15 results on '"Azrieli Foundation"'
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2. Modular adjuvant-free pan-HLA-DR-immunotargeting subunit vaccine against SARS-CoV-2 elicits broad sarbecovirus-neutralizing antibody responses
- Author
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Hospital for Sick Children (Canada), Canadian Institutes of Health Research, Azrieli Foundation, European Commission, Julien, Jean-Philippe [0000-0001-7602-3995], Kassardjian, Audrey, Sun, Eric, Sookhoo, Jamie, Muthuraman, Krithika, Boligan, Kayluz Frias, Kucharska, Iga, Rujas, Edurne, Jetha, Arif, Branch, Donald R., Babiuk, Shawn, Barber, Brian, Julien, Jean-Philippe, Hospital for Sick Children (Canada), Canadian Institutes of Health Research, Azrieli Foundation, European Commission, Julien, Jean-Philippe [0000-0001-7602-3995], Kassardjian, Audrey, Sun, Eric, Sookhoo, Jamie, Muthuraman, Krithika, Boligan, Kayluz Frias, Kucharska, Iga, Rujas, Edurne, Jetha, Arif, Branch, Donald R., Babiuk, Shawn, Barber, Brian, and Julien, Jean-Philippe
- Abstract
Subunit vaccines typically require co-administration with an adjuvant to elicit protective immunity, adding development hurdles that can impede rapid pandemic responses. To circumvent the need for adjuvant in a severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) subunit vaccine, we engineer a thermostable immunotargeting vaccine (ITV) that leverages the pan-HLA-DR monoclonal antibody 44H10 to deliver the viral spike protein receptor-binding domain (RBD) to antigen-presenting cells. X-ray crystallography shows that 44H10 binds to a conserved epitope on HLA-DR, providing the basis for its broad HLA-DR reactivity. Adjuvant-free ITV immunization in rabbits and ferrets induces robust anti-RBD antibody responses that neutralize SARS-CoV-2 variants of concern and protect recipients from SARS-CoV-2 challenge. We demonstrate that the modular nature of the ITV scaffold with respect to helper T cell epitopes and diverse RBD antigens facilitates broad sarbecovirus neutralization. Our findings support anti-HLA-DR immunotargeting as an effective means to induce strong antibody responses to subunit antigens without requiring an adjuvant.
- Published
- 2023
3. APLF and long non-coding RNA NIHCOLE promote stable DNA synapsis in non-homologous end joining
- Author
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Ministerio de Ciencia e Innovación (España), Agencia Estatal de Investigación (España), European Commission, Comunidad de Madrid, Consejo Superior de Investigaciones Científicas (España), Asociación Española Contra el Cáncer, Azrieli Foundation, EMBO, Instituto de Salud Carlos III, Bragança, Sara de, Aicart-Ramos, Clara, Arribas-Bosacoma, Raquel, Rivera-Calzada, Ángel, Unfried, Juan P., Prats-Mari, Laura, Marin-Baquero, Mikel, Fortes, Puri, Llorca, Óscar, Moreno-Herrero, Fernando, Ministerio de Ciencia e Innovación (España), Agencia Estatal de Investigación (España), European Commission, Comunidad de Madrid, Consejo Superior de Investigaciones Científicas (España), Asociación Española Contra el Cáncer, Azrieli Foundation, EMBO, Instituto de Salud Carlos III, Bragança, Sara de, Aicart-Ramos, Clara, Arribas-Bosacoma, Raquel, Rivera-Calzada, Ángel, Unfried, Juan P., Prats-Mari, Laura, Marin-Baquero, Mikel, Fortes, Puri, Llorca, Óscar, and Moreno-Herrero, Fernando
- Abstract
The synapsis of DNA ends is a critical step for the repair of double-strand breaks by non-homologous end joining (NHEJ). This is performed by a multicomponent protein complex assembled around Ku70-Ku80 heterodimers and regulated by accessory factors, including long non-coding RNAs, through poorly understood mechanisms. Here, we use magnetic tweezers to investigate the contributions of core NHEJ proteins and APLF and lncRNA NIHCOLE to DNA synapsis. APLF stabilizes DNA end bridging and, together with Ku70-Ku80, establishes a minimal complex that supports DNA synapsis for several minutes under piconewton forces. We find the C-terminal acidic region of APLF to be critical for bridging. NIHCOLE increases the dwell time of the synapses by Ku70-Ku80 and APLF. This effect is further enhanced by a small and structured RNA domain within NIHCOLE. We propose a model where Ku70-Ku80 can simultaneously bind DNA, APLF, and structured RNAs to promote the stable joining of DNA ends.
- Published
- 2023
4. Restoration of lysosomal acidification rescues autophagy and metabolic dysfunction in non-alcoholic fatty liver disease
- Author
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Boston University, Nanyang Technological University, Azrieli Foundation, National Institutes of Health (US), Zeng, Jialiu, Acín-Pérez, Rebeca, Assali, Essam A., Martin, Andrew, Brownstein, Alexandra J., Petcherski, Anton, Fernández del Río, Lucía, Xiao, Ruiqing, Hung Lo, Chih, Shum, Michaël, Liesa, Marc, Han, Xue, Shirihai, Orian S., Grinstaff, Mark W., Boston University, Nanyang Technological University, Azrieli Foundation, National Institutes of Health (US), Zeng, Jialiu, Acín-Pérez, Rebeca, Assali, Essam A., Martin, Andrew, Brownstein, Alexandra J., Petcherski, Anton, Fernández del Río, Lucía, Xiao, Ruiqing, Hung Lo, Chih, Shum, Michaël, Liesa, Marc, Han, Xue, Shirihai, Orian S., and Grinstaff, Mark W.
- Abstract
Non-alcoholic fatty liver disease (NAFLD) is the most common liver disease in the world. High levels of free fatty acids in the liver impair hepatic lysosomal acidification and reduce autophagic flux. We investigate whether restoration of lysosomal function in NAFLD recovers autophagic flux, mitochondrial function, and insulin sensitivity. Here, we report the synthesis of novel biodegradable acid-activated acidifying nanoparticles (acNPs) as a lysosome targeting treatment to restore lysosomal acidity and autophagy. The acNPs, composed of fluorinated polyesters, remain inactive at plasma pH, and only become activated in lysosomes after endocytosis. Specifically, they degrade at pH of ~6 characteristic of dysfunctional lysosomes, to further acidify and enhance the function of lysosomes. In established in vivo high fat diet mouse models of NAFLD, re-acidification of lysosomes via acNP treatment restores autophagy and mitochondria function to lean, healthy levels. This restoration, concurrent with reversal of fasting hyperglycemia and hepatic steatosis, indicates the potential use of acNPs as a first-in-kind therapