2018/1/00037 This work was supported by grants to P. Skoglund from the European Research Council (grant no. 852558), the Erik Philip Sörensen Foundation and the Science for Life Laboratory, Swedish Biodiversity Program, made available by support from the Knut and Alice Wallenberg Foundation. A.B., L.S., P. Swali and P. Skoglund were supported by Francis Crick Institute core funding (FC001595) from Cancer Research UK, the UK Medical Research Council and the Wellcome Trust. P. Skoglund was also supported by the Vallee Foundation, the European Molecular Biology Organisation and the Wellcome Trust (217223/Z/19/Z). Computations were supported by SNIC-UPPMAX. We also acknowledge support from Science for Life Laboratory, the Knut and Alice Wallenberg Foundation, the National Genomics Infrastructure funded by the Swedish Research Council and the Uppsala Multidisciplinary Center for Advanced Computational Science for assistance with massively parallel sequencing and access to the UPPMAX computational infrastructure. We thank the Yukon gold mining community and First Nations, including the Tr’ondëk Hwëch’in, for continued support of our palaeontology research in the Yukon Territories, Canada. We thank the Danish National High-Throughput Sequencing Centre and BGI-Europe for assistance in sequencing data generation and the Danish National Supercomputer for Life Sciences–Computerome ( https://computerome.dtu.dk ) for computational resources. We thank National Museum Wales for continued sampling support. M. Germonpré acknowledges support from the Brain.be 2.0 ICHIE project (BELSPO B2/191/P2/ICHIE). M.T.P.G. was supported by the European Research Council (grant no. 681396). M.-H.S.S. was supported by the Velux Foundations through the Qimmeq Project, the Aage og Johanne Louis-Hansens Fond and the Independent Research Fund Denmark (8028-00005B). L.D. acknowledges support from FORMAS (2018-01640). D.W.G.S. received funding for this project from the European Union’s Horizon 2020 research and innovation programme under Marie Skłodowska-Curie grant agreement no. 796877. M.P. was supported by the Polish National Agency for Academic Exchange–NAWA (grant no. PPN/PPO/2018/1/00037). V.J.S. was supported by the University of Zurich’s University Research Priority Program ‘Evolution in Action: From Genomes to Ecosystems’. This research was done with the participation of ZIN RAS (grant no. 075-15-2021-1069). We are grateful to the museum of the Institute of Plant and Animal Ecology UB RAS (Ekaterinburg, Russia) for provision of samples. R.P.J. and C.O’D. were supported by the Standing Committee for Archaeology of the Royal Irish Academy through the Archaeological Excavation Research Grant Scheme. E.Y.P., P.N. and V.V.P. are supported by the Russian Science Foundation (grant no. 16-18-10265-RNF and 21-18-00457-RNF). Y.V.K. was supported by the Russian Science Foundation (grant no. 20-17-00033). M.H. was supported by the European Research Council (consolidator grant GeneFlow no. 310763). M.L.-G. was supported by the Czech Science Foundation GAČR (grant no. 15-06446S) and institutional financing of the Moravian Museum from the Czech Ministry of Culture (IP DKRVO 2019-2023, MK000094862). L.S. is supported by the Sir Henry Wellcome fellowship (220457/Z/20/Z). We thank Staatliches Museum für Naturkunde Stuttgart for sample access. L.F. and G.L. were supported by European Research Council grants (ERC-2013-StG-337574-UNDEAD and ERC-2019-StG-853272-PALAEOFARM) and Natural Environmental Research Council grants (NE/K005243/1, NE/K003259/1, NE/S007067/1 and NE/S00078X/1). L.F. was also supported by the Wellcome Trust (210119/Z/18/Z). This research was funded in whole, or in part, by the Wellcome Trust (FC001595). For the purpose of open access, the author has applied a CC-BY public copyright licence to any author accepted manuscript version arising from this submission.
Published: 2022
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22. Testis formation in XX individuals resulting from novel pathogenic variants in Wilms’ tumor 1 ( WT1 ) gene

Author: Masomeh Askari, Svetlana A. Yatsenko, Robin Lovell-Badge, Tiphanie Merel-Chali, Balázs Gellén, Nitzan Gonen, Leila Fusee, Rana Mainpal, Mariana Costanzo, Inas Mazen, Anu Bashamboo, Anahita Mohseni Meybodi, Esperanza Berensztein, Joelle Bignon-Topalovic, Caroline Eozenou, Natalia Perez Garrido, Alicia Belgorosky, Andrea J. Berman, Roberta Migale, Ken McElreavey, Rita Bertalan, Alaa K. Kamel, Mona K. Mekkawy, Maria Sol Touzon, Priti Singh, Pablo Ramirez, Gabriela Guercio, Aleksandar Rajkovic, Mehdi Totonchi, Selma F. Witchel, Roxana Marino, John C. Schimenti, Anne Jørgensen, Génétique du développement humain, Institut Pasteur [Paris], The Francis Crick Institute [London], The Mina & Everard Goodman Faculty of Life Sciences [Ramat Gan, Israël], Université Bar-Ilan [Israel], Hospital Nacional de Pediatría Prof. Dr Juan P. Garrahan [Buenos Aires], Copenhagen University Hospital, University of Pittsburgh (PITT), Pennsylvania Commonwealth System of Higher Education (PCSHE), National Research Centre - NRC (EGYPT), University of Szeged [Szeged], Cornell University [New York], Children's Hospital of Pittsburgh of UPMC [Etats-Unis], Royan Institute for Reproductive Biomedicine [Tehran, Iran], Semmelweis University [Budapest], University of California, Génétique du Développement humain - Human developmental genetics, Institut Pasteur [Paris]-Centre National de la Recherche Scientifique (CNRS), This work is supported by the European Cooperation in Science and Technology (COST) Action DSDnet BM1303 (to A. Bashamboo and K.M.). N.G and R.L.-B. are funded by the Francis Crick Institute. The Francis Crick Institute receives its core funding from Cancer Research UK Grant FC001107, UK Medical Research Council Grant FC001107, Wellcome Grant FC001107, and by UK Medical Research Council Grant U117512772. M.S.T. and A. Belgorosky are supported by PIDC-20160028 Fondo Nacional de Ciencia y Tecnologia, Argentina, Grant PICT-2013-0181y PICT2016-0214, Agencia Nacional para Ciencia y Tecnologia, Argentina, and Consejo Nacional de Investigaciones Cientificas y Tecnologicas, Argentina. A.R. is funded by NIH Grants R01HD070647 and R21HD074278. A.J. is funded by a research grant from the Svend Andersen Foundation and the Danish Government’s support to Department of Growth and Reproduction for the International Center for Research and Research Training in Endocrine Disruption of Male Reproduction and Child Health (EDMaRC) programme. A.J.B. is supported by NIH Grant GM116889 and American Cancer Society Research Scholar Grant RSG-17-1.97-01-RMC, We are grateful to the Biological Research Facility, Genetic Modification Service, and Experimental Histopathology Facilities of the Francis Crick Institute. We acknowledge Dr. László Tiszlavicz (Pathological Department, University of Szeged, Hungary) for the histological examination of Patients 5a and 5b and Dr. Alejandro Suárez-Bonnet (Experimental Histopathology at Francis Crick Institute) for pathology report on mouse embryonic kidneys., Institut Pasteur [Paris] (IP), Bar-Ilan University [Israël], University of California (UC), Institut Pasteur [Paris] (IP)-Centre National de la Recherche Scientifique (CNRS), and ANR-17-CE14-0038,MGonDev,Etude des mécanismes du développement des gonades chez l'homme(2017)
Subjects: 0301 basic medicine, Wt1 gene, Gonad, organogenesis, sex determination, 030209 endocrinology & metabolism, Biology, 03 medical and health sciences, 0302 clinical medicine, β-CATENIN, medicine, Gene, Exome sequencing, Zinc finger, Genetics, Multidisciplinary, urogenital system, Wilms' tumor, medicine.disease, XX TDSD/OTDSD, WT1, 030104 developmental biology, medicine.anatomical_structure, Testis determining factor, [SDV.GEN.GH]Life Sciences [q-bio]/Genetics/Human genetics, Etiology
Abstract: International audience; Sex determination in mammals is governed by antagonistic interactions of two genetic pathways, imbalance in which may lead to disorders/differences of sex development (DSD) in human. Among 46,XX individuals with testicular DSD (TDSD) or ovotesticular DSD (OTDSD), testicular tissue is present in the gonad. Although the testis-determining gene SRY is present in many cases, the etiology is unknown in most SRY-negative patients. We performed exome sequencing on 78 individuals with 46,XX TDSD/OTDSD of unknown genetic etiology and identified seven (8.97%) with heterozygous variants affecting the fourth zinc finger (ZF4) of Wilms' tumor 1 (WT1) (p.Ser478Thrfs*17, p.Pro481Leufs*15, p.Lys491Glu, p.Arg495Gln [x3], p.Arg495Gly). The variants were de novo in six families (P = 4.4 × 10-6), and the incidence of WT1 variants in 46,XX DSD is enriched compared to control populations (P < 1.8 × 10-4). The introduction of ZF4 mutants into a human granulosa cell line resulted in up-regulation of endogenous Sertoli cell transcripts and Wt1 Arg495Gly/Arg495Gly XX mice display masculinization of the fetal gonads. The phenotype could be explained by the ability of the mutated proteins to physically interact with and sequester a key pro-ovary factor β-CATENIN, which may lead to up-regulation of testis-specific pathway. Our data show that unlike previous association of WT1 and 46,XY DSD, ZF4 variants of WT1 are a relatively common cause of 46,XX TDSD/OTDSD. This expands the spectrum of phenotypes associated with WT1 variants and shows that the WT1 protein affecting ZF4 can function as a protestis factor in an XX chromosomal context.
Published: 2020
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23. Intracellular niche switching as host subversion strategy of bacterial pathogens

Author: Gutierrez, Maximiliano, Enninga, Jost, The Francis Crick Institute [London], Dynamique des Interactions Hôte-Pathogène - Dynamics of Host-Pathogen Interactions, Institut Pasteur [Paris] (IP)-Centre National de la Recherche Scientifique (CNRS)-Université Paris Cité (UPCité), Work in the Host pathogen-interactions in tuberculosis lab is supported by the Francis Crick Institute (to MGG), which receives its core funding from Cancer Research UK (FC001092), the UK Medical Research Council (FC001092) and the Wellcome Trust (FC001092). This research was funded in whole, or in part, by the Wellcome Trust (FC001092). The Dynamics of Host Pathogen Interaction Unit acknowledges funding from the Institut Pasteur, the European Union (ERC-CoG 'Endosubvert'), and the Agence National pour la Recherche (Program 'HBP Sensing', 'PureMagRupture'). Furthermore, the JE team is supported by the LabExes 'Milieu Interieur' and 'IBEID'., ANR-17-CE15-0006,HBPsensing,Mécanisme de détection de l'heptose 1,7-bisphosphate lors d'infections bactériennes à Gram négatif(2017), ANR-21-CE35-0007,PureMagRupture,Un flux de travail de la gMEP (Genetic magnetic-extraction-proteomics) pour comprendre le lien entre la rupture vacuolaire de Shigella et l'autophagie(2021), ANR-10-LABX-0069,MILIEU INTERIEUR,GENETIC & ENVIRONMENTAL CONTROL OF IMMUNE PHENOTYPE VARIANCE: ESTABLISHING A PATH TOWARDS PERSONALIZED MEDICINE(2010), ANR-10-LABX-0062,IBEID,Integrative Biology of Emerging Infectious Diseases(2010), and European Project: 682809,EndoSubvert(2017)
Subjects: Model organisms, Cytosol, Bacteria, [SDV.BC.IC]Life Sciences [q-bio]/Cellular Biology/Cell Behavior [q-bio.CB], Host-Pathogen Interactions, Infectious Disease, Cell Biology, [SDV.BBM.BC]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Biochemistry [q-bio.BM]
Abstract: International audience; Numerous bacterial pathogens “confine” themselves within host cells with an intracellular localization as main or exclusive niche. Many of them switch dynamically between a membrane-bound or cytosolic lifestyle. This requires either membrane damage and/or repair of the bacterial-containing compartment. Niche switching has profound consequences on how the host cell recognizes the pathogens in time and space for elimination. Moreover, niche switching impacts how bacteria communicate with host cells to obtain nutrients, and it affects the accessibility to antibiotics. Understanding the local environments and cellular phenotypes that lead to niche switching is critical for developing new host-targeted antimicrobial strategies, and has the potential to shed light into fundamental cellular processes.
Published: 2021
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24. jULIEs: nanostructured polytrodes for low traumatic extracellular recordings and stimulation in the mammalian brain

Author: Romeo R Racz, Mihaly Kollo, Gabriella Racz, Ciprian Bulz, Tobias Ackels, Tom Warner, William Wray, Nikolai Kiskin, Chi Chen, Zhiwen Ye, Livia de Hoz, Ede Rancz, Andreas T Schaefer, The Francis Crick Institute [London], University College of London [London] (UCL), Institute of Experimental Medicine [Budapest] (KOKI), Hungarian Academy of Sciences (MTA), Lawrence Berkeley National Laboratory [Berkeley] (LBNL), Institut de Neurobiologie de la Méditerranée [Aix-Marseille Université] (INMED - INSERM U1249), Aix Marseille Université (AMU)-Institut National de la Santé et de la Recherche Médicale (INSERM), and We thank Justin Molloy for performing the atomic force microscopy experiments. We thank Martyn Stopps for help with electronic design, Isabell Whiteley for technical help with histological processing. We also thank Lucy Collison and the EM STP team for help with SEM imaging, the Making Lab and the BRF for technical help. We also thank Ecaterina Ware and Mahmoud Ardakani from Imperial College Faculty of Engineering, Department of Materials for their help with characterizing and imaging nanoAu and IrOx nanostructures. We thank Howard Marriage and Veronique Birault and the Translational team at the Crick for supporting the development of jULIEs through the Idea 2 Innovation grant scheme. This work was also supported by the Francis Crick Institute which receives its core funding from Cancer Research UK (FC001153), the UK Medical Research Council (FC001153), and HFSP Grant (RGP 00048/2013), an NIH BRAIN Initiative Grant (1U01NS094248-01) and the Wellcome Trust (FC001153) and the Medical Research Council (MC_UP_1202/5). Ede A Rancz is a Sir Henry Dale Fellow (Wellcome, 104285/B/14/Z). Andreas Schaefer is a Wellcome Trust investigator (110174/Z/15/Z).
Subjects: Neurons, [SDV]Life Sciences [q-bio], FOS: Clinical medicine, Biomedical Engineering, Neurosciences, Brain, Silicon Dioxide, Imaging, Electrodes, Implanted, Cellular and Molecular Neuroscience, Mice, Ecology,Evolution & Ethology, Electric Impedance, Animals, Microfabrication & Bioengineering, Microelectrodes, Computational & Systems Biology
Abstract: Objective. Extracellular microelectrode techniques are the most widely used approach to interrogate neuronal populations. However, regardless of the manufacturing method used, damage to the vasculature and circuit function during probe insertion remains a concern. This issue can be mitigated by minimising the footprint of the probe used. Reducing the size of probes typically requires either a reduction in the number of channels present in the probe, or a reduction in the individual channel area. Both lead to less effective coupling between the probe and extracellular signals of interest. Approach. Here, we show that continuously drawn SiO2-insulated ultra-microelectrode fibres offer an attractive substrate to address these challenges. Individual fibres can be fabricated to >10 m continuous stretches and a selection of diameters below 30 µm with low resistance (−1) continuously conductive metal core of µm and atomically flat smooth shank surfaces. To optimize the properties of the miniaturised electrode-tissue interface, we electrodeposit rough Au structures followed by ∼20 nm IrOx film resulting in the reduction of the interfacial impedance to Main results. We demonstrate that these ultra-low impedance electrodes can record and stimulate both single and multi-unit activity with minimal tissue disturbance and exceptional signal-to-noise ratio in both superficial (∼40 µm) and deep (∼6 mm) structures of the mouse brain. Further, we show that sensor modifications are stable and probe manufacturing is reproducible. Significance. Minimally perturbing bidirectional neural interfacing can reveal circuit function in the mammalian brain in vivo.
Published: 2021
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25. Structures of the cGMP-dependent protein kinase in malaria parasites reveal a unique structural relay mechanism for activation

Author: El Bakkouri, Majida, Kouidmi, Imène, Wernimont, Amy K., Amani, Mehrnaz, Hutchinson, Ashley, Loppnau, Peter, Kim, Jeong Joo, Flueck, Christian, Walker, John R., Seitova, Alma, Senisterra, Guillermo, Kakihara, Yoshito, Kim, Choel, Blackman, Michael J., Calmettes, Charles, Baker, David A., Hui, Raymond, University of Toronto, Institut Armand Frappier (INRS-IAF), Institut National de la Recherche Scientifique [Québec] (INRS)-Réseau International des Instituts Pasteur (RIIP), Baylor College of Medicine (BCM), Baylor University, London School of Hygiene and Tropical Medicine (LSHTM), The Francis Crick Institute [London], Toronto General Hospital Research Institute [Canada] (TGHRI), The Structural Genomics Consortium is a registered charity (no. 1097737) that receives funds from AbbVie, Boehringer Ingelheim, the Canada Foundation for Innovation, the Canadian Institutes for Health Research, Genome Canada through the Ontario Genomics Institute (OGI-055), GlaxoSmithKline, Janssen, Lilly Canada, the Novartis Research Foundation, the Ontario Ministry of Economic Development and Innovation, Pfizer, Takeda, and the Wellcome Trust. This work was also supported by Wellcome Trust Grants 092809/Z/10/Z, 106240/Z/14/Z and 106239/Z/14/A (to D.A.B. and M.J.B.). This work was also supported by the Francis Crick Institute (M.J.B.) , which receives its core funding from Cancer Research UK Grant FC001043, UK Medical Research Council Grant FC001043, and Wellcome Trust Grant FC001043. C.C. is the recipient of Fonds de Recherche Québec–Santé (FRQS) Research Scholar Junior 1 Career Award 251848, supported by Natural Sciences and Engineering Research Council of Canada (NSERC) Discovery Grant RGPIN-2017-06091, Fonds de Recherche Québec–Nature et Technologies (FRQNT) Grant 2019-NC-253753, as well as with instrumentation and infrastructure support provided by the Armand–Frappier Foundation. This research used resources of the Canadian Light Source at Beamline 08ID-1, which is supported by the Canada Foundation for Innovation, Natural Sciences and Engineering Research Council of Canada, and Canadian Institutes of Health Research, and and of the Advanced Photon Source, a US Department of Energy (DOE) Office of Science User Facility operated for the DOE Office of Science by Argonne National Laboratory under Contract DE-AC02-06CH11357.
Subjects: Plasmodium, Medical Sciences, Binding Sites, Protein Conformation, [SDV]Life Sciences [q-bio], Plasmodium falciparum, malaria, Biological Sciences, Crystallography, X-Ray, Kinetics, [SDV.MP]Life Sciences [q-bio]/Microbiology and Parasitology, PNAS Plus, cyclic GMP, Catalytic Domain, cardiovascular system, Cyclic GMP-Dependent Protein Kinases, Animals, Humans, [SDV.BBM]Life Sciences [q-bio]/Biochemistry, Molecular Biology, structure, Amino Acid Sequence, signal transduction, Protein Binding
Abstract: Significance Despite being one of the first protein kinases discovered, cyclic guanosine-3′,5′-monophosphate (cGMP)-dependent protein kinase (PKG) has not been successfully crystallized previously, leaving many unanswered questions about its mechanism of activation. We report herein the structure of cGMP-free PKG from Plasmodium parasites, the causative agents of malaria, one of the world’s deadliest infectious diseases. The structures, combined with data from biochemical and biophysical experiments, provide insight into a mechanism of activation that involves previously unpredicted interdomain communication via a structural relay system. In addition to the full structure of PKG, our work contributes important functional information for a key antimalarial drug target., The cyclic guanosine-3′,5′-monophosphate (cGMP)-dependent protein kinase (PKG) was identified >25 y ago; however, efforts to obtain a structure of the entire PKG enzyme or catalytic domain from any species have failed. In malaria parasites, cooperative activation of PKG triggers crucial developmental transitions throughout the complex life cycle. We have determined the cGMP-free crystallographic structures of PKG from Plasmodium falciparum and Plasmodium vivax, revealing how key structural components, including an N-terminal autoinhibitory segment (AIS), four predicted cyclic nucleotide-binding domains (CNBs), and a kinase domain (KD), are arranged when the enzyme is inactive. The four CNBs and the KD are in a pentagonal configuration, with the AIS docked in the substrate site of the KD in a swapped-domain dimeric arrangement. We show that although the protein is predominantly a monomer (the dimer is unlikely to be representative of the physiological form), the binding of the AIS is necessary to keep Plasmodium PKG inactive. A major feature is a helix serving the dual role of the N-terminal helix of the KD as well as the capping helix of the neighboring CNB. A network of connecting helices between neighboring CNBs contributes to maintaining the kinase in its inactive conformation. We propose a scheme in which cooperative binding of cGMP, beginning at the CNB closest to the KD, transmits conformational changes around the pentagonal molecule in a structural relay mechanism, enabling PKG to orchestrate rapid, highly regulated developmental switches in response to dynamic modulation of cGMP levels in the parasite.
Published: 2019
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26. MICAL2 enhances branched actin network disassembly by oxidizing Arp3B-containing Arp2/3 complexes

Author: Christophe Guérin, Pavithra Singaravelu, Laurent Blanchoin, Naoko Kogata, Svend Kjaer, Davide Carra, Michael Way, Chiara Galloni, Jasmine V. Abella, David J. Barry, The Francis Crick Institute, Cellular Signalling and Cytoskeletal Function Laboratory, The Francis Crick Institute, Structural Biology Science Technology Platform, CytoMorphoLab, Physiologie cellulaire et végétale (LPCV), Centre National de la Recherche Scientifique (CNRS)-Institut de Recherche Interdisciplinaire de Grenoble (IRIG), Direction de Recherche Fondamentale (CEA) (DRF (CEA)), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Direction de Recherche Fondamentale (CEA) (DRF (CEA)), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE)-Université Grenoble Alpes (UGA)-Centre National de la Recherche Scientifique (CNRS)-Institut de Recherche Interdisciplinaire de Grenoble (IRIG), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE)-Université Grenoble Alpes (UGA), CytoMorphoLab UMR976 HIPI, CEA, INSERM, Université de Paris, Paris, France, The Francis Crick Institute, Advanced Light Microscopy Facility, Imperial College, Department of infectious diseases, Cancer Research UK (FC001209), UK Medical Research Council (FC001209), Wellcome Trust (FC001209) funding at the Francis Crick Institute, European Project: Grant 810207, European Project: 741773,AAA, Martin-Laffon, Jacqueline, European Union’s Horizon 2020 research and innovation programme (grant 810207) - Grant 810207 - INCOMING, Adaptive Actin Architectures - AAA - 741773 - INCOMING, Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE)-Institut de Recherche Interdisciplinaire de Grenoble (IRIG), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université Grenoble Alpes (UGA)-Centre National de la Recherche Scientifique (CNRS)-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE)-Institut de Recherche Interdisciplinaire de Grenoble (IRIG), and Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université Grenoble Alpes (UGA)-Centre National de la Recherche Scientifique (CNRS)
Subjects: Gene isoform, [SDV.BC]Life Sciences [q-bio]/Cellular Biology, macromolecular substances, Biochemistry, Article, Actin-Related Protein 2-3 Complex, 03 medical and health sciences, chemistry.chemical_compound, 0302 clinical medicine, Oxidizing agent, Threonine, [SDV.BC] Life Sciences [q-bio]/Cellular Biology, Actin, Cytoskeleton, 030304 developmental biology, 0303 health sciences, Methionine, biology, Cell Biology, Monooxygenase, Actins, Glutamine, Actin Cytoskeleton, chemistry, biology.protein, Biophysics, 030217 neurology & neurosurgery, Cortactin
Abstract: Galloni, Carra, et al. demonstrate that Arp3B isoform–specific Arp2/3 complexes generate branched actin networks with faster disassembly kinetics. This increased turnover is due to oxidation of Met293 of Arp3B by the methionine monooxygenase MICAL2, which is recruited to the branched actin network by coronin 1C., The mechanisms regulating the disassembly of branched actin networks formed by the Arp2/3 complex still remain to be fully elucidated. In addition, the impact of Arp3 isoforms on the properties of Arp2/3 are also unexplored. We now demonstrate that Arp3 and Arp3B isocomplexes promote actin assembly equally efficiently but generate branched actin networks with different disassembly rates. Arp3B dissociates significantly faster than Arp3 from the network, and its depletion increases actin stability. This difference is due to the oxidation of Arp3B, but not Arp3, by the methionine monooxygenase MICAL2, which is recruited to the actin network by coronin 1C. Substitution of Arp3B Met293 by threonine, the corresponding residue in Arp3, increases actin network stability. Conversely, replacing Arp3 Thr293 with glutamine to mimic Met oxidation promotes disassembly. The ability of MICAL2 to enhance network disassembly also depends on cortactin. Our observations demonstrate that coronin 1C, cortactin, and MICAL2 act together to promote disassembly of branched actin networks by oxidizing Arp3B-containing Arp2/3 complexes.
Published: 2021
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27. Local retinoic acid signaling directs emergence of the extraocular muscle functional unit

Author: Comai, G., Tesařová, Markéta, Dupé, Valerie, Rhinn, Muriel, Vallecillo-García, Pedro, Da Silva, Fabio, Feret, Betty, Exelby, Katherine, Dollé, Pascal, Carlsson, Leif, Pryce, Brian, Spitz, François, Stricker, Sigmar, Zikmund, Tomáš, Kaiser, Jozef, Briscoe, James, Schedl, Andreas, Ghyselinck, Norbert, Schweitzer, Ronen, Tajbakhsh, Shahragim, Cellules Souches et Développement / Stem Cells and Development, Institut Pasteur [Paris]-Centre National de la Recherche Scientifique (CNRS), Brno University of Technology [Brno] (BUT), Institut de Génétique et Développement de Rennes (IGDR), Université de Rennes 1 (UR1), Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES)-Centre National de la Recherche Scientifique (CNRS)-Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique ), Institut de Génétique et de Biologie Moléculaire et Cellulaire (IGBMC), Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université de Strasbourg (UNISTRA), Freie Universität Berlin, Institut de Biologie Valrose (IBV), Université Nice Sophia Antipolis (... - 2019) (UNS), COMUE Université Côte d'Azur (2015 - 2019) (COMUE UCA)-COMUE Université Côte d'Azur (2015 - 2019) (COMUE UCA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Côte d'Azur (UCA)-Centre National de la Recherche Scientifique (CNRS), The Francis Crick Institute, Umeå University, Shriners Hospital for Children [Portland], Génomique et Epigénomique du Développement des Animaux - Genomics and Epigenomics of Animal Development, Institut Pasteur [Paris] (IP)-Centre National de la Recherche Scientifique (CNRS), Université de Rennes (UR)-Centre National de la Recherche Scientifique (CNRS)-Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique ), Université de Strasbourg (UNISTRA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Université Nice Sophia Antipolis (1965 - 2019) (UNS), COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Côte d'Azur (UCA), The Francis Crick Institute [London], Génomique et Epigénomique du Développement des Vertébrés - Genomics and Epigenomics of Vertebrates Development, Institut Pasteur, French Muscular Dystrophy Association, ANR-10-LABX-73, Laboratoire d’Excellence Revive, Investissement d’Avenir, CNRS, ANR-10-LABX-0073,REVIVE,Stem Cells in Regenerative Biology and Medicine(2010), Comai, Glenda, Laboratoires d'excellence - Stem Cells in Regenerative Biology and Medicine - - REVIVE2010 - ANR-10-LABX-0073 - LABX - VALID, Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique )-Centre National de la Recherche Scientifique (CNRS)-Université de Rennes 1 (UR1), Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES), COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Côte d'Azur (UCA)-Centre National de la Recherche Scientifique (CNRS), and Génomique et Epigénomique du Développement des Vertébrés - Genomics and Epigenomics of Vertebrate Development
Subjects: Cell- och molekylärbiologi, [SDV]Life Sciences [q-bio], Retinoic Acid, Immunostaining, Eye, Biochemistry, Tendons, Mice, Cell Signaling, Retinoic Acid Signaling Cascade, Medicine and Health Sciences, Morphogenesis, Metabolites, Biology (General), [SDV.BDD]Life Sciences [q-bio]/Development Biology, Staining, [SDV.BDD.EO] Life Sciences [q-bio]/Development Biology/Embryology and Organogenesis, Eye Muscles, Muscle Differentiation, eye, Signaling Cascades, [SDV.BDD.MOR] Life Sciences [q-bio]/Development Biology/Morphogenesis, [SDV] Life Sciences [q-bio], Chemistry, Connective Tissue, Mice, Inbred DBA, extraocular muscles, Physical Sciences, embryogenesis, Anatomy, Research Article, Signal Transduction, QH301-705.5, Ocular Anatomy, Muscle Tissue, Embryonic Development, Tretinoin, Research and Analysis Methods, Imaging, Three-Dimensional, Ocular System, [SDV.BDD] Life Sciences [q-bio]/Development Biology, Animals, Retinoid Signaling, development, EOM, Chemical Compounds, Biology and Life Sciences, [SDV.BDD.MOR]Life Sciences [q-bio]/Development Biology/Morphogenesis, Cell Biology, eye diseases, Mice, Inbred C57BL, Biological Tissue, Metabolism, [SDV.BDD.EO]Life Sciences [q-bio]/Development Biology/Embryology and Organogenesis, Specimen Preparation and Treatment, Oculomotor Muscles, sense organs, Acids, Cell and Molecular Biology, Developmental Biology
Abstract: Coordinated development of muscles, tendons, and their attachment sites ensures emergence of functional musculoskeletal units that are adapted to diverse anatomical demands among different species. How these different tissues are patterned and functionally assembled during embryogenesis is poorly understood. Here, we investigated the morphogenesis of extraocular muscles (EOMs), an evolutionary conserved cranial muscle group that is crucial for the coordinated movement of the eyeballs and for visual acuity. By means of lineage analysis, we redefined the cellular origins of periocular connective tissues interacting with the EOMs, which do not arise exclusively from neural crest mesenchyme as previously thought. Using 3D imaging approaches, we established an integrative blueprint for the EOM functional unit. By doing so, we identified a developmental time window in which individual EOMs emerge from a unique muscle anlage and establish insertions in the sclera, which sets these muscles apart from classical muscle-to-bone type of insertions. Further, we demonstrate that the eyeballs are a source of diffusible all-trans retinoic acid (ATRA) that allow their targeting by the EOMs in a temporal and dose-dependent manner. Using genetically modified mice and inhibitor treatments, we find that endogenous local variations in the concentration of retinoids contribute to the establishment of tendon condensations and attachment sites that precede the initiation of muscle patterning. Collectively, our results highlight how global and site-specific programs are deployed for the assembly of muscle functional units with precise definition of muscle shapes and topographical wiring of their tendon attachments., The extraocular muscles (EOMs) are an evolutionarily conserved group of muscles that are precisely engineered for fine displacement of the eyeball, and thus crucial for visual acuity. This study presents the first integrative blueprint for morphogenesis of the EOM functional unit, providing genetic evidence for the existence of a retinoic acid signaling module that coordinates the emergence of individual EOMs, their tendons and insertion sites.
Published: 2020
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28. The antibiotic bedaquiline activates host macrophage innate immune resistance to bacterial infection

Author: Alexandre Giraud-Gatineau, Brigitte Gicquel, Juan Manuel Coya, Roland Brosch, Gerald Larrouy-Maumus, Elliott M. Bernard, Alexandra Maure, Anne Biton, Michael Thomson, Jade Marrec, Ludovic Tailleux, Maximiliano G. Gutierrez, Pathogénomique mycobactérienne intégrée - Integrated Mycobacterial Pathogenomics, Institut Pasteur [Paris] (IP)-Centre National de la Recherche Scientifique (CNRS), Cellule Pasteur UPMC, Institut Pasteur [Paris] (IP)-Sorbonne Université (SU), Génétique mycobactérienne - Mycobacterial genetics, Institut Pasteur [Paris] (IP), Hub Bioinformatique et Biostatistique - Bioinformatics and Biostatistics HUB, Medical Research Council Centre for Molecular Bacteriology and Infection [Londres, Royaume-Uni] (MRC CMBI), Imperial College London, Host-Pathogen Interactions in Tuberculosis Laboratory [London], The Francis Crick Institute [London], Shenzhen Nanshan Center for Chronic Disease Control [Shenzhen, China] (ShenZhenCDC), European Commission (604237) (Brigitte Gicquel), Institut Pasteur (Roland Brosch, Brigitte Gicquel, Ludovic Tailleux), Francis Crick Institute (Maximiliano G Gutierrez), Cancer Research UK (FC001092) (Maximiliano G Gutierrez), Medical Research Council (FC001092) (Maximiliano G Gutierrez), Wellcome (FC001092) (Maximiliano G Gutierrez), Engineering and Physical Sciences Research Council (EP/M027007/1) (Gérald Larrouy-Maumus), Fondation pour la Recherche Médicale (FDM201806006250) (Alexandra Maure), Agence Nationale de la Recherche (ANR-10-LABX-62-IBEID) (Roland Brosch), We thank Olivier Neyrolles and Howard E Takiff for reading the manuscript and helpful discussion. We gratefully acknowledge the UTechS Cytometry and Biomarkers and the UTechS Photonic BioImaging (Imagopole) Citech of Institut Pasteur (Paris, France) as well as the France–BioImaging infrastructure network supported by the French National Research Agency (ANR-10–INSB–04, Investments for the Future) for support in conducting this study, in particular PH. Commere for help with flow cytometry. We also thank Charles Privé (CHU Sainte-Justine Integrated Centre for Pediatric Clinical Genomics, Montreal, Canada) and Mickael Orgeur (Unit for Integrated Mycobacterial Pathogenomics, Institut Pasteur) for their technical support., ANR-10-LABX-0062,IBEID,Integrative Biology of Emerging Infectious Diseases(2010), European Project: 604237,EC:FP7:NMP,FP7-NMP-2013-LARGE-7,NAREB(2014), Institut Pasteur [Paris]-Centre National de la Recherche Scientifique (CNRS), Institut Pasteur [Paris]-Sorbonne Université (SU), and Institut Pasteur [Paris]
Subjects: [SDV]Life Sciences [q-bio], Antibiotics, host-pathogen interaction, 0601 Biochemistry and Cell Biology, [SDV.IMM.II]Life Sciences [q-bio]/Immunology/Innate immunity, antibiotics, immunology, chemistry.chemical_compound, 0302 clinical medicine, Immunology and Inflammation, [SDV.MHEP.MI]Life Sciences [q-bio]/Human health and pathology/Infectious diseases, Biology (General), Diarylquinolines, innate immunity, 0303 health sciences, Microbiology and Infectious Disease, Phagocytes, Basic Helix-Loop-Helix Leucine Zipper Transcription Factors, General Neuroscience, General Medicine, 3. Good health, Anti-Bacterial Agents, macrophages, [SDV.MP]Life Sciences [q-bio]/Microbiology and Parasitology, tuberculosis, Host-Pathogen Interactions, Medicine, [SDV.IMM]Life Sciences [q-bio]/Immunology, Research Article, Modern medicine, Tuberculosis, QH301-705.5, medicine.drug_class, Science, Host–pathogen interaction, infectious disease, Biology, General Biochemistry, Genetics and Molecular Biology, Microbiology, 03 medical and health sciences, Immune system, Immunity, medicine, Autophagy, Humans, Calcium Signaling, human, 030304 developmental biology, Innate immune system, General Immunology and Microbiology, microbiology, Mycobacterium tuberculosis, Macrophage Activation, medicine.disease, Immunity, Innate, HEK293 Cells, chemistry, inflammation, Other, Bedaquiline, Lysosomes, 030217 neurology & neurosurgery, [SDV.MHEP]Life Sciences [q-bio]/Human health and pathology
Abstract: Antibiotics are widely used in the treatment of bacterial infections. Although known for their microbicidal activity, antibiotics may also interfere with the host’s immune system. Here, we analyzed the effects of bedaquiline (BDQ), an inhibitor of the mycobacterial ATP synthase, on human macrophages. Genome-wide gene expression analysis revealed that BDQ reprogramed cells into potent bactericidal phagocytes. We found that 579 and 1,495 genes were respectively differentially expressed in naive- and M. tuberculosis-infected macrophages incubated with the drug, with an over-representation of lysosome-associated genes. BDQ treatment triggered a variety of antimicrobial defense mechanisms, including phagosome-lysosome fusion, and autophagy. These effects were associated with activation of transcription factor EB, involved in the transcription of lysosomal genes, resulting in enhanced intracellular killing of different bacterial species that were naturally insensitive to BDQ. Thus, BDQ could be used as a host-directed therapy against a wide range of bacterial infections., eLife digest The discovery of antibiotic drugs, which treat diseases caused by bacteria, has been a hugely valuable advance in modern medicine. They work by targeting specific cellular processes in bacteria, ultimately stopping them from multiplying or killing them outright. Antibiotics sometimes also affect their human hosts and can cause side-effects, such as gut problems or skin reactions. Recent evidence suggests that antibiotics also have an impact on the human immune system. This may happen either indirectly, by affecting ‘friendly’ bacteria normally present in the body, or through direct effects on immune cells. In turn, this could change the effectiveness of drug treatments. For example, if an antibiotic weakens immune cells, the body could have difficulty fighting off the existing infection – or become more vulnerable to new ones. However, even though new drugs are being introduced to combat the worldwide rise of antibiotic-resistant bacteria, their effects on immunity are still not well understood. For example, bedaquiline is an antibiotic recently developed to treat tuberculosis infections that are resistant to several drugs. Giraud-Gatineau et al. wanted to determine if bedaquiline altered the human immune response to bacterial infection independently from its direct anti-microbial effects. Macrophages engulf foreign particles like bacteria and break them down using enzymes stored within small internal compartments, or ‘lysosomes’. Initial experiments using human macrophages, grown both with and without bedaquiline, showed that the drug did not harm the cells and that they grew normally. A combination of microscope imaging and genetic analysis revealed that exposure to bedaquiline not only increased the number of lysosomes within macrophage cells, but also the activity of genes and proteins that increase lysosomes’ ability to break down foreign particles. These results suggested that bedaquiline treatment might make macrophages better at fighting infection, even if the drug itself had no direct effect on bacterial cells. Further studies, where macrophages were first treated with bedaquiline and then exposed to different types of bacteria known to be resistant to the drug, confirmed this hypothesis: in every case, the treated macrophages became efficient bacterial killers. In contrast, older anti-tuberculosis drugs did not have any such potentiating effect on the macrophages. This work sheds new light on our how antibiotic drugs can interact with the cells of the human immune system, and can sometimes even boost our innate defences. Such immune-boosting effects could one day be exploited to make more effective treatments against bacterial infections.
Published: 2020
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29. Mechanism and Regulation of DNA-Protein Crosslink Repair by the DNA-Dependent Metalloprotease SPRTN

Author: Boulton, Simon [The Francis Crick Institute, London (United Kingdom)]
Published: 2016
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30. Biology and therapeutic potential of interleukin-10

Author: Anne O'Garra, Paulo Vieira, Margarida Saraiva, Instituto de Investigação e Inovação em Saúde (I3S), Universidade do Porto = University of Porto, Lymphopoïèse (Lymphopoïèse (UMR_1223 / U1223 / U-Pasteur_4)), Institut Pasteur [Paris] (IP)-Université Paris Diderot - Paris 7 (UPD7)-Institut National de la Santé et de la Recherche Médicale (INSERM), Cellule Pasteur, Université Paris Diderot - Paris 7 (UPD7)-PRES Sorbonne Paris Cité, The Francis Crick Institute [London], Imperial College London, M. Saraiva is financed by Fundo Europeu de Desenvolvimento Regional funds through the COMPETE 2020 Operational Program for Competitiveness and Internationalisation, Portugal 2020, and by Portuguese funds through Fundação para a Ciência e Tecnologia in the framework of the project ‘‘Institute for Research and Innovation in Health Sciences’’ (POCI-01-0145-FEDER-007274), and by Fundação para a Ciência e Tecnologia through Estimulo Individual ao Emprego Científico. P. Vieira is funded by Agence National de la Recherche, through the project MYELOTEN (ANR-13-ISV1-0003-01), and by the Institut Pasteur, France. A. O’Garra is funded by the Francis Crick Institute, which receives its core funding from Cancer Research UK (FC001126), the UK Medical Research Council (FC001126), and the Wellcome Trust (FC001126), ANR-13-ISV1-0003,MYELOTEN,DEREGULATION DE L'HEMATOPOIESE PAR LA SUREXPRESSION DE L'INTERLEUKINE-10 : IMPLICATIONS DANS LE DEVELOPPEMENT DE PATHOLOGIES HEMATOLOGIQUES(2013), Universidade do Porto [Porto], Institut Pasteur [Paris]-Université Paris Diderot - Paris 7 (UPD7)-Institut National de la Santé et de la Recherche Médicale (INSERM), PRES Sorbonne Paris Cité-Université Paris Diderot - Paris 7 (UPD7), The Francis Crick Institute, and Universidade do Porto
Subjects: medicine.medical_treatment, Immunology, Reviews, Adipose tissue, Autoimmunity, Context (language use), Review, Biology, medicine.disease_cause, 03 medical and health sciences, 0302 clinical medicine, Mediator, Neoplasms, medicine, Animals, Humans, Immunology and Allergy, Cytotoxic T cell, 030304 developmental biology, Inflammation, 0303 health sciences, Interleukin-10, 3. Good health, Interleukin 10, Cytokine, Cytokines, [SDV.IMM]Life Sciences [q-bio]/Immunology, Wound healing, Neuroscience, 030215 immunology
Abstract: The authors review the molecular mechanisms regulating IL-10 production and response and describe classic and novel functions of IL-10 in immune and non-immune cells. They further discuss the therapeutic potential of IL-10 in different diseases and the outstanding questions underlying an effective application of IL-10 in clinical settings., The cytokine IL-10 is a key anti-inflammatory mediator ensuring protection of a host from over-exuberant responses to pathogens and microbiota, while playing important roles in other settings as sterile wound healing, autoimmunity, cancer, and homeostasis. Here we discuss our current understanding of the regulation of IL-10 production and of the molecular pathways associated with IL-10 responses. In addition to IL-10’s classic inhibitory effects on myeloid cells, we also describe the nonclassic roles attributed to this pleiotropic cytokine, including how IL-10 regulates basic processes of neural and adipose cells and how it promotes CD8 T cell activation, as well as epithelial repair. We further discuss its therapeutic potential in the context of different diseases and the outstanding questions that may help develop an effective application of IL-10 in diverse clinical settings.
Published: 2019
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31. Switching states: dynamic remodelling of polarity complexes as a toolkit for cell polarization

Author: Florent Peglion, Nathan W. Goehring, Polarité cellulaire, Migration et Cancer - Cell Polarity, Migration and Cancer, Centre National de la Recherche Scientifique (CNRS)-Institut Pasteur [Paris], The Francis Crick Institute [London], University College of London [London] (UCL), The authors acknowledge support from the Francis Crick Institute (NWG), which receives its core funding from Cancer Research UK (FC001086), the UK Medical Research Council (FC001086), and the Wellcome Trust (FC001086), and the Fondation ARC pour la recherche sur le cancer (FP)., Polarité cellulaire, Migration et cancer, Institut Pasteur [Paris]-Centre National de la Recherche Scientifique (CNRS), and Institut Pasteur [Paris] (IP)-Centre National de la Recherche Scientifique (CNRS)
Subjects: 0303 health sciences, Cell signaling, Time Factors, Effector, Polarity (physics), Organogenesis, Cell Cycle, Cell Polarity, Cell Biology, [SDV.BC.BC]Life Sciences [q-bio]/Cellular Biology/Subcellular Processes [q-bio.SC], Biology, Models, Biological, Article, 03 medical and health sciences, 0302 clinical medicine, Cell polarity, Biophysics, State switching, Animals, Signal transduction, ComputingMilieux_MISCELLANEOUS, 030217 neurology & neurosurgery, 030304 developmental biology, Signal Transduction
Abstract: International audience; Polarity is defined by the segregation of cellular components along a defined axis. To polarize robustly, cells must be able to break symmetry and subsequently amplify these nascent asymmetries. Finally, asymmetric localization of signaling molecules must be translated into functional regulation of downstream effector pathways. Central to these behaviors are a diverse set of cell polarity networks. Within these networks, molecules exhibit varied behaviors, dynamically switching among different complexes and states, active versus inactive, bound versus unbound, immobile versus diffusive. This ability to switch dynamically between states is intimately connected to the ability of molecules to generate asymmetric patterns within cells. Focusing primarily on polarity pathways governed by the conserved PAR proteins, we discuss strategies enabled by these dynamic behaviors that are used by cells to polarize. We highlight not only how switching between states is linked to the ability of polarity proteins to localize asymmetrically, but also how cells take advantage of ‘state switching’ to regulate polarity in time and space.
Published: 2019
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32. Role of a patatin-like phospholipase in Plasmodium falciparum gametogenesis and malaria transmission

Author: Aditi Alaganan, Chetan E. Chitnis, Lhousseine Touqui, Julien Guglielmini, Kunal R. More, Micheline Guillotte Blisnick, Sabine Thiberge, Shailja Singh, Audrey Lorthiois, Olivier Gorgette, Pallavi Singh, Shivani Shankar Aguilera, Biologie de Plasmodium et Vaccins - Malaria Parasite Biology and Vaccines, Institut Pasteur [Paris], ED 515 - Complexité du vivant, Sorbonne Université (SU), Centre de Production et Infection des Anophèles (plateforme) - Center for the Production and Infection of Anopheles (platform) (CEPIA), Plateforme BioImagerie Ultrastructurale – Ultrastructural BioImaging Platform (UTechS UBI), Hub Bioinformatique et Biostatistique - Bioinformatics and Biostatistics HUB, Institut Pasteur [Paris]-Centre National de la Recherche Scientifique (CNRS), Mucoviscidose et bronchopathies chroniques : biopathologie et phénotype cliniques - Cystic Fibrosis and Bronchial Diseases, CHU Saint-Antoine [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut Pasteur [Paris], Service de Pédiatrie et Réanimations néonatales [Béclère], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-AP-HP - Hôpital Antoine Béclère [Clamart], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Jawaharlal Nehru University (JNU), This work was supported by a grant from Agence Nationale de la Recherche (ANR-17-CE15-0010) (C.E.C.) and internal funds from Institut Pasteur (C.E.C.). P.S. was a student of the Pasteur Paris Universities International Doctoral Program and was supported by a fellowship from Chronopost. P.S. was also supported by an Institut Carnot postdoctoral fellowship. A.A. was supported by a European Molecular Biology Organization (EMBO) postdoctoral fellowship., We thank Catherine Lavazec, Institut Cochin, Paris, for providing us P. falciparum NF54 strain and helping us initiate work on gametocytes. We thank Ellen Knuepfer and Tony Holder, Francis Crick Institute, London, for providing the CRISPR-Cas9 plasmids and Marta Tiburcio and Moritz Treeck, Francis Crick Institute, London, for providing the P. falciparum NF54 DiCre line. We also thank Jacomine Krijnse-Locker, of the electron microscopy Ultrastructural Bioimaging (UBI) platform, Insitut Pasteur, Paris, for providing ready access to the electron microscopy facility and Pietro Alano, Istituto Superiore di Sanita, Rome, for rabbit antisera against Pfg377., ANR-17-CE15-0010,MolSigMal,Evènements moléculaires de la signalisation induite par l'invasion des globules rouges par les parasites paludéens(2017), Institut Pasteur [Paris] (IP), Institut Pasteur [Paris] (IP)-Centre National de la Recherche Scientifique (CNRS), Institut Pasteur [Paris] (IP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Saint-Antoine [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Lorthiois, Audrey, and Evènements moléculaires de la signalisation induite par l'invasion des globules rouges par les parasites paludéens - - MolSigMal2017 - ANR-17-CE15-0010 - AAPG2017 - VALID
Subjects: MESH: Plasmodium falciparum / physiology, MESH: Malaria, Falciparum / parasitology, [SDV]Life Sciences [q-bio], malaria, MESH: Protozoan Proteins / genetics, Phospholipase, MESH: Gametogenesis, MESH: Malaria, Falciparum / transmission, MESH: Phospholipases / genetics, 03 medical and health sciences, MESH: Protozoan Proteins / metabolism, parasitic diseases, medicine, Gametocyte, Secretion, malaria transmission, MESH: Life Cycle Stages, Gametogenesis, Plasmodium gametogenesis, 030304 developmental biology, 0303 health sciences, Multidisciplinary, MESH: Humans, biology, MESH: Computational Biology / methods, 030302 biochemistry & molecular biology, Anopheles, Plasmodium falciparum, MESH: Sequence Deletion, biology.organism_classification, 3. Good health, Cell biology, [SDV] Life Sciences [q-bio], patatin-like phospholipases, medicine.anatomical_structure, MESH: Plasmodium falciparum / ultrastructure, Patatin-like phospholipase, Gamete, MESH: Phospholipases / metabolism
Abstract: International audience; Transmission of Plasmodium falciparum involves a complex process that starts with the ingestion of gametocytes by female Anopheles mosquitoes during a blood meal. Activation of gametocytes in the mosquito midgut triggers "rounding up" followed by egress of both male and female gametes. Egress requires secretion of a perforin-like protein, PfPLP2, from intracellular vesicles to the periphery, which leads to destabilization of peripheral membranes. Male gametes also develop flagella, which assist in binding female gametes for fertilization. This process of gametogenesis, which is key to malaria transmission, involves extensive membrane remodeling as well as vesicular discharge. Phospholipase A2 enzymes (PLA2) are known to mediate membrane remodeling and vesicle secretion in diverse organisms. Here, we show that a P. falciparum patatin-like phospholipase (PfPATPL1) with PLA2 activity plays a key role in gametogenesis. Conditional deletion of the gene encoding PfPATPL1 does not affect P. falciparum blood stage growth or gametocyte development but reduces efficiency of rounding up, egress, and exflagellation of gametocytes following activation. Interestingly, deletion of the PfPATPL1 gene inhibits secretion of PfPLP2, reducing the efficiency of gamete egress. Deletion of PfPATPL1 also reduces the efficiency of oocyst formation in mosquitoes. These studies demonstrate that PfPATPL1 plays a role in gametogenesis, thereby identifying PLA2 phospholipases such as PfPATPL1 as potential targets for the development of drugs to block malaria transmission.
Published: 2019
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33. A Nuclear Role for miR-9 and Argonaute Proteins in Balancing Quiescent and Activated Neural Stem Cell States

Author: Laure Bally-Cuif, François Guillemot, Marion Coolen, Delphine Cussigh, Noelia Urbán, Isabelle Maria Blomfield, Shauna Katz, Institut des Neurosciences Paris-Saclay (NeuroPSI), Université Paris-Sud - Paris 11 (UP11)-Centre National de la Recherche Scientifique (CNRS), Biologie du Développement et Cellules souches (CNRS UMR3738), Institut Pasteur [Paris] (IP)-Centre National de la Recherche Scientifique (CNRS)-Université Paris Cité (UPCité), The Francis Crick Institute [London], Work in the L.B.-C. lab was funded by the EU project ZF-Health (FP7/2010-2015 grant agreement 242048), the ANR (grant ANR-2012-BSV4-0004-01), the Ecole des Neurosciences de Paris (ENP), the FRM (FRP 'Equipe' DEQ20120323692), and the European Research Council (AdG 322936). M.C. is supported by INSERM. S.K. was recipient of fellowships from the ENP, the DIM Cerveau et Pensée of Région Ile de France, and The Company of Biologists Limited (Travelling Fellowship DEVTF-140404). N.U. was supported by the BBSRC (BB/K005316/1). Work in F.G.’s lab was supported by The Francis Crick Institute that receives its core funding from Cancer Research UK (FC001089), the UK Medical Research Council (FC001089), and the Wellcome Trust (FC001089)., We thank members of the ZEN lab and Eric Miska for their critical input. We are grateful to J. Ninkovic for the 4C4 antibody., ANR-12-BSV4-0004,HOMEOSTEM,Contrôle moléculaire et cellulaire de l'homéostasie des zones germinatives dans le télencéphale adulte chez le poisson zébré(2012), European Project: 242048,EC:FP7:HEALTH,FP7-HEALTH-2009-two-stage,ZF-HEALTH(2010), European Project: 322936,EC:FP7:ERC,ERC-2012-ADG_20120314,SYSTEMATICS(2013), Département de Biologie du Développement et Cellules souches - Department of Developmental and Stem Cell Biology, and Institut Pasteur [Paris]
Subjects: MESH: Neural Stem Cells, MESH: Signal Transduction, 0301 basic medicine, Telencephalon, Aging, [SDV]Life Sciences [q-bio], radial glia, MESH: Cell Cycle, neural stem cell, Mice, MESH: Argonaute Proteins, Neural Stem Cells, MESH: Aging, MESH: Animals, lcsh:QH301-705.5, Zebrafish, reproductive and urinary physiology, Receptors, Notch, Neurogenesis, Cell Cycle, Argonaute, Cell cycle, MESH: Gene Expression Regulation, Neural stem cell, Cell biology, adult neurogenesis, medicine.anatomical_structure, Argonaute Proteins, MESH: Neuroglia, Neuroglia, Signal Transduction, MESH: Cell Nucleus, Notch, Notch signaling pathway, Biology, Models, Biological, General Biochemistry, Genetics and Molecular Biology, Article, 03 medical and health sciences, medicine, Animals, quiescence, MESH: Zebrafish, MESH: Mice, Cell Nucleus, miR-9, MESH: Models, Biological, biology.organism_classification, zebrafish, Cell nucleus, MicroRNAs, 030104 developmental biology, lcsh:Biology (General), nervous system, Gene Expression Regulation, MESH: Telencephalon, MESH: Receptors, Notch, MESH: MicroRNAs, Nuclear localization sequence
Abstract: Summary Throughout life, adult neural stem cells (NSCs) produce new neurons and glia that contribute to crucial brain functions. Quiescence is an essential protective feature of adult NSCs; however, the establishment and maintenance of this state remain poorly understood. We demonstrate that in the adult zebrafish pallium, the brain-enriched miR-9 is expressed exclusively in a subset of quiescent NSCs, highlighting a heterogeneity within these cells, and is necessary to maintain NSC quiescence. Strikingly, miR-9, along with Argonaute proteins (Agos), is localized to the nucleus of quiescent NSCs, and manipulating their nuclear/cytoplasmic ratio impacts quiescence. Mechanistically, miR-9 permits efficient Notch signaling to promote quiescence, and we identify the RISC protein TNRC6 as a mediator of miR-9/Agos nuclear localization in vivo. We propose a conserved non-canonical role for nuclear miR-9/Agos in controlling the balance between NSC quiescence and activation, a key step in maintaining adult germinal pools., Graphical Abstract, Highlights • miR-9 highlights a state heterogeneity among adult quiescent neural stem cells (NSC) • miR-9 maintains NSC quiescence notably through permitting efficient Notch signaling • miR-9, along with Argonaute proteins, is present in the nucleus of adult quiescent NSCs • Active nucleo-cytoplasmic shuttling of miR-9/Ago impacts NSCs quiescence status, An essential protective feature of adult neural stem cells is their relative quiescence. Katz et al. identify microRNA-9 as crucial factor that maintains adult NSCs quiescence and sets a heterogeneity within these cells, through a non-canonical nuclear mode of action.
Published: 2016
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34. Analysis of the genetically tractable crustacean Parhyale hawaiensis reveals the organisation of a sensory system for low-resolution vision Analysis of the genetically tractable crustacean Parhyale hawaiensis reveals the organisation of a sensory system for low-resolution vision

Author: Ramos, Ana Patricia, Gustafsson, Ola, Labert, Nicolas, Salecker, Iris, Nilsson, Dan-Eric, Averof, Michalis, Institut de Génomique Fonctionnelle de Lyon (IGFL), École normale supérieure de Lyon (ENS de Lyon)-Institut National de la Recherche Agronomique (INRA)-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Centre National de la Recherche Scientifique (CNRS), Lund University [Lund], The Francis Crick Institute [London], École normale supérieure - Lyon (ENS Lyon)-Institut National de la Recherche Agronomique (INRA)-Université Claude Bernard Lyon 1 (UCBL), and The Francis Crick Institute
Subjects: genetic structures, [SDV]Life Sciences [q-bio], [SDV.BA]Life Sciences [q-bio]/Animal biology, sense organs, eye diseases
Abstract: International audience; Background: Arthropod eyes have diversified during evolution to serve multiple needs, such as finding mates,hunting prey and navigating in complex surroundings under varying light conditions. This diversity is reflected in theoptical apparatus, photoreceptors and neural circuits that underpin vision. Yet our ability to genetically manipulate thevisual system to investigate its function is largely limited to a single species, the fruit fly Drosophila melanogaster. Here,we describe the visual system of Parhyale hawaiensis, an amphipod crustacean for which we have established tailoredgenetic tools.Results: Adult Parhyale have apposition-type compound eyes made up of ~50 ommatidia. Each ommatidium containsfour photoreceptor cells with large rhabdomeres (R1–4), expected to be sensitive to the polarisation of light, and onephotoreceptor cell with a smaller rhabdomere (R5). The two types of photoreceptors express different opsins, belongingto families with distinct wavelength sensitivities. Using the cis-regulatory regions of opsin genes, we establishedtransgenic reporters expressed in each photoreceptor cell type. Based on these reporters, we show that R1–4 andR5 photoreceptors extend axons to the first optic lobe neuropil, revealing striking differences compared with thephotoreceptor projections found in related crustaceans and insects. Investigating visual function, we show thatParhyale have a positive phototactic response and are capable of adapting their eyes to different levels of lightintensity.Conclusions: We propose that the visual system of Parhyale serves low-resolution visual tasks, such as orientation andnavigation, based on broad gradients of light intensity and polarisation. Optic lobe structure and photoreceptorprojections point to significant divergence from the typical organisation found in other malacostracan crustaceans andinsects, which could be associated with a shift to low-resolution vision. Our study provides the foundation for researchin the visual system of this genetically tractable species.
Published: 2019
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35. Reading and editing the Pleurodeles waltl genome reveals novel features of tetrapod regeneration

Author: Rickard Sandberg, Ahmed Elewa, L. Shahul Hameed, Carlos Talavera-López, Heng Wang, Manfred Grabherr, Goncalo Brito, May Penrad-Mobayed, Zeyu Yao, Anoop Kumar, Yamen Abbas, András Simon, Ilgar Abdullayev, Neda Zamani, Alberto Joven, Björn Andersson, Karolinska Institutet [Stockholm], The Francis Crick Institute [London], Institut Jacques Monod (IJM (UMR_7592)), Université Paris Diderot - Paris 7 (UPD7)-Centre National de la Recherche Scientifique (CNRS), Uppsala University, Harvard Stem Cell Institute, Harvard University [Cambridge], and The Francis Crick Institute
Subjects: 0301 basic medicine, Pleurodeles, Science, Medical Biotechnology (with a focus on Cell Biology (including Stem Cell Biology), Molecular Biology, Microbiology, Biochemistry or Biopharmacy), General Physics and Astronomy, Genomics, Genome, General Biochemistry, Genetics and Molecular Biology, Tetrapod, Article, 03 medical and health sciences, 0302 clinical medicine, Genome editing, [SDV.BBM.GTP]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Genomics [q-bio.GN], biology.animal, Proto-Oncogenes, Animals, Regeneration, lcsh:Science, Regeneration (ecology), Ambystoma mexicanum, Muscle, Skeletal, Medicinsk bioteknologi (med inriktning mot cellbiologi (inklusive stamcellsbiologi), molekylärbiologi, mikrobiologi, biokemi eller biofarmaci), PAX3 Transcription Factor, Embryonic Stem Cells, Gene Editing, Multidisciplinary, biology, Gene Expression Profiling, PAX7 Transcription Factor, Extremities, General Chemistry, biology.organism_classification, humanities, [SDV.GEN.GA]Life Sciences [q-bio]/Genetics/Animal genetics, MicroRNAs, 030104 developmental biology, Evolutionary biology, DNA Transposable Elements, Salamander, lcsh:Q, CRISPR-Cas Systems, 030217 neurology & neurosurgery
Abstract: Salamanders exhibit an extraordinary ability among vertebrates to regenerate complex body parts. However, scarce genomic resources have limited our understanding of regeneration in adult salamanders. Here, we present the ~20 Gb genome and transcriptome of the Iberian ribbed newt Pleurodeles waltl, a tractable species suitable for laboratory research. We find that embryonic stem cell-specific miRNAs mir-93b and mir-427/430/302, as well as Harbinger DNA transposons carrying the Myb-like proto-oncogene have expanded dramatically in the Pleurodeles waltl genome and are co-expressed during limb regeneration. Moreover, we find that a family of salamander methyltransferases is expressed specifically in adult appendages. Using CRISPR/Cas9 technology to perturb transcription factors, we demonstrate that, unlike the axolotl, Pax3 is present and necessary for development and that contrary to mammals, muscle regeneration is normal without functional Pax7 gene. Our data provide a foundation for comparative genomic studies that generate models for the uneven distribution of regenerative capacities among vertebrates., The Iberian ribbed newt Pleurodeles waltl has a wide spectrum of regeneration abilities. Here, Elewa et al. sequence its ~20 Gb genome and transcriptome to investigate the molecular features underlying its regenerative capacities.
Published: 2017
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36. Update on hypoxia-inducible factors and hydroxylases in oxygen regulatory pathways: from physiology to therapeutics

Author: Lisa Oliver, Peter J. Ratcliffe, Betty Gardie, Jiannis Ragoussis, Peppi Koivunen, Valérie Trichet, Claire Vinatier, Ines Batinic-Haberle, Judith V.M.G. Bovée, Johanna Myllyharju, Florence Robriquet, The Francis Crick Institute, Target Discovery Institute [Oxford, UK], University of Oxford [U.K.], Oulu Center for Cell-Matrix Research [Oulu, Finland], Biocenter Oulu and Faculty of Biochemistry & Molecular Medicine [Oulu, Finland]-University of Oulu [Finland], McGill University, Montréal (McGill University) ( McGill ), Department of Pathology [Leiden, The Netherlands], Leiden University Medical Center (LUMC), Duke university [Durham], Regenerative Medicine and Skeleton research lab ( RMeS ), Université de Nantes ( UN ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Centre hospitalier universitaire de Nantes ( CHU Nantes ), Sarcomes osseux et remodelage des tissus calcifiés - Phy-Os, Université de Nantes ( UN ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ), Centre de recherche de Cancérologie et d'Immunologie / Nantes - Angers ( CRCINA ), Université d'Angers ( UA ) -Université de Nantes ( UN ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Centre National de la Recherche Scientifique ( CNRS ) -Institut de Recherche en Santé de l'Université de Nantes ( IRS-UN ) -Centre hospitalier universitaire de Nantes ( CHU Nantes ), École pratique des hautes études ( EPHE ), The meeting 'Hypoxia Nantes 2106' (https://hypoxia.univ-nantes.fr) was financially supported by Alliance Bio Expertise, Baker Ruskinn, the Région Pays de la Loire, project 'ERRATA' and 'EryCan', Laboratory of Excellence GR-Ex, reference ANR-11-LABX-0051, Nantes University, and Dove Press., ANR-11-IDEX-0005-02/11-LABX-0051,GR-Ex,Biogenèse et pathologies du globule rouge ( 2011 ), Target Discovery Institute [Oxford, UK] (TDI), University of Oxford [Oxford], The Francis Crick Institute [London], Genome Quebec Innovation Centre [Montréal, Canada], McGill University = Université McGill [Montréal, Canada], Department of Radiation Oncology [Durham, NC, USA], Duke University Medical Center, Université de Nantes - UFR Odontologie, Université de Nantes (UN), Team STEP 'Skeletal physiopathology and joint regenerative medicine' (Inserm U1229 - RMeS), Regenerative Medicine and Skeleton research lab (RMeS), Ecole Nationale Vétérinaire, Agroalimentaire et de l'alimentation Nantes-Atlantique (ONIRIS)-Centre hospitalier universitaire de Nantes (CHU Nantes)-Université de Nantes - UFR de Médecine et des Techniques Médicales (UFR MEDECINE), Université de Nantes (UN)-Université de Nantes (UN)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Ecole Nationale Vétérinaire, Agroalimentaire et de l'alimentation Nantes-Atlantique (ONIRIS)-Centre hospitalier universitaire de Nantes (CHU Nantes)-Université de Nantes - UFR de Médecine et des Techniques Médicales (UFR MEDECINE), Université de Nantes (UN)-Université de Nantes (UN)-Institut National de la Santé et de la Recherche Médicale (INSERM), Sarcomes osseux et remodelage des tissus calcifiés - Phy-Os [Nantes - INSERM U1238] (Phy-Os), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Bretagne Loire (UBL)-Centre hospitalier universitaire de Nantes (CHU Nantes)-Université de Nantes - UFR de Médecine et des Techniques Médicales (UFR MEDECINE), Université de Nantes (UN)-Université de Nantes (UN), Centre de Recherche en Cancérologie et Immunologie Nantes-Angers (CRCINA), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Nantes - UFR de Médecine et des Techniques Médicales (UFR MEDECINE), Université de Nantes (UN)-Université de Nantes (UN)-Centre hospitalier universitaire de Nantes (CHU Nantes)-Centre National de la Recherche Scientifique (CNRS)-Université d'Angers (UA), École pratique des hautes études (EPHE), Université Paris sciences et lettres (PSL), ANR-11-IDEX-0005,USPC,Université Sorbonne Paris Cité(2011), University of Oxford, RMeS - Skeletal Physiopathology and Joint Regenerative Medicine (RMeS-REJOINT), Regenerative Medicine and Skeleton (RMeS), École nationale vétérinaire, agroalimentaire et de l'alimentation Nantes-Atlantique (ONIRIS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre hospitalier universitaire de Nantes (CHU Nantes)-Université de Nantes - UFR de Médecine et des Techniques Médicales (UFR MEDECINE), Université de Nantes (UN)-Université de Nantes (UN)-École nationale vétérinaire, agroalimentaire et de l'alimentation Nantes-Atlantique (ONIRIS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre hospitalier universitaire de Nantes (CHU Nantes)-Université de Nantes - UFR de Médecine et des Techniques Médicales (UFR MEDECINE), Université d'Angers (UA)-Université de Nantes (UN)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Centre hospitalier universitaire de Nantes (CHU Nantes), Jehan, Frederic, and Université Sorbonne Paris Cité - - USPC2011 - ANR-11-IDEX-0005 - IDEX - VALID
Subjects: 0301 basic medicine, Physiology, Review, Biology, [ SDV.CAN ] Life Sciences [q-bio]/Cancer, 03 medical and health sciences, lipid metabolism, medicine, genomics, cancer, oxidative stress, lcsh:R5-920, [SDV.MHEP.RSOA] Life Sciences [q-bio]/Human health and pathology/Rhumatology and musculoskeletal system, musculoskeletal, [SDV.MHEP.GEG] Life Sciences [q-bio]/Human health and pathology/Geriatry and gerontology, hypoxia, [SDV.MHEP.GEG]Life Sciences [q-bio]/Human health and pathology/Geriatry and gerontology, Hypoxia (medical), 3. Good health, Oxidative stress, 030104 developmental biology, Hypoxia-inducible factors, [SDV.MHEP.RSOA]Life Sciences [q-bio]/Human health and pathology/Rhumatology and musculoskeletal system, medicine.symptom, Large group, lcsh:Medicine (General)
Abstract: Peter Ratcliffe,1,2 Peppi Koivunen,3 Johanna Myllyharju,3 Jiannis Ragoussis,4 Judith VMG Bovée,5 Ines Batinic-Haberle,6 Claire Vinatier,7 Valérie Trichet,8 Florence Robriquet,9 Lisa Oliver,9 Betty Gardie9,10 1Target Discovery Institute, University of Oxford, 2The Francis Crick Institute, London, UK; 3Oulu Center for Cell-Matrix Research, Biocenter Oulu and Faculty of Biochemistry and Molecular Medicine, University of Oulu, Oulu, Finland; 4McGill University and Genome Quebec Innovation Centre, McGill University, Montreal, Canada; 5Department of Pathology, Leiden University Medical Center, Leiden, the Netherlands; 6Department of Radiation Oncology, Duke University School of Medicine, Durham, NC, USA; 7INSERM UMR 1229, Regenerative Medicine and Skeleton-RMeS, Team STEP, University of Nantes, UFR Odontology, 8UMR 1238 INSERM, Université de Nantes, Faculté de Médecine, 9CRCINA, INSERM, Université de Nantes, Nantes, 10Ecole Pratique des Hautes Etudes, PSL Research University, Paris, France Abstract: The “Hypoxia Nantes 2016” organized its second conference dedicated to the field of hypoxia research. This conference focused on “the role of hypoxia under physiological conditions as well as in cancer” and took place in Nantes, France, in October 6–7, 2016. The main objective of this conference was to bring together a large group of scientists from different spheres of hypoxia. Recent advances were presented and discussed around different topics: genomics, physiology, musculoskeletal, stem cells, microenvironment and cancer, and oxidative stress. This review summarizes the major highlights of the meeting. Keywords: hypoxia, genomics, lipid metabolism, musculoskeletal, cancer, oxidative stress&nbsp
Published: 2017
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37. Triangles bridge the scales: Quantifying cellular contributions to tissue deformation

Author: Marko Popovic, Raphaël Etournay, Matthias Merkel, Suzanne Eaton, Frank Jülicher, Guillaume Salbreux, Max Planck Institute for the Physics of Complex Systems (MPI-PKS), Max-Planck-Gesellschaft, Syracuse University, Génétique et Physiologie de l'Audition, Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut Pasteur [Paris]-Institut National de la Santé et de la Recherche Médicale (INSERM), Max Planck Institute of Molecular Cell Biology and Genetics (MPI-CBG), The Francis Crick Institute [London], This work was supported by the Max Planck Gesellschaft and by the BMBF. M.M. also acknowledges funding from the Alfred P. Sloan Foundation, the Gordon and Betty Moore Foundation, and Grant No. NSF-DMR-1352184. R.E. acknowledges a Marie Curie fellowship from the 774 EU 7th Framework Programme (FP7). S.E. acknowledges funding from the ERC. G.S. was supported by the Francis Crick Institute, which receives its core funding from Cancer Research UK (FC001317), the UK Medical Research Council (FC001317), and the Wellcome Trust (FC001317)., Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut Pasteur [Paris] (IP)-Institut National de la Santé et de la Recherche Médicale (INSERM), and Etournay, Raphael
Subjects: 0301 basic medicine, Plasticity, Morphogenesis, FOS: Physical sciences, Geometry, [SDV.BC]Life Sciences [q-bio]/Cellular Biology, Condensed Matter - Soft Condensed Matter, Deformation (meteorology), 01 natural sciences, Models, Biological, Cell Physiological Phenomena, Strain, 03 medical and health sciences, 0103 physical sciences, Animals, Wings, Animal, [PHYS.MECA.MEFL] Physics [physics]/Mechanics [physics]/Fluid mechanics [physics.class-ph], Biomechanics, [PHYS.MECA.MEFL]Physics [physics]/Mechanics [physics]/Fluid mechanics [physics.class-ph], 010306 general physics, Tissues and Organs (q-bio.TO), Plastic deformation, [SDV.BC] Life Sciences [q-bio]/Cellular Biology, Topology (chemistry), Physics, Structure formation and active systems, Wing, biology, Cell growth, Quantitative Biology - Tissues and Organs, Viscoelasticity, biology.organism_classification, Viscoplasticity, Biomechanical Phenomena, [PHYS.COND.CM-SCM] Physics [physics]/Condensed Matter [cond-mat]/Soft Condensed Matter [cond-mat.soft], Multicellular organism, 030104 developmental biology, Drosophila melanogaster, FOS: Biological sciences, Elastic deformation, Soft Condensed Matter (cond-mat.soft), Elongation, Biological system, [PHYS.COND.CM-SCM]Physics [physics]/Condensed Matter [cond-mat]/Soft Condensed Matter [cond-mat.soft], Shear deformation
Abstract: In this article, we propose a general framework to study the dynamics and topology of cellular networks that capture the geometry of cell packings in two-dimensional tissues. Such epithelia undergo large-scale deformation during morphogenesis of a multicellular organism. Large-scale deformations emerge from many individual cellular events such as cell shape changes, cell rearrangements, cell divisions, and cell extrusions. Using a triangle-based representation of cellular network geometry, we obtain an exact decomposition of large-scale material deformation. Interestingly, our approach reveals contributions of correlations between cellular rotations and elongation as well as cellular growth and elongation to tissue deformation. Using this Triangle Method, we discuss tissue remodeling in the developing pupal wing of the fly Drosophila melanogaster., Comment: 26 pages, 18 figures
Published: 2017
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38. Blind prediction of homo- and hetero- protein complexes: The CASP13-CAPRI experiment

Author: Lensink, Marc F., Brysbaert, Guillaume, Nadzirin, Nurul, Velankar, Sameer, Chaleil, Raphaël A. G., Gerguri, Tereza, Bates, Paul A., Laine, Elodie, Carbone, Alessandra, Grudinin, Sergei, Kong, Ren, Liu, Ran-Ran, Xu, Xi-Ming, Shi, Hang, Chang, Shan, Eisenstein, Miriam, Karczynska, Agnieszka, Czaplewski, Cezary, Lubecka, Emilia, Lipska, Agnieszka, Krupa, Paweł, Mozolewska, Magdalena, Golon, Łukasz, Samsonov, Sergey, Liwo, Adam, Crivelli, Silvia, Pagès, Guillaume, Karasikov, Mikhail, Kadukova, Maria, Yan, Yumeng, Huang, Sheng-You, Rosell, Mireia, Rodríguez-Lumbreras, Luis A., Romero-Durana, Miguel, Díaz-Bueno, Lucía, Fernandez-Recio, Juan, Christoffer, Charles, Terashi, Genki, Shin, Woong-Hee, Aderinwale, Tunde, Maddhuri Venkata Subraman, Sai Raghavendra, Kihara, Daisuke, Kozakov, Dima, Vajda, Sandor, Porter, Kathryn, Padhorny, Dzmitry, Desta, Israel, Beglov, Dmitri, Ignatov, Mikhail, Kotelnikov, Sergey, Moal, Iain H., Ritchie, David W., Chauvot de Beauchêne, Isaure, Maigret, Bernard, Devignes, Marie-Dominique, Ruiz Echartea, Maria E., Barradas-Bautista, Didier, Cao, Zhen, Cavallo, Luigi, Oliva, Romina, Cao, Yue, Shen, Yang, Baek, Minkyung, Park, Taeyong, Woo, Hyeonuk, Seok, Chaok, Braitbard, Merav, Bitton, Lirane, Scheidman-Duhovny, Dina, Dapkūnas, Justas, Olechnovič, Kliment, Venclovas, Česlovas, Kundrotas, Petras J., Belkin, Saveliy, Chakravarty, Devlina, Badal, Varsha D., Vakser, Ilya A., Vreven, Thom, Vangaveti, Sweta, Borrman, Tyler, Weng, Zhiping, Guest, Johnathan D., Gowthaman, Ragul, Pierce, Brian G., Xu, Xianjin, Duan, Rui, Qiu, Liming, Hou, Jie, Ryan Merideth, Benjamin, Ma, Zhiwei, Cheng, Jianlin, Zou, Xiaoqin, Koukos, Panagiotis I., Roel-Touris, Jorge, Ambrosetti, Francesco, Geng, Cunliang, Schaarschmidt, Jörg, Trellet, Mikael E., Melquiond, Adrien S. J., Xue, Li, Jiménez-García, Brian, van Noort, Charlotte W., Honorato, Rodrigo V., Bonvin, Alexandre M. J. J., Wodak, Shoshana J., 0000-0003-3957-9470, 0000-0003-2759-2088, 0000-0003-0621-0925, 0000-0003-2098-5743, 0000-0001-7169-9398, 0000-0002-0294-3403, 0000-0002-4209-4565, 0000-0002-7787-8896, 0000-0002-3986-7686, 0000-0002-6163-6323, 0000-0003-4091-6614, 0000-0003-0464-4500, 0000-0002-4960-5487, 0000-0002-7035-3042, 0000-0002-1703-7796, 0000-0002-1419-9888, 0000-0002-0496-6107, 0000-0002-4215-0213, 0000-0002-5743-2934, 0000-0003-3413-806X, 0000-0002-3032-7966, 0000-0002-1409-8358, 0000-0001-7369-1322, 0000-0002-0701-6545, Unité de Glycobiologie Structurale et Fonctionnelle UMR 8576 (UGSF), Institut National de la Recherche Agronomique (INRA)-Université de Lille-Centre National de la Recherche Scientifique (CNRS), European Bioinformatics Institute [Hinxton] (EMBL-EBI), EMBL Heidelberg, The Francis Crick Institute [London], School of Geographical Sciences [Bristol], University of Bristol [Bristol], Biologie Computationnelle et Quantitative = Laboratory of Computational and Quantitative Biology (LCQB), Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS)-Institut de Biologie Paris Seine (IBPS), Sorbonne Université (SU)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Institut Universitaire de France (IUF), Ministère de l'Education nationale, de l’Enseignement supérieur et de la Recherche (M.E.N.E.S.R.), Algorithms for Modeling and Simulation of Nanosystems (NANO-D), Inria Grenoble - Rhône-Alpes, Institut National de Recherche en Informatique et en Automatique (Inria)-Institut National de Recherche en Informatique et en Automatique (Inria)-Institut polytechnique de Grenoble - Grenoble Institute of Technology (Grenoble INP )-Laboratoire Jean Kuntzmann (LJK ), Institut polytechnique de Grenoble - Grenoble Institute of Technology (Grenoble INP )-Institut National de Recherche en Informatique et en Automatique (Inria)-Centre National de la Recherche Scientifique (CNRS)-Université Grenoble Alpes [2016-2019] (UGA [2016-2019])-Centre National de la Recherche Scientifique (CNRS)-Université Grenoble Alpes [2016-2019] (UGA [2016-2019]), JiangSu University, Chemical Research Support [Rehovot], Weizmann Institute of Science [Rehovot, Israël], University of Gdańsk (UG), Department of Environmental Analytics [Univ Gdańsk], Faculty of Chemistry [Univ Gdańsk], University of Gdańsk (UG)-University of Gdańsk (UG), Institute of Physics [Warsaw] (IFPAN), Polish Academy of Sciences (PAN), Department of Computer Science [Davis] (UC Davis), University of California [Davis] (UC Davis), University of California-University of California, Moscow Institute of Physics and Technology [Moscow] (MIPT), Huazhong University of Science and Technology [Wuhan] (HUST), Barcelona Supercomputing Center - Centro Nacional de Supercomputacion (BSC - CNS), Purdue University [West Lafayette], Kitasato University, Stony Brook University [SUNY] (SBU), State University of New York (SUNY), Department of Biomedical Engineering [Boston], Boston University [Boston] (BU), Computational Algorithms for Protein Structures and Interactions (CAPSID), Inria Nancy - Grand Est, Institut National de Recherche en Informatique et en Automatique (Inria)-Institut National de Recherche en Informatique et en Automatique (Inria)-Department of Complex Systems, Artificial Intelligence & Robotics (LORIA - AIS), Laboratoire Lorrain de Recherche en Informatique et ses Applications (LORIA), Centre National de la Recherche Scientifique (CNRS)-Université de Lorraine (UL)-Institut National de Recherche en Informatique et en Automatique (Inria)-Centre National de la Recherche Scientifique (CNRS)-Université de Lorraine (UL)-Institut National de Recherche en Informatique et en Automatique (Inria)-Laboratoire Lorrain de Recherche en Informatique et ses Applications (LORIA), Centre National de la Recherche Scientifique (CNRS)-Université de Lorraine (UL)-Institut National de Recherche en Informatique et en Automatique (Inria)-Centre National de la Recherche Scientifique (CNRS)-Université de Lorraine (UL), Technische Universität Munchen - Université Technique de Munich [Munich, Allemagne] (TUM), King Abdullah University of Science and Technology (KAUST), University of Naples Federico II, Service des Recherches Métallurgiques Appliquées (SRMA), Département des Matériaux pour le Nucléaire (DMN), CEA-Direction des Energies (ex-Direction de l'Energie Nucléaire) (CEA-DES (ex-DEN)), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université Paris-Saclay-CEA-Direction des Energies (ex-Direction de l'Energie Nucléaire) (CEA-DES (ex-DEN)), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université Paris-Saclay, Department of Chemistry, Seoul National University [Seoul] (SNU), The Hebrew University of Jerusalem (HUJ), Vilnius University [Vilnius], Department of Molecular Biosciences [Lawrence], University of Kansas [Lawrence] (KU), University of Kansas [Kansas City], University of Massachusetts Medical School [Worcester] (UMASS), University of Massachusetts System (UMASS), Program in Bioinformatics and Integrative Biology [Worcester], University of Massachusetts System (UMASS)-University of Massachusetts System (UMASS), University of Maryland [Baltimore], Beijing University of Technology, University of Missouri [Columbia] (Mizzou), University of Missouri System, Bijvoet Center for Biomolecular Research [Utrecht], Utrecht University [Utrecht], Dalton Cardiovascular Research Center [Columbia], University of Missouri System-University of Missouri System, Shandong University, Laboratoire d'Informatique pour la Mécanique et les Sciences de l'Ingénieur (LIMSI), Université Paris-Sud - Paris 11 (UP11)-Sorbonne Université - UFR d'Ingénierie (UFR 919), Sorbonne Université (SU)-Sorbonne Université (SU)-Université Paris-Saclay-Centre National de la Recherche Scientifique (CNRS)-Université Paris Saclay (COmUE), University of California [Santa Cruz] (UCSC), University of California, The Hospital for sick children [Toronto] (SickKids), Unité de Glycobiologie Structurale et Fonctionnelle - UMR 8576 (UGSF), Université de Lille-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Recherche Agronomique (INRA), Institut des Hautes Etudes Scientifiques (IHES), IHES, The Francis Crick Institute, Institut de Biologie Paris Seine (IBPS), Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS)-Centre National de la Recherche Scientifique (CNRS), Institut National de Recherche en Informatique et en Automatique (Inria)-Institut National de Recherche en Informatique et en Automatique (Inria)-Laboratoire Jean Kuntzmann (LJK), Université Pierre Mendès France - Grenoble 2 (UPMF)-Université Joseph Fourier - Grenoble 1 (UJF)-Institut Polytechnique de Grenoble - Grenoble Institute of Technology-Centre National de la Recherche Scientifique (CNRS)-Université Grenoble Alpes (UGA)-Université Pierre Mendès France - Grenoble 2 (UPMF)-Université Joseph Fourier - Grenoble 1 (UJF)-Institut Polytechnique de Grenoble - Grenoble Institute of Technology-Centre National de la Recherche Scientifique (CNRS)-Université Grenoble Alpes (UGA)-Institut National Polytechnique de Grenoble (INPG), Weizmann Institute of Science, University of Gdańsk, Department of Environmental Analytics [Gdańsk], Institut National de Recherche en Informatique et en Automatique (Inria)-Université de Lorraine (UL)-Centre National de la Recherche Scientifique (CNRS)-Institut National de Recherche en Informatique et en Automatique (Inria)-Université de Lorraine (UL)-Centre National de la Recherche Scientifique (CNRS)-Laboratoire Lorrain de Recherche en Informatique et ses Applications (LORIA), Institut National de Recherche en Informatique et en Automatique (Inria)-Université de Lorraine (UL)-Centre National de la Recherche Scientifique (CNRS)-Université de Lorraine (UL)-Centre National de la Recherche Scientifique (CNRS), Technische Universität München [München] (TUM), CEA-Direction de l'Energie Nucléaire (CEA-DEN), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université Paris-Saclay-CEA-Direction de l'Energie Nucléaire (CEA-DEN), University of Missouri [Columbia], Université Paris-Sud - Paris 11 (UP11)-Université Paris-Saclay-Sorbonne Université - UFR d'Ingénierie (UFR 919), Sorbonne Université (SU)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS)-Université Paris Saclay (COmUE), Université de Lille, CNRS, Unité de Glycobiologie Structurale et Fonctionnelle UMR 8576 [UGSF], Agence Nationale de la Recherche (France), Cancer Research UK, European Commission, Medical Research Council (UK), National Institutes of Health (US), National Natural Science Foundation of China, National Research Foundation of Korea, National Science Foundation (US), Ministerio de Economía y Competitividad (España), Università degli Studi di Napoli PARTHENOPE, Wellcome Trust, Université de Lille-Centre National de la Recherche Scientifique (CNRS), Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Algorithms for Modeling and Simulating Nanosystems [2018-...] (NANO-D-POST [2018-2020]), Institut National de Recherche en Informatique et en Automatique (Inria)-Institut National de Recherche en Informatique et en Automatique (Inria), Department of Computer Science [Univ California Davis] (CS - UC Davis), University of California (UC)-University of California (UC), University of Naples Federico II = Università degli studi di Napoli Federico II, University of California [Santa Cruz] (UC Santa Cruz), University of California (UC), and Grudinin, Sergei
Subjects: Models, Molecular, Computer science, Protein Conformation, Protein complexes, Template‐based modeling, Oligomeric state, Biochemistry, Docking, protein-protein interaction, Structural Biology, Protein Interaction Mapping, Taverne, Blind prediction, Protein assemblies, Databases, Protein, [INFO.INFO-BI] Computer Science [cs]/Bioinformatics [q-bio.QM], 0303 health sciences, oligomeric state, 030302 biochemistry & molecular biology, protein assemblies, computer.file_format, 3. Good health, CASP, docking, blind prediction, Protein‐protein interaction, CAPRI, proteincomplexes, Algorithms, Protein Binding, protein complexes, template-based modeling, Computational biology, Article, Protein–protein interaction, 03 medical and health sciences, protein‐protein interaction, template‐based modeling, Molecular Biology, 030304 developmental biology, Binding Sites, Computational Biology, Proteins, Protein Data Bank, Docking (molecular), Structural Homology, Protein, [INFO.INFO-BI]Computer Science [cs]/Bioinformatics [q-bio.QM], computer, Software
Abstract: We present the results for CAPRI Round 46, the third joint CASP‐CAPRI protein assembly prediction challenge. The Round comprised a total of 20 targets including 14 homo‐oligomers and 6 heterocomplexes. Eight of the homo‐oligomer targets and one heterodimer comprised proteins that could be readily modeled using templates from the Protein Data Bank, often available for the full assembly. The remaining 11 targets comprised 5 homodimers, 3 heterodimers, and two higher‐order assemblies. These were more difficult to model, as their prediction mainly involved “ab‐initio” docking of subunit models derived from distantly related templates. A total of ~30 CAPRI groups, including 9 automatic servers, submitted on average ~2000 models per target. About 17 groups participated in the CAPRI scoring rounds, offered for most targets, submitting ~170 models per target. The prediction performance, measured by the fraction of models of acceptable quality or higher submitted across all predictors groups, was very good to excellent for the nine easy targets. Poorer performance was achieved by predictors for the 11 difficult targets, with medium and high quality models submitted for only 3 of these targets. A similar performance “gap” was displayed by scorer groups, highlighting yet again the unmet challenge of modeling the conformational changes of the protein components that occur upon binding or that must be accounted for in template‐based modeling. Our analysis also indicates that residues in binding interfaces were less well predicted in this set of targets than in previous Rounds, providing useful insights for directions of future improvements., Agence Nationale de la Recherche, Grant/Award Number: ANR‐15‐CE11‐0029‐03; Cancer Research UK, Grant/Award Number: FC001003; H2020 European Institute of Innovation and Technology, Grant/Award Numbers: 675728, 777536, 823830; Lietuvos Mokslo Taryba, Grant/Award Number: S‐MIP‐17‐60; Medical Research Council, Grant/Award Number: FC001003; National Institutes of Health, Grant/Award Numbers: R01GM074255, R01GM123055, R35GM124952; National Natural Science Foundation of China, Grant/Award Number: 31670724; National Research Foundation of Korea, Grant/Award Number: 2016M3C4A7952630; National Science Foundation, Grant/Award Number: DBI1565107; Nederlandse Organisatie voor Wetenschappelijk Onderzoek, Grant/Award Number: 718.015.001; Spanish >Programma Estatal I+D+i>, Grant/Award Number: BIO2016‐79930‐R; University Parthenope, Grant/Award Number: Finanziamento per il Sostegno alla Ricerca Individ; Wellcome Trust, Grant/Award Number: FC001003
Published: 2019
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39. CLUH couples mitochondrial distribution to the energetic and metabolic status

Author: Valérie Desquiret-Dumas, Stéphanie Chupin, Rodolphe Perrot, Naïg Gueguen, Dominique Bonneau, David C. Logan, Ilaria Dalla Rosa, Vincent Procaccio, David Goudenège, Jamal Wakim, Morgane Le Mao, Guy Lenaers, Juan Manuel Chao de la Barca, Pascal Reynier, Florence Manero, Salim Khiati, Arnaud Chevrollier, Physiopathologie Cardiovasculaire et Mitochondriale (MITOVASC), Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université d'Angers (UA), Centre National de la Recherche Scientifique (CNRS), Institut National de la Santé et de la Recherche Médicale (INSERM), Inst Biol Sante, Université d'Angers (UA), Mill Hill Laboratory, The Francis Crick Institute [London], Institut de Recherche en Horticulture et Semences (IRHS), Université d'Angers (UA)-Institut National de la Recherche Agronomique (INRA)-AGROCAMPUS OUEST, Institut national d'enseignement supérieur pour l'agriculture, l'alimentation et l'environnement (Institut Agro)-Institut national d'enseignement supérieur pour l'agriculture, l'alimentation et l'environnement (Institut Agro), Region Pays de Loire and Angers Loire Metropole, Fondation VISIO, Ouvrir les Yeux, Union Nationale des Aveugles et Deficients Visuels, Association contre les Maladies Mitochondriales, Retina France, Kjer France, Inst MitoVasc, Equipe MitoLab, The Francis Crick Institute, AGROCAMPUS OUEST-Institut National de la Recherche Agronomique (INRA)-Université d'Angers (UA), Université d'Angers (UA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), AGROCAMPUS OUEST, and Institut national d'enseignement supérieur pour l'agriculture, l'alimentation et l'environnement (Institut Agro)-Institut national d'enseignement supérieur pour l'agriculture, l'alimentation et l'environnement (Institut Agro)-Institut National de la Recherche Agronomique (INRA)-Université d'Angers (UA)
Subjects: 0301 basic medicine, Mitochondrial translation, [SDV]Life Sciences [q-bio], Citric Acid Cycle, Oxidative phosphorylation, Biology, Mitochondrion, DNA, Mitochondrial, Oxidative Phosphorylation, 03 medical and health sciences, chemistry.chemical_compound, Adenosine Triphosphate, Ethidium, Humans, Metabolomics, Beta oxidation, Palmitoylcarnitine, Optical Imaging, RNA-Binding Proteins, Cell Biology, Metabolism, Cell size, Cell biology, Mitochondria, Citric acid cycle, 030104 developmental biology, chemistry, CLUH, Phosphatidylcholines, Mitochondrial dynamics, CRISPR-Cas Systems, Oxidation-Reduction, Adenosine triphosphate, Gene Deletion, DNA Damage, HeLa Cells
Abstract: Mitochondrial dynamics and distribution are critical for supplying ATP in response to energy demand. CLUH is a protein involved in mitochondrial distribution whose dysfunction leads to mitochondrial clustering, the metabolic consequences of which remain unknown. To gain insight into the role of CLUH on mitochondrial energy production and cellular metabolism, we have generated CLUH-knockout cells using CRISPR/Cas9. Mitochondrial clustering was associated with a smaller cell size and with decreased abundance of respiratory complexes, resulting in oxidative phosphorylation (OXPHOS) defects. This energetic impairment was found to be due to the alteration of mitochondrial translation and to a metabolic shift towards glucose dependency. Metabolomic profiling by mass spectroscopy revealed an increase in the concentration of some amino acids, indicating a dysfunctional Krebs cycle, and increased palmitoylcarnitine concentration, indicating an alteration of fatty acid oxidation, and a dramatic decrease in the concentrations of phosphatidylcholine and sphingomyeline, consistent with the decreased cell size. Taken together, our study establishes a clear function for CLUH in coupling mitochondrial distribution to the control of cell energetic and metabolic status.
Published: 2017
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40. Eleventh International Foamy Virus Conference 2016 - Meeting Report

Author: Buseyne, Florence, Gessain, Antoine, Soares, Marcello A., Santos, Marcelo A, Materniak-Kornas, Magdalena, Lesage, Pascale, Zamborlini, Alessia, Löchelt, Martin, Qiao, Wentao, Lindemann, Dirk, Wöhrl, Birgitta, Stoye, Jonathan P., Taylor, Ian A, Khan, Africa A., Epidémiologie et Physiopathologie des Virus Oncogènes (EPVO (UMR_3569 / U-Pasteur_3)), Institut Pasteur [Paris]-Université Paris Diderot - Paris 7 (UPD7)-Centre National de la Recherche Scientifique (CNRS), Universidade Federal do Rio de Janeiro (UFRJ), Department of Biochemistry, National Veterinary Research Institute, 24-100 Pulawy, Poland, National Veterinary Research Institute [Pulawy, Pologne] (NVRI), Institut Universitaire d'Hématologie (IUH), Université Paris Diderot - Paris 7 (UPD7), Centre d'enseignement Cnam Paris (CNAM Paris), Conservatoire National des Arts et Métiers [CNAM] (CNAM), Division of Genome Modifications and Carcinogenesis, German Cancer Research Center - Deutsches Krebsforschungszentrum [Heidelberg] (DKFZ), Nankai University (NKU), Institute of Virology [Dresden], Technische Universität Dresden = Dresden University of Technology (TU Dresden), Biopolymere, Universität Bayreuth, The Francis Crick Institute [London], U.S. Food and Drug Administration (FDA), ANR-10-LABX-0062,IBEID,Integrative Biology of Emerging Infectious Diseases(2010), ANR-15-CE15-0008,REEMFOAMY,L'infection humaine par les virus foamy simiens zoonotiques : rôle des facteurs virologiques et immunologiques dans la restrcition de l'emergence virale(2015), Universidade Federal do Rio de Janeiro [Rio de Janeiro] (UFRJ), National Veterinary Research Institute [Pulawy] (NVRI), Technische Universität Dresden (TUD), The Francis Crick Institute, ANR-10-LABX-62-IBEID,IBEID,Laboratoire d'Excellence 'Integrative Biology of Emerging Infectious Diseases'(2010), ANR-15-CE15-0008,REEMFOAMY,Human infection with zoonotic simian foamy retroviruses: role of virological and immunological factors in restricting viral emergence, Institut Pasteur [Paris] (IP)-Université Paris Diderot - Paris 7 (UPD7)-Centre National de la Recherche Scientifique (CNRS), and HESAM Université - Communauté d'universités et d'établissements Hautes écoles Sorbonne Arts et métiers université (HESAM)-HESAM Université - Communauté d'universités et d'établissements Hautes écoles Sorbonne Arts et métiers université (HESAM)
Subjects: latent infection, foamy virus, [SDV.MHEP.ME]Life Sciences [q-bio]/Human health and pathology/Emerging diseases, [SDV.IMM.IA]Life Sciences [q-bio]/Immunology/Adaptive immunology, cross-species virus transmission, viruses, [SDV.MP.VIR]Life Sciences [q-bio]/Microbiology and Parasitology/Virology, zoonosis, FV vectors, restriction factors, immune responses, virus replication
Abstract: International audience; The Eleventh International Foamy Virus Conference took place on 9–10 June 2016 at the Institut Pasteur, Paris, France. The meeting reviewed progress on foamy virus (FV) research, as well as related current topics in retrovirology. FVs are complex retroviruses that are widespread in several animal species. Several research topics on these viruses are relevant to human health: cross-species transmission and viral emergence, vectors for gene therapy, development of antiretroviral drugs, retroviral evolution and its influence on the human genome. In this article, we review the conference presentations on these viruses and highlight the major questions to be answered.
Published: 2016
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41. Prediction of homo- and hetero-protein complexes by protein docking and template-based modeling: a CASP-CAPRI experiment

Author: Eichiro Ichiishi, Dmitri Beglov, Bernard Maigret, Gyu Rie Lee, Artem B. Mamonov, Shoshana J. Wodak, Jonathan C. Fuller, Dima Kozakov, Jong Young Joung, Petr Popov, Xiaofeng Yu, Keehyoung Joo, João P. G. L. M. Rodrigues, Anna Vangone, Koen M. Visscher, Xiaoqin Zou, Paul A. Bates, Andriy Kryshtafovych, Shourya S. Roy Burman, Daisuke Kihara, Romina Oliva, Efrat Ben-Zeev, Jeffrey J. Gray, Yang Shen, Li C. Xue, Sameer Velankar, Emilie Neveu, Shruthi Viswanath, Dina Schneidman-Duhovny, Juan Esquivel-Rodríguez, Mieczyslaw Torchala, Amit Roy, Alexandre M. J. J. Bonvin, David R. Hall, Tanggis Bohnuud, Xusi Han, David W. Ritchie, Ron Elber, Daisuke Kuroda, Zhiwei Ma, Joan Segura, Carlos A. Del Carpio, Nicholas A. Marze, Jong Yun Kim, Andrej Sali, Petras J. Kundrotas, Ezgi Karaca, Neil J. Bruce, Chaok Seok, Panagiotis L. Kastritis, Shen You Huang, Ilya A. Vakser, Lim Heo, Sanbo Qin, Raphael A. G. Chaleil, Adrien S. J. Melquiond, Miguel Romero-Durana, Anisah W. Ghoorah, Surendra S. Negi, Andrey Tovchigrechko, Françoise Ochsenbein, Narcis Fernandez-Fuentes, Liming Qiu, Miriam Eisenstein, Mehdi Nellen, Marie-Dominique Devignes, Lenna X. Peterson, Jinchao Yu, Minkyung Baek, Brian G. Pierce, Hasup Lee, Toshiyuki Oda, Rebecca C. Wade, Raphael Guerois, Juan Fernández-Recio, Iain H. Moal, Edrisse Chermak, Sergei Grudinin, Sangwoo Park, Ivan Anishchenko, Chengfei Yan, Thom Vreven, Kentaro Tomii, Bing Xia, Hyung Rae Kim, Chiara Pallara, Jooyoung Lee, Kazunori D. Yamada, Xianjin Xu, Kenichiro Imai, Zhiping Weng, Luigi Cavallo, Tyler M. Borrman, Jianlin Cheng, Marc F. Lensink, Huan-Xiang Zhou, Jilong Li, Gydo C. P. van Zundert, Brian Jiménez-García, Tsukasa Nakamura, Scott E. Mottarella, Sandor Vajda, Institut de Recherche Interdisciplinaire [Villeneuve d'Ascq] ( IRI ), Université de Lille, Sciences et Technologies-Université de Lille, Droit et Santé-Centre National de la Recherche Scientifique ( CNRS ), European Molecular Biology Laboratory, European Bioinformatics Institute, Genome Center [UC Davis], University of California at Davis, Research Support Computing [Columbia], University of Missouri-Columbia, Bioinformatics Consortium and Department of Computer Science [Columbia], Department of Bioengineering and Therapeutic Sciences, University of California [San Francisco] ( UCSF ), Department of Pharmaceutical Chemistry, Department of Bioengineering and Therapeutic Sciences, Department of Pharmaceutical Chemistry, University of California [San Francisco] ( UCSF ) -California Institute for Quantitative Biosciences, GN7 of the National Institute for Bioinformatics (INB) and Biocomputing Unit, Centro Nacional de Biotecnología (CSIC), Institute of Biological, Environmental and Rural Sciences ( IBERS ), Institute for Computational Engineering and Sciences [Austin] ( ICES ), University of Texas at Austin [Austin], Department of Computer Science, Department of Chemistry, Algorithms for Modeling and Simulation of Nanosystems ( NANO-D ), Inria Grenoble - Rhône-Alpes, Institut National de Recherche en Informatique et en Automatique ( Inria ) -Institut National de Recherche en Informatique et en Automatique ( Inria ) -Laboratoire Jean Kuntzmann ( LJK ), Université Pierre Mendès France - Grenoble 2 ( UPMF ) -Université Joseph Fourier - Grenoble 1 ( UJF ) -Institut Polytechnique de Grenoble - Grenoble Institute of Technology-Centre National de la Recherche Scientifique ( CNRS ) -Université Grenoble Alpes ( UGA ) -Université Pierre Mendès France - Grenoble 2 ( UPMF ) -Université Joseph Fourier - Grenoble 1 ( UJF ) -Institut Polytechnique de Grenoble - Grenoble Institute of Technology-Centre National de la Recherche Scientifique ( CNRS ) -Université Grenoble Alpes ( UGA ) -Institut National Polytechnique de Grenoble ( INPG ), Moscow Institute of Physics and Technology [Moscow] ( MIPT ), Seoul National University [Seoul], Florida State University [Tallahassee] ( FSU ), Computational Algorithms for Protein Structures and Interactions ( CAPSID ), Inria Nancy - Grand Est, Institut National de Recherche en Informatique et en Automatique ( Inria ) -Institut National de Recherche en Informatique et en Automatique ( Inria ) -Department of Complex Systems, Artificial Intelligence & Robotics ( LORIA - AIS ), Laboratoire Lorrain de Recherche en Informatique et ses Applications ( LORIA ), Institut National de Recherche en Informatique et en Automatique ( Inria ) -Université de Lorraine ( UL ) -Centre National de la Recherche Scientifique ( CNRS ) -Institut National de Recherche en Informatique et en Automatique ( Inria ) -Université de Lorraine ( UL ) -Centre National de la Recherche Scientifique ( CNRS ) -Laboratoire Lorrain de Recherche en Informatique et ses Applications ( LORIA ), Institut National de Recherche en Informatique et en Automatique ( Inria ) -Université de Lorraine ( UL ) -Centre National de la Recherche Scientifique ( CNRS ) -Université de Lorraine ( UL ) -Centre National de la Recherche Scientifique ( CNRS ), University of Mauritius, Biomolecular Modelling Laboratory, The Francis Crick Institute, Lincoln's Inn Fields Laboratory, G-INCPM, Weizmann Institute of Science, Chemical Research Support [Rehovot], Sealy Center for Structural Biology and Molecular Biophysics, The University of Texas Medical Branch ( UTMB ), Program in Bioinformatics and Integrative Biology [Worcester], University of Massachusetts Medical School [Worcester] ( UMASS ), Institut de Biologie Intégrative de la Cellule ( I2BC ), Université Paris-Saclay-Centre National de la Recherche Scientifique ( CNRS ) -Commissariat à l'énergie atomique et aux énergies alternatives ( CEA ) -Université Paris-Sud - Paris 11 ( UP11 ), Bijvoet Center for Biomolecular Research [Utrecht], Utrecht University [Utrecht], Dalton Cardiovascular Research Center [Columbia], Department of Computer Science [Columbia], Informatics Intitute, Department of Biochemistry, University of Missouri, UNIVERSITY OF MISSOURI, Toyota Technological Institute at Chicago [Chicago] ( TTIC ), Department of Biological Sciences, Purdue University, Purdue University [West Lafayette], Department of Computer Science [Purdue], Bioinformatics and Computational Biosciences Branch, Rocky Mountain Laboratories, Molecular and Cellular Modeling Group, Heidelberg Institute of Theoretical Studies, Center for Molecular Biology ( ZMBH ), Universität Heidelberg [Heidelberg], Interdisciplinary Center for Scientiﬁc Computing ( IWR ), Department of Molecular Biosciences [Lawrence], University of Kansas [Lawrence] ( KU ), Computational Biology Research Center ( CBRC ), National Institute of Advanced Industrial Science and Technology ( AIST ), Graduate School of Frontier Sciences, The University of Tokyo, Joint BSC-CRG-IRB Research Program in Computational Biology, Barcelona Supercomputing Center - Centro Nacional de Supercomputacion ( BSC - CNS ), Center for In-Silico Protein Science, Korea Institute for Advanced Study ( KIAS ), Center for Advanced Computation, Department of Biomedical Engineering [Boston], Boston University [Boston] ( BU ), Institute of Biological Diversity, International Pacific Institute of Indiana, Drosophila Genetic Resource Center, Kyoto Institute of Technology, International University of Health and Welfare Hospital ( IUHW Hospital ), International University of Health and Welfare Hospital, Department of Chemical and Biomolecular Engineering [Baltimore], Johns Hopkins University ( JHU ), Program in Molecular Biophysics [Baltimore], King Abdullah University of Science and Technology ( KAUST ), University of Naples, J Craig Venter Institute, Structural Biology Research Center, VIB, 1050 Brussels, Belgium, Institut de Recherche Interdisciplinaire [Villeneuve d'Ascq] (IRI), Université de Lille, Sciences et Technologies-Université de Lille, Droit et Santé-Centre National de la Recherche Scientifique (CNRS), European Bioinformatics Institute [Hinxton] (EMBL-EBI), EMBL Heidelberg, University of California [Davis] (UC Davis), University of California (UC)-University of California (UC), University of Missouri [Columbia] (Mizzou), University of Missouri System, University of California [San Francisco] (UC San Francisco), Centro Nacional de Biotecnología [Madrid] (CNB-CSIC), Consejo Superior de Investigaciones Científicas [Madrid] (CSIC)-Consejo Superior de Investigaciones Científicas [Madrid] (CSIC), Institute of Biological, Environmental and Rural Sciences (IBERS), Institute for Computational Engineering and Sciences [Austin] (ICES), Algorithms for Modeling and Simulation of Nanosystems (NANO-D), Institut National de Recherche en Informatique et en Automatique (Inria)-Institut National de Recherche en Informatique et en Automatique (Inria)-Institut polytechnique de Grenoble - Grenoble Institute of Technology (Grenoble INP )-Laboratoire Jean Kuntzmann (LJK ), Institut polytechnique de Grenoble - Grenoble Institute of Technology (Grenoble INP )-Institut National de Recherche en Informatique et en Automatique (Inria)-Centre National de la Recherche Scientifique (CNRS)-Université Grenoble Alpes [2016-2019] (UGA [2016-2019])-Centre National de la Recherche Scientifique (CNRS)-Université Grenoble Alpes [2016-2019] (UGA [2016-2019]), Moscow Institute of Physics and Technology [Moscow] (MIPT), Seoul National University [Seoul] (SNU), Florida State University [Tallahassee] (FSU), Computational Algorithms for Protein Structures and Interactions (CAPSID), Institut National de Recherche en Informatique et en Automatique (Inria)-Institut National de Recherche en Informatique et en Automatique (Inria)-Department of Complex Systems, Artificial Intelligence & Robotics (LORIA - AIS), Laboratoire Lorrain de Recherche en Informatique et ses Applications (LORIA), Institut National de Recherche en Informatique et en Automatique (Inria)-Université de Lorraine (UL)-Centre National de la Recherche Scientifique (CNRS)-Institut National de Recherche en Informatique et en Automatique (Inria)-Université de Lorraine (UL)-Centre National de la Recherche Scientifique (CNRS)-Laboratoire Lorrain de Recherche en Informatique et ses Applications (LORIA), Institut National de Recherche en Informatique et en Automatique (Inria)-Université de Lorraine (UL)-Centre National de la Recherche Scientifique (CNRS)-Université de Lorraine (UL)-Centre National de la Recherche Scientifique (CNRS), Biomolecular Modelling Laboratory [London], The Francis Crick Institute [London], Weizmann Institute of Science [Rehovot, Israël], The University of Texas Medical Branch (UTMB), University of Massachusetts Medical School [Worcester] (UMASS), University of Massachusetts System (UMASS)-University of Massachusetts System (UMASS), Institut de Biologie Intégrative de la Cellule (I2BC), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université Paris-Saclay-Centre National de la Recherche Scientifique (CNRS), Assemblage moléculaire et intégrité du génome (AMIG), Département Biochimie, Biophysique et Biologie Structurale (B3S), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université Paris-Saclay-Centre National de la Recherche Scientifique (CNRS)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université Paris-Saclay-Centre National de la Recherche Scientifique (CNRS)-Institut de Biologie Intégrative de la Cellule (I2BC), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université Paris-Saclay-Centre National de la Recherche Scientifique (CNRS)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université Paris-Saclay-Centre National de la Recherche Scientifique (CNRS), University of Missouri System-University of Missouri System, Toyota Technological Institute at Chicago [Chicago] (TTIC), Department of Biological Sciences [Lafayette IN], Heidelberg Institute for Theoretical Studies (HITS ), Center for Molecular Biology (ZMBH), Universität Heidelberg [Heidelberg] = Heidelberg University, Interdisciplinary Center for Scientiﬁc Computing (IWR), University of Kansas [Lawrence] (KU), Computational Biology Research Center (CBRC), National Institute of Advanced Industrial Science and Technology (AIST), The University of Tokyo (UTokyo), Barcelona Supercomputing Center - Centro Nacional de Supercomputacion (BSC - CNS), Korea Institute for Advanced Study (KIAS), Boston University [Boston] (BU), International University of Health and Welfare Hospital (IUHW Hospital), Johns Hopkins University (JHU), King Abdullah University of Science and Technology (KAUST), University of Naples Federico II = Università degli studi di Napoli Federico II, J. Craig Venter Institute, VIB-VUB Center for Structural Biology [Bruxelles], VIB [Belgium], Centre National de la Recherche Scientifique (CNRS)-Université de Lille, Droit et Santé-Université de Lille, Sciences et Technologies, University of California-University of California, University of California [San Francisco] (UCSF), Centre National de la Recherche Scientifique (CNRS)-Université de Lorraine (UL)-Institut National de Recherche en Informatique et en Automatique (Inria)-Centre National de la Recherche Scientifique (CNRS)-Université de Lorraine (UL)-Institut National de Recherche en Informatique et en Automatique (Inria)-Laboratoire Lorrain de Recherche en Informatique et ses Applications (LORIA), Centre National de la Recherche Scientifique (CNRS)-Université de Lorraine (UL)-Institut National de Recherche en Informatique et en Automatique (Inria)-Centre National de la Recherche Scientifique (CNRS)-Université de Lorraine (UL), University of Naples Federico II, Barcelona Supercomputing Center, NMR Spectroscopy, and Sub NMR Spectroscopy
Subjects: 0301 basic medicine, Protein Conformation, alpha-Helical, Protein Folding, Computer science, International Cooperation, Amino Acid Motifs, Oligomer state, Homoprotein, DATA-BANK, computer.software_genre, Molecular Docking Simulation, Biochemistry, CAPRI Round 30, DESIGN, Structural Biology, ALIGN, Blind prediction, AFFINITY, Protein interaction, Enginyeria biomèdica [Àrees temàtiques de la UPC], ZDOCK, Oligomer State, computer.file_format, Articles, Protein structure prediction, Proteïnes--Investigació, 3. Good health, WEB SERVER, CASP, Thermodynamics, Data mining, CAPRI, Protein docking, Molecular Biology, Algorithms, INTERFACES, Protein Binding, [ INFO.INFO-MO ] Computer Science [cs]/Modeling and Simulation, Bioinformatics, STRUCTURAL BIOLOGY, Computational biology, Molecular Dynamics Simulation, Article, 03 medical and health sciences, [ INFO.INFO-BI ] Computer Science [cs]/Bioinformatics [q-bio.QM], Heteroprotein, Humans, Protein binding, Macromolecular docking, Protein Interaction Domains and Motifs, Homology modeling, ALGORITHM, Protein-protein docking, Internet, Binding Sites, Models, Statistical, 030102 biochemistry & molecular biology, Bacteria, Sequence Homology, Amino Acid, Computational Biology, Proteins, Protein Data Bank, [INFO.INFO-MO]Computer Science [cs]/Modeling and Simulation, Protein Structure, Tertiary, 030104 developmental biology, Structural biology, Docking (molecular), Protein structure, Protein Conformation, beta-Strand, Protein Multimerization, oligomer state, blind prediction, protein interaction, protein docking, [INFO.INFO-BI]Computer Science [cs]/Bioinformatics [q-bio.QM], computer, Software
Abstract: We present the results for CAPRI Round 30, the first joint CASP-CAPRI experiment, which brought together experts from the protein structure prediction and protein–protein docking communities. The Round comprised 25 targets from amongst those submitted for the CASP11 prediction experiment of 2014. The targets included mostly homodimers, a few homotetramers, and two heterodimers, and comprised protein chains that could readily be modeled using templates from the Protein Data Bank. On average 24 CAPRI groups and 7 CASP groups submitted docking predictions for each target, and 12 CAPRI groups per target participated in the CAPRI scoring experiment. In total more than 9500 models were assessed against the 3D structures of the corresponding target complexes. Results show that the prediction of homodimer assemblies by homology modeling techniques and docking calculations is quite successful for targets featuring large enough subunit interfaces to represent stable associations. Targets with ambiguous or inaccurate oligomeric state assignments, often featuring crystal contact-sized interfaces, represented a confounding factor. For those, a much poorer prediction performance was achieved, while nonetheless often providing helpful clues on the correct oligomeric state of the protein. The prediction performance was very poor for genuine tetrameric targets, where the inaccuracy of the homology-built subunit models and the smaller pair-wise interfaces severely limited the ability to derive the correct assembly mode. Our analysis also shows that docking procedures tend to perform better than standard homology modeling techniques and that highly accurate models of the protein components are not always required to identify their association modes with acceptable accuracy. We are most grateful to the PDBe at the European Bioinformatics Institute in Hinxton, UK, for hosting the CAPRI website. Our deepest thanks go to all the structural biologists and to the following structural genomics initiatives: Northeast Structural Genomics Consortium, Joint Center for Structural Genomics, NatPro PSI:Biology, New York Structural Genomics Research Center, Midwest Center for Structural Genomics, Structural Genomics Consortium, for contributing the targets for this joint CASP-CAPRI experiment. MFL acknowledges support from the FRABio FR3688 Research Federation “Structural & Functional Biochemistry of Biomolecular Assemblies.”
Published: 2016
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42. Apicoplast-Localized Lysophosphatidic Acid Precursor Assembly Is Required for Bulk Phospholipid Synthesis in Toxoplasma gondii and Relies on an Algal/Plant-Like Glycerol 3-Phosphate Acyltransferase

Author: Souad Amiar, Yoshiki Yamaryo-Botté, Malcolm J. McConville, Melanie J. Shears, James I. MacRae, Geoffrey I. McFadden, Damien L. Callahan, David Dubois, Cyrille Y. Botté, Eric Maréchal, Marie-France Cesbron-Delauw, Giel G. van Dooren, ApicoLipid group, UMR5309, Institut Albert Bonniot-<span class='valid'>Institut Albert Bonniot</span>, The Francis Crick Institute, Department of Biochemistry and Molecular Biology, University of Melbourne, Centre for Chemistry and Biotechnology, Deakin University [Burwood], School of BioSciences [Melbourne], Faculty of Science [Melbourne], University of Melbourne-University of Melbourne, Research School of Biology, Australian National University (ANU), Techniques de l'Ingénierie Médicale et de la Complexité - Informatique, Mathématiques et Applications, Grenoble - UMR 5525 (TIMC-IMAG), Université Joseph Fourier - Grenoble 1 (UJF)-Institut polytechnique de Grenoble - Grenoble Institute of Technology (Grenoble INP)-IMAG-Centre National de la Recherche Scientifique (CNRS)-Université Grenoble Alpes (UGA), Barrière Naturelle et Infectiosité (TIMC-IMAG-BNI), Université Joseph Fourier - Grenoble 1 (UJF)-Institut polytechnique de Grenoble - Grenoble Institute of Technology (Grenoble INP)-IMAG-Centre National de la Recherche Scientifique (CNRS)-Université Grenoble Alpes (UGA)-Université Joseph Fourier - Grenoble 1 (UJF)-Institut polytechnique de Grenoble - Grenoble Institute of Technology (Grenoble INP)-IMAG-Centre National de la Recherche Scientifique (CNRS)-Université Grenoble Alpes (UGA), Laboratoire de physiologie cellulaire végétale (LPCV), Université Joseph Fourier - Grenoble 1 (UJF)-Institut National de la Recherche Agronomique (INRA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Centre National de la Recherche Scientifique (CNRS), Institut Albert Bonniot, The Francis Crick Institute [London], Research School of Biology [Canberra, Australia], Institut polytechnique de Grenoble - Grenoble Institute of Technology (Grenoble INP )-VetAgro Sup - Institut national d'enseignement supérieur et de recherche en alimentation, santé animale, sciences agronomiques et de l'environnement (VAS)-Centre National de la Recherche Scientifique (CNRS)-Université Grenoble Alpes [2016-2019] (UGA [2016-2019]), Institut polytechnique de Grenoble - Grenoble Institute of Technology (Grenoble INP )-VetAgro Sup - Institut national d'enseignement supérieur et de recherche en alimentation, santé animale, sciences agronomiques et de l'environnement (VAS)-Centre National de la Recherche Scientifique (CNRS)-Université Grenoble Alpes [2016-2019] (UGA [2016-2019])-Institut polytechnique de Grenoble - Grenoble Institute of Technology (Grenoble INP )-VetAgro Sup - Institut national d'enseignement supérieur et de recherche en alimentation, santé animale, sciences agronomiques et de l'environnement (VAS)-Centre National de la Recherche Scientifique (CNRS)-Université Grenoble Alpes [2016-2019] (UGA [2016-2019]), Physiologie cellulaire et végétale (LPCV), Université Grenoble Alpes [2016-2019] (UGA [2016-2019])-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Recherche Agronomique (INRA)-Institut de Recherche Interdisciplinaire de Grenoble (IRIG), Direction de Recherche Fondamentale (CEA) (DRF (CEA)), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Direction de Recherche Fondamentale (CEA) (DRF (CEA)), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA), Agence Nationale pour la recherche (ANR RPDOC Apicolipid and Parafrap labex, France) [ANR-11-LABX-0024], ATIP-Avenir (CNRS-Inserm France), Fondation Innovation en Infectiologie (Finovi Apicolipid), Universite Grenoble Alpes (AGIR Apicolipid), National Health and Medical Research Council (Australia), Australian Research Counci, Kami Kim, Institut National de la Recherche Agronomique (INRA)-Centre National de la Recherche Scientifique (CNRS)-Université Grenoble Alpes [2016-2019] (UGA [2016-2019])-Institut de Recherche Interdisciplinaire de Grenoble (IRIG), Amiar, Souad, MacRae, James I., McFadden, Geoffrey I., Yamaryo-Botte, Yoshiki, and Botte, Cyrille Y.
Subjects: Glycerol, Models, Molecular, 0301 basic medicine, Protozoan Proteins, Fluorescent Antibody Technique, Biochemistry, Polymerase Chain Reaction, Mass Spectrometry, Toxoplasma Gondii, chemistry.chemical_compound, Macromolecular Structure Analysis, Biology (General), Phospholipids, Phylogeny, ComputingMilieux_MISCELLANEOUS, Protozoans, Lipid Analysis, Fatty Acids, Phosphatidic acid, Lipids, 3. Good health, Cell biology, Physical sciences, Chemistry, [SDV.MP]Life Sciences [q-bio]/Microbiology and Parasitology, Gene Knockdown Techniques, Acyltransferase, Toxoplasma, Research Article, QH301-705.5, Immunology, Monomers (Chemistry), Apicoplasts, Biology, Biosynthesis, Microbiology, Parasite Replication, 03 medical and health sciences, Microscopy, Electron, Transmission, Virology, Lipid biosynthesis, parasitic diseases, Genetics, Polymer chemistry, Amino Acid Sequence, Plastid, Molecular Biology, Fatty acid synthesis, Apicoplast, 030102 biochemistry & molecular biology, Organisms, Biology and Life Sciences, RC581-607, Parasitic Protozoans, Metabolic pathway, 030104 developmental biology, chemistry, Glycerol-3-Phosphate O-Acyltransferase, Membrane biogenesis, Parasitology, Immunologic diseases. Allergy, Lysophospholipids, Chromatography, Liquid
Abstract: Most apicomplexan parasites possess a non-photosynthetic plastid (the apicoplast), which harbors enzymes for a number of metabolic pathways, including a prokaryotic type II fatty acid synthesis (FASII) pathway. In Toxoplasma gondii, the causative agent of toxoplasmosis, the FASII pathway is essential for parasite growth and infectivity. However, little is known about the fate of fatty acids synthesized by FASII. In this study, we have investigated the function of a plant-like glycerol 3-phosphate acyltransferase (TgATS1) that localizes to the T. gondii apicoplast. Knock-down of TgATS1 resulted in significantly reduced incorporation of FASII-synthesized fatty acids into phosphatidic acid and downstream phospholipids and a severe defect in intracellular parasite replication and survival. Lipidomic analysis demonstrated that lipid precursors are made in, and exported from, the apicoplast for de novo biosynthesis of bulk phospholipids. This study reveals that the apicoplast-located FASII and ATS1, which are primarily used to generate plastid galactolipids in plants and algae, instead generate bulk phospholipids for membrane biogenesis in T. gondii., Author Summary Apicomplexan parasites are the causative agents of several major human diseases including toxoplasmosis and malaria, caused by Toxoplasma gondii and Plasmodium spp. respectively. Obligate intracellular stages of these parasites undergo periods of rapid asexual replication which require synthesis of large amounts of lipids for membrane biogenesis. These lipids can either be scavenged from the host cell and/or synthesized de novo by the parasite. Many of the enzymes involved in de novo fatty acid biosynthesis are localized in a non-photosynthetic relict plastid, named the apicoplast, suggesting that this organelle may generate fatty acids and phospholipids that are used for bulk membrane biogenesis. However, it is not known to what extent fatty acids generated by the apicoplast are exported to other cell membranes. Here we show that a key enzyme required for bulk phospholipid biosynthesis, glycerol 3-phosphate acyltransferase, is localized to the T. gondii apicoplast. Comprehensive lipidomic analysis of an acyltransferase null mutant suggested that apicoplast-synthesized phospholipid precursors are subsequently exported and used for bulk phospholipid synthesis. This process is essential for parasite growth and virulence in host cells.
Published: 2016
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43. Active dynamics of tissue shear flow

Author: Popović, Marko, Nandi, Amitabha, Merkel, Matthias, Etournay, Raphael, Eaton, Suzanne, Jülicher, Frank, Salbreux, Guillaume, Max Planck Institute for the Physics of Complex Systems (MPI-PKS), Max-Planck-Gesellschaft, Indian Institute of Technology Bombay (IIT Bombay), Syracuse University, Institut Pasteur [Paris], Max Planck Institute of Molecular Cell Biology and Genetics (MPI-CBG), The Francis Crick Institute [London], MP, AN, MM, FJ and GS acknowledge funding by the Max-Planck-Gesellschaft. RE acknowledges a Marie Curie fellowship from the EU 7th Framework Programme (FP7). SE acknowledge funding from the ERC. MP, MM, SE and FJ acknowledge funding by Bundesministerium für Bildung und Forschung. MM also acknowledges funding from the Alfred P Sloan Foundation, the Gordon and Betty Moore Foundation, and NSF-DMR-1352184. GS acknowledges support by the Francis Crick Institute which receives its core funding from Cancer Research UK (FC001317), the UK Medical Research Council (FC001317), and the Wellcome Trust (FC001317). AN acknowledges Industrial Research & Consultancy Centre at IIT Bombay for financial support., and Institut Pasteur [Paris] (IP)
Subjects: FOS: Physical sciences, [SDV.BC]Life Sciences [q-bio]/Cellular Biology, Mechanics, Planar Polarity, Wing Epithelium, Extension, Cell Behavior (q-bio.CB), Morphogenesis, biological physics, [PHYS.MECA.MEFL]Physics [physics]/Mechanics [physics]/Fluid mechanics [physics.class-ph], Physics - Biological Physics, Tissues and Organs (q-bio.TO), [SDV.BDD]Life Sciences [q-bio]/Development Biology, Migration, Shape, Quantitative Biology - Tissues and Organs, [PHYS.MECA]Physics [physics]/Mechanics [physics], [SDV.BIBS]Life Sciences [q-bio]/Quantitative Methods [q-bio.QM], Living matter, Biological Physics (physics.bio-ph), Rearranging Disordered Patterns, tissue mechanics, FOS: Biological sciences, hydrodynamics, Quantitative Biology - Cell Behavior, Drosophila, rheology, active matter, [PHYS.COND.CM-SCM]Physics [physics]/Condensed Matter [cond-mat]/Soft Condensed Matter [cond-mat.soft], Cell Intercalation
Abstract: International audience; We present a hydrodynamic theory to describe shear flows in developing epithelial tissues. We introduce hydrodynamic fields corresponding to state properties of constituent cells as well as a contribution to overall tissue shear flow due to rearrangements in cell network topology. We then construct a generic linear constitutive equation for the shear rate due to topological rearrangements and we investigate a novel rheological behaviour resulting from memory effects in the tissue. We identify two distinct active cellular processes: generation of active stress in the tissue, and actively driven topological rearrangements. We find that these two active processes can produce distinct cellular and tissue shape changes, depending on boundary conditions applied on the tissue. Our findings have consequences for the understanding of tissue morphogenesis during development.
Published: 2016
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44. Harnessing the Vnn1 pantetheinase pathway boosts short chain fatty acids production and mucosal protection in colitis

Author: Virginie Millet, Thomas Gensollen, Michael Maltese, Melanie Serrero, Nathalie Lesavre, Christophe Bourges, Christophe Pitaval, Sophie Cadra, Lionel Chasson, Thien Phong Vu Man, Marion Masse, Juan Jose Martinez-Garcia, Fabrice Tranchida, Laetitia Shintu, Konrad Mostert, Erick Strauss, Patricia Lepage, Mathias Chamaillard, Achille Broggi, Laurent Peyrin-Biroulet, Jean-Charles Grimaud, Philippe Naquet, Franck Galland, Centre d'Immunologie de Marseille - Luminy (CIML), Aix Marseille Université (AMU)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Harvard Medical School [Boston] (HMS), Brigham & Women’s Hospital [Boston] (BWH), Service de Gastro-entérologie [CHU Hôpital Nord - Marseille], Hôpital Nord [CHU - APHM]-Assistance publique Hôpitaux de Marseille (APHM), CIC - Hôpital Nord AP-HM Marseille, The Francis Crick Institute [London], Centre d’Infection et d’Immunité de Lille - INSERM U 1019 - UMR 9017 - UMR 8204 (CIIL), Institut Pasteur de Lille, Réseau International des Instituts Pasteur (RIIP)-Réseau International des Instituts Pasteur (RIIP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Lille-Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille)-Centre National de la Recherche Scientifique (CNRS), Institut des Sciences Moléculaires de Marseille (ISM2), Aix Marseille Université (AMU)-École Centrale de Marseille (ECM)-Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS), Stellenbosch University, MICrobiologie de l'ALImentation au Service de la Santé (MICALIS), AgroParisTech-Université Paris-Saclay-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE), Nutrition-Génétique et Exposition aux Risques Environnementaux (NGERE), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Lorraine (UL), Service d’Hépato-gastro-entérologie et oncologie digestive [Hôpital Nord, AP-HM], and Hôpital Nord [CHU - APHM]
Subjects: [SDV]Life Sciences [q-bio], Gastroenterology
Abstract: ObjectiveIn the management of patients with IBD, there is a need to identify prognostic markers and druggable biological pathways to improve mucosal repair and probe the efficacy of tumour necrosis factor alpha biologics. Vnn1 is a pantetheinase that degrades pantetheine to pantothenate (vitamin B5, a precursor of coenzyme A (CoA) biosynthesis) and cysteamine. Vnn1 is overexpressed by inflamed colonocytes. We investigated its contribution to the tolerance of the intestinal mucosa to colitis-induced injury.DesignWe performed an RNA sequencing study on colon biopsy samples from patients with IBD stratified according to clinical severity and modalities of treatment. We generated the VIVA mouse transgenic model, which specifically overexpresses Vnn1 on intestinal epithelial cells and explored its susceptibility to colitis. We developed a pharmacological mimicry of Vnn1 overexpression by administration of Vnn1 derivatives.ResultsVNN1 overexpression on colonocytes correlates with IBD severity. VIVA mice are resistant to experimentally induced colitis. The pantetheinase activity of Vnn1 is cytoprotective in colon: it enhances CoA regeneration and metabolic adaptation of colonocytes; it favours microbiota-dependent production of short chain fatty acids and mostly butyrate, shown to regulate mucosal energetics and to be reduced in patients with IBD. This prohealing phenotype is recapitulated by treating control mice with the substrate (pantethine) or the products of pantetheinase activity prior to induction of colitis. In severe IBD, the protection conferred by the high induction of VNN1 might be compromised because its enzymatic activity may be limited by lack of available substrates. In addition, we identify the elevation of indoxyl sulfate in urine as a biomarker of Vnn1 overexpression, also detected in patients with IBD.ConclusionThe induction of Vnn1/VNN1 during colitis in mouse and human is a compensatory mechanism to reinforce the mucosal barrier. Therefore, enhancement of vitamin B5-driven metabolism should improve mucosal healing and might increase the efficacy of anti-inflammatory therapy.
Published: 2022
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45. Affinity-enhanced RNA-binding domains as tools to understand RNA recognition

Author: Chaves-Arquero, Belén, Collins, Katherine M, Abis, Giancarlo, Kelly, Geoff, Christodoulou, Evangelos, Taylor, Ian A, Ramos, Andres, Medical Research Council (UK), University College London, Francis Crick Institute, Cancer Research UK, Wellcome Trust, Chaves-Arquero, Belén, Abis, Giancarlo, Kelly, Geoff, Christodoulou, Evangelos, Taylor, Ian A., and Ramos, Andrés
Subjects: Model organisms, Chemical Biology & High Throughput, Transient protein-RNA interactions, Fragile X, RNA recognition, Method, Infectious Disease, RNA-binding proteins, FMRP, NMR, Imaging, Structural Biology & Biophysics
Abstract: 13 p.-4 fig.-1 graph. abst., 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., This work was supported by the UK Medical Research Council (MC_PC_13051, U117574558, and MR/S000305/1) and the UK BBRSC research grant S014438/1. It was also supported by University College London and by the Francis Crick Institute, which receives its core funding from Cancer Research UK (CC2029), the UK Medical Research Council (CC2029), and the Wellcome Trust (CC2029). NMR spectra were recorded at the MRC Biomedical NMR Facility Francis Crick Institute UK, which is funded by Cancer Research UK (CC1078), the UK Medical Research Council (CC1078), and the Wellcome Trust (CC1078) and at UCL NMR facilities.
Published: 2023

46. Thiophenecarboxamide Derivatives Activated by EthA Kill Mycobacterium tuberculosis by Inhibiting the CTP Synthetase PyrG

Author: Ana Luisa de Jesus Lopes Ribeiro, Maria Rosalia Pasca, Laurent R. Chiarelli, Giulia Degiacomi, Nathalie Barilone, Marco Fondi, Vadim Makarov, Leonardo B. Marino, Riccardo Manganelli, Marco Bellinzoni, Giuseppe Zanoni, Stewart T. Cole, Francesca Boldrin, Renato Fani, Alessio Porta, Giorgia Mori, Alain R. Baulard, Ruben C. Hartkoorn, Giovanna Riccardi, Jaroslav Blaško, Luiz Pedro S. de Carvalho, Pedro M. Alzari, Zuzana Svetlíková, Ivana Centárová, Elena Kazakova, Sean Ekins, Alexander Lepioshkin, Katarína Mikušová, Marta Esposito, University of Pavia, Russian Academy of Sciences [Moscow] (RAS), Microbiologie structurale - Structural Microbiology (Microb. Struc. (UMR_3528 / U-Pasteur_5)), Institut Pasteur [Paris]-Centre National de la Recherche Scientifique (CNRS)-Université de Paris (UP), Ecole Polytechnique Fédérale de Lausanne (EPFL), University of Padova, Partenaires IRSTEA, Institut national de recherche en sciences et technologies pour l'environnement et l'agriculture (IRSTEA)-Institut national de recherche en sciences et technologies pour l'environnement et l'agriculture (IRSTEA), Collaborative Drug Discovery, The Francis Crick Institute [London], Universidade Estadual Paulista Júlio de Mesquita Filho = São Paulo State University (UNESP), Comenius University in Bratislava, Università degli Studi di Firenze = University of Florence [Firenze] (UNIFI), Institut Pasteur de Lille, Réseau International des Instituts Pasteur (RIIP), The research leading to these results received funding mainly from the European Community's Seventh Framework Program (Grant 260872). Additional funding was from the Slovak Research and Development Agency (Contract No. DO7RP-0015-11), the Francis Crick Institute which receives core funding from Cancer Research UK, the UK Medical Research Council (MC_UP_A253_1111), and the Wellcome Trust. The CDD TB database was funded by the Bill and Melinda Gates Foundation (Grant no. 49852). L.B.M. receives partial support from the FAPESP (2011/21232-1), CNPq (140079/2013-0), and CAPES PDSE (99999.003125/2014-09) programs., European Project: 260872,EC:FP7:HEALTH,FP7-HEALTH-2010-single-stage,MM4TB(2011), Università degli Studi di Pavia = University of Pavia (UNIPV), Institut Pasteur [Paris] (IP)-Centre National de la Recherche Scientifique (CNRS)-Université Paris Cité (UPCité), Università degli Studi di Padova = University of Padua (Unipd), and Università degli Studi di Firenze = University of Florence (UniFI)
Subjects: Models, Molecular, MESH: Mycobacterium tuberculosis, MESH: Carbon-Nitrogen Ligases, Protein Conformation, Mutant, Clinical Biochemistry, Antitubercular Agents, Drug Evaluation, Preclinical, MESH: Drug Design, Biochemistry, Activation, Metabolic, Mice, chemistry.chemical_compound, MESH: Protein Conformation, Drug Discovery, Carbon-Nitrogen Ligases, MESH: Animals, CTP synthetase, MESH: Bacterial Proteins, chemistry.chemical_classification, 0303 health sciences, MESH: Microbial Sensitivity Tests, biology, [SDV.BBM.BS]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Structural Biology [q-bio.BM], Hep G2 Cells, General Medicine, MESH: Thiophenes, 3. Good health, Drug Discovery3003 Pharmaceutical Science, Molecular Biology, Molecular Medicine, Pharmacology, MESH: Drug Evaluation, Preclinical, Oxidoreductases, MESH: Models, Molecular, MESH: Activation, Metabolic, MESH: High-Throughput Screening Assays, Phenotypic screening, [PHYS.PHYS.PHYS-BIO-PH]Physics [physics]/Physics [physics]/Biological Physics [physics.bio-ph], Drug design, MESH: Hep G2 Cells, Microbial Sensitivity Tests, Thiophenes, [SDV.BC]Life Sciences [q-bio]/Cellular Biology, Article, Mycobacterium tuberculosis, 03 medical and health sciences, Bacterial Proteins, [CHIM.CRIS]Chemical Sciences/Cristallography, Animals, Humans, [SDV.BBM]Life Sciences [q-bio]/Biochemistry, Molecular Biology, MESH: Oxidoreductases, Gene, MESH: Mice, 030304 developmental biology, DNA ligase, MESH: Humans, 030306 microbiology, biology.organism_classification, MESH: Antitubercular Agents, High-Throughput Screening Assays, chemistry, Drug Design, biology.protein, [INFO.INFO-BI]Computer Science [cs]/Bioinformatics [q-bio.QM], DNA
Abstract: Summary To combat the emergence of drug-resistant strains of Mycobacterium tuberculosis, new antitubercular agents and novel drug targets are needed. Phenotypic screening of a library of 594 hit compounds uncovered two leads that were active against M. tuberculosis in its replicating, non-replicating, and intracellular states: compounds 7947882 (5-methyl-N-(4-nitrophenyl)thiophene-2-carboxamide) and 7904688 (3-phenyl-N-[(4-piperidin-1-ylphenyl)carbamothioyl]propanamide). Mutants resistant to both compounds harbored mutations in ethA (rv3854c), the gene encoding the monooxygenase EthA, and/or in pyrG (rv1699) coding for the CTP synthetase, PyrG. Biochemical investigations demonstrated that EthA is responsible for the activation of the compounds, and by mass spectrometry we identified the active metabolite of 7947882, which directly inhibits PyrG activity. Metabolomic studies revealed that pharmacological inhibition of PyrG strongly perturbs DNA and RNA biosynthesis, and other metabolic processes requiring nucleotides. Finally, the crystal structure of PyrG was solved, paving the way for rational drug design with this newly validated drug target., Graphical Abstract, Highlights • Two compounds activated by EthA kill M. tuberculosis through PyrG inhibition • EthA metabolite is active against PyrG and M. tuberculosis growth • Definition of the mechanism of activation and validation of PyrG as a new drug target, CTP synthetase PyrG, essential in Mycobacterium tuberculosis, could represent a new potential drug target. With a multidisciplinary approach, Mori et al. identify two compounds killing growing and dormant mycobacteria through PyrG inhibition, and define their mechanism of action.
Published: 2015
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47. Isoform diversity in the Arp2/3 complex determines actin filament dynamics

Author: Svend Kjaer, Michael Way, Marie-France Carlier, Chiara Galloni, Jasmine V. Abella, Julien Pernier, David J. Barry, Cellular Signalling and Cytoskeletal Function, The Francis Crick Institute, Lincoln's Inn Fields Laboratory, Laboratoire d'Enzymologie et Biochimie Structurales ( LEBS ), Centre National de la Recherche Scientifique ( CNRS ), Institut de Biologie Intégrative de la Cellule ( I2BC ), Université Paris-Sud - Paris 11 ( UP11 ) -Commissariat à l'énergie atomique et aux énergies alternatives ( CEA ) -Université Paris-Saclay-Centre National de la Recherche Scientifique ( CNRS ), The Francis Crick Institute [London], Laboratoire d'Enzymologie et Biochimie Structurales (LEBS), Centre National de la Recherche Scientifique (CNRS), Institut de Biologie Intégrative de la Cellule (I2BC), and Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université Paris-Saclay-Centre National de la Recherche Scientifique (CNRS)
Subjects: 0301 basic medicine, Gene isoform, [SDV]Life Sciences [q-bio], Arp2/3 complex, macromolecular substances, Biology, Cell Line, Protein filament, 03 medical and health sciences, Mice, Animals, Humans, Protein Isoforms, Actin-binding protein, Actin, Angiopoietin-Like Protein 2, [ SDV ] Life Sciences [q-bio], Microfilament Proteins, Cell Biology, Actin cytoskeleton, Cell biology, Actin Cytoskeleton, 030104 developmental biology, Angiopoietin-like Proteins, Actin-Related Protein 3, Actin-Related Protein 2, biology.protein, Angiopoietins, Cortactin
Abstract: International audience; The Arp2/3 complex consists of seven evolutionarily conserved subunits (Arp2, Arp3 and ARPC1-5) and plays an essential role in generating branched actin filament networks during many different cellular processes. In mammals, however, the ARPC1 and ARPC5 subunits are each encoded by two isoforms that are 67% identical. This raises the possibility that Arp2/3 complexes with different properties may exist. We found that Arp2/3 complexes containing ARPC1B and ARPC5L are significantly better at promoting actin assembly than those with ARPC1A and ARPC5, both in cells and in vitro. Branched actin networks induced by complexes containing ARPC1B or ARPC5L are also disassembled ∼2-fold slower than those formed by their counterparts. This difference reflects the ability of cortactin to stabilize ARPC1B- and ARPC5L- but not ARPC1A- and ARPC5-containing complexes against coronin-mediated disassembly. Our observations demonstrate that the Arp2/3 complex in higher eukaryotes is actually a family of complexes with different properties.
Published: 2015
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48. ACT-Discover: identifying karyotype heterogeneity in pancreatic cancer evolution using ctDNA

Author: Ariana Huebner, James R. M. Black, Francesca Sarno, Roberto Pazo, Ignacio Juez, Laura Medina, Rocio Garcia-Carbonero, Carmen Guillén, Jaime Feliú, Carolina Alonso, Carlota Arenillas, Ana Belén Moreno-Cárdenas, Helena Verdaguer, Teresa Macarulla, Manuel Hidalgo, Nicholas McGranahan, Rodrigo A. Toledo, Institut Català de la Salut, [Huebner A] Cancer Research UK Lung Cancer Centre of Excellence, University College London Cancer Institute, London, UK. Cancer Genome Evolution Research Group, Cancer Research UK Lung Cancer Centre of Excellence, University College London Cancer Institute, London, UK. Cancer Evolution and Genome Instability Laboratory, The Francis Crick Institute, London, UK. [Black JRM] Cancer Research UK Lung Cancer Centre of Excellence, University College London Cancer Institute, London, UK. Cancer Genome Evolution Research Group, Cancer Research UK Lung Cancer Centre of Excellence, University College London Cancer Institute, London, UK. [Sarno F] Peaches Biotech, Madrid, Spain. [Pazo R] Hospital Universitario Miguel Servet, Zaragoza, Spain. [Juez I] Hospital Universitario de Fuenlabrada, Madrid, Spain. [Medina L] IBIMA, Virgen de La Victoria, Malaga, Spain. [Arenillas C, Toledo RA] Vall d’Hebron Institute of Oncology (VHIO), Barcelona, Spain. Centro de Investigación Biomédica en Red de Cáncer (CIBERONC), Madrid, Spain. [Moreno-Cárdenas AB] Vall d’Hebron Institute of Oncology (VHIO), Barcelona, Spain. [Verdaguer H, Macarulla T] Vall d’Hebron Institute of Oncology (VHIO), Barcelona, Spain. Vall d’Hebron Hospital Universitari, Barcelona, Spain, and Vall d'Hebron Barcelona Hospital Campus
Subjects: Pàncrees - Càncer - Aspectes genètics, Neoplasms::Neoplasms by Site::Digestive System Neoplasms::Pancreatic Neoplasms [DISEASES], nucleótidos y nucleósidos de ácidos nucleicos::ácidos nucleicos::ácidos nucleicos libres de células::ADN tumoral circulante [COMPUESTOS QUÍMICOS Y DROGAS], Nucleic Acids, Nucleotides, and Nucleosides::Nucleic Acids::Cell-Free Nucleic Acids::Circulating Tumor DNA [CHEMICALS AND DRUGS], Genetic Phenomena::Genetic Structures::Chromosomes::Karyotype [PHENOMENA AND PROCESSES], Marcadors tumorals, Genetics, Molecular Medicine, fenómenos genéticos::estructuras genéticas::cromosomas::cariotipo [FENÓMENOS Y PROCESOS], Cariotips, neoplasias::neoplasias por localización::neoplasias del sistema digestivo::neoplasias pancreáticas [ENFERMEDADES], Molecular Biology, Genetics (clinical)
Abstract: Circulating tumour DNA; Pancreatic cancer; Tumour evolution ADN tumoral circulant; Càncer de pàncrees; Evolució tumoral ADN tumoral circulante; Cáncer de páncreas; Evolución tumoral Background Liquid biopsies and the dynamic tracking of somatic mutations within circulating tumour DNA (ctDNA) can provide insight into the dynamics of cancer evolution and the intra-tumour heterogeneity that fuels treatment resistance. However, identifying and tracking dynamic changes in somatic copy number alterations (SCNAs), which have been associated with poor outcome and metastasis, using ctDNA is challenging. Pancreatic adenocarcinoma is a disease which has been considered to harbour early punctuated events in its evolution, leading to an early fitness peak, with minimal further subclonal evolution. Methods To interrogate the role of SCNAs in pancreatic adenocarcinoma cancer evolution, we applied whole-exome sequencing of 55 longitudinal cell-free DNA (cfDNA) samples taken from 24 patients (including 8 from whom a patient-derived xenograft (PDX) was derived) with metastatic disease prospectively recruited into a clinical trial. We developed a method, Aneuploidy in Circulating Tumour DNA (ACT-Discover), that leverages haplotype phasing of paired tumour biopsies or PDXs to identify SCNAs in cfDNA with greater sensitivity. Results SCNAs were observed within 28 of 47 evaluable cfDNA samples. Of these events, 30% could only be identified by harnessing the haplotype-aware approach leveraged in ACT-Discover. The exceptional purity of PDX tumours enabled near-complete phasing of genomic regions in allelic imbalance, highlighting an important auxiliary function of PDXs. Finally, although the classical model of pancreatic cancer evolution emphasises the importance of early, homogenous somatic events as a key requirement for cancer development, ACT-Discover identified substantial heterogeneity of SCNAs, including parallel focal and arm-level events, affecting different parental alleles within individual tumours. Indeed, ongoing acquisition of SCNAs was identified within tumours throughout the disease course, including within an untreated metastatic tumour. Conclusions This work demonstrates the power of haplotype phasing to study genomic variation in cfDNA samples and reveals undiscovered intra-tumour heterogeneity with important scientific and clinical implications. Implementation of ACT-Discover could lead to important insights from existing cohorts or underpin future prospective studies seeking to characterise the landscape of tumour evolution through liquid biopsy. This work was supported by the European Research Council (ERC) no. 670582 (Call: ERC-2014-ADG) to Dr. Hidalgo. R.A.T is supported by the Miguel Servet-II Research Award and the 2021 call for Proyectos de generación de conocimiento by the Institute of Health Carlos III (ISCIII) of the Ministry of Economy [CP17/00199], the Olga Torres Foundation Award to emerging researchers [2017, to R.A.T, 2601], and received research grants from Novartis, Astrazeneca, and Beigene pharmaceuticals, not related to this study. N.M is a Sir Henry Dale Fellow, jointly funded by the Wellcome Trust and the Royal Society (Grant Number 211179/Z/18/Z), and also receives funding from Cancer Research UK Lung Cancer Centre of Excellence, Rosetrees, and the NIHR BRC at University College London Hospitals.
Published: 2023
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49. An end-to-end pipeline based on open source deep learning tools for reliable analysis of complex 3D images of ovaries

Author: Manon Lesage, Manon Thomas, Thierry Pécot, Tu-Ky Ly, Nathalie Hinfray, Remy Beaudouin, Michelle Neumann, Robin Lovell-Badge, Jérôme Bugeon, Violette Thermes, Laboratoire de Physiologie et Génomique des Poissons (LPGP), Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique )-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE), Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique ), Institut National de l'Environnement Industriel et des Risques (INERIS), Stress Environnementaux et BIOsurveillance des milieux aquatiques (SEBIO), Institut National de l'Environnement Industriel et des Risques (INERIS)-Université de Reims Champagne-Ardenne (URCA)-Université Le Havre Normandie (ULH), Normandie Université (NU)-Normandie Université (NU)-SFR Condorcet, Université de Reims Champagne-Ardenne (URCA)-Centre National de la Recherche Scientifique (CNRS)-Université de Reims Champagne-Ardenne (URCA)-Centre National de la Recherche Scientifique (CNRS), and The Francis Crick Institute [London]
Subjects: Deep learning segmentation, Fish, 3D imaging, [SDV]Life Sciences [q-bio], Ovary, Clearing, Cellpose, Molecular Biology, Developmental Biology
Abstract: Computational analysis of bio-images by deep learning (DL) algorithms has made exceptional progress in recent years and has become much more accessible to non-specialists with the development of ready-to-use tools. The study of oogenesis mechanisms and female reproductive success has also recently benefited from the development of efficient protocols for three-dimensional (3D) imaging of ovaries. Such datasets have a great potential for generating new quantitative data but are, however, complex to analyze due to the lack of efficient workflows for 3D image analysis. Here, we have integrated two existing open-source DL tools, Noise2Void and Cellpose, into an analysis pipeline dedicated to 3D follicular content analysis, which is available on Fiji. Our pipeline was developed on larvae and adult medaka ovaries but was also successfully applied to different types of ovaries (trout, zebrafish and mouse). Image enhancement, Cellpose segmentation and post-processing of labels enabled automatic and accurate quantification of these 3D images, which exhibited irregular fluorescent staining, low autofluorescence signal or heterogeneous follicles sizes. In the future, this pipeline will be useful for extensive cellular phenotyping in fish or mammals for developmental or toxicology studies.
Published: 2023
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50. Tirap controls Mycobacterium tuberculosis phagosomal acidification

Author: Imène Belhaouane, Amine Pochet, Jonathan Chatagnon, Eik Hoffmann, Christophe J. Queval, Nathalie Deboosère, Céline Boidin-Wichlacz, Laleh Majlessi, Valentin Sencio, Séverine Heumel, Alexandre Vandeputte, Elisabeth Werkmeister, Laurence Fievez, Fabrice Bureau, Yves Rouillé, François Trottein, Mathias Chamaillard, Priscille Brodin, Arnaud Machelart, Centre d’Infection et d’Immunité de Lille - INSERM U 1019 - UMR 9017 - UMR 8204 (CIIL), Institut Pasteur de Lille, Réseau International des Instituts Pasteur (RIIP)-Réseau International des Instituts Pasteur (RIIP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Lille-Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille)-Centre National de la Recherche Scientifique (CNRS), The Francis Crick Institute [London], Laboratoire commun Pasteur-TheraVectys, Institut Pasteur [Paris] (IP)-TheraVectys-Université Paris Cité (UPCité), Plateformes Lilloises en Biologie et Santé - UAR 2014 - US 41 (PLBS), GIGA [Université Liège], Université de Liège, Laboratoire de Physiologie Cellulaire : Canaux ioniques, inflammation et cancer - U 1003 (PHYCELL), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Lille, Financial support for this work was provided by the Agence Nationale de la Recherche (n°ANR-16-CE35-0009 and ANR-18-JAM2-0002 to PB), the EMBO Young Investigator Program (to PB), the Feder (n°12001407 (D-AL) Equipex Imaginex BioMed to PB), the I-SITE ULNE Foundation (ERC Generator Grant to EH) and the Fondation pour la Recherche Medicale (n°SPF20170938709 to AM). Parts of this project were also supported under the framework of the JPIAMR – Joint Programming Initiative on Anti-microbial Resistance 2018-00969 (to PB, AM and JC)., ANR-16-CE35-0009,TBemerg,Naissance d'un tueur: facteurs génétiques et adaptations métaboliques impliquées dans l'émergence des bacilles tuberculeux épidémiques(2016), and ANR-18-JAM2-0002,MTI4MDR-TB(2018)
Subjects: Virology, [SDV]Life Sciences [q-bio], Immunology, Genetics, Parasitology, Molecular Biology, Microbiology
Abstract: Progression of tuberculosis is tightly linked to a disordered immune balance, resulting in inability of the host to restrict intracellular bacterial replication and its subsequent dissemination. The immune response is mainly characterized by an orchestrated recruitment of inflammatory cells secreting cytokines. This response results from the activation of innate immunity receptors that trigger downstream intracellular signaling pathways involving adaptor proteins such as the TIR-containing adaptor protein (Tirap). In humans, resistance to tuberculosis is associated with a loss-of-function in Tirap. Here, we explore how genetic deficiency in Tirap impacts resistance to Mycobacterium tuberculosis (Mtb) infection in a mouse model and ex vivo. Interestingly, compared to wild type littermates, Tirap heterozygous mice were more resistant to Mtb infection. Upon investigation at the cellular level, we observed that mycobacteria were not able to replicate in Tirap-deficient macrophages compared to wild type counterparts. We next showed that Mtb infection induced Tirap expression which prevented phagosomal acidification and rupture. We further demonstrate that the Tirap-mediated anti-tuberculosis effect occurs through a Cish-dependent signaling pathway. Our findings provide new molecular evidence about how Mtb manipulates innate immune signaling to enable intracellular replication and survival of the pathogen, thus paving the way for host-directed approaches to treat tuberculosis.
Published: 2023
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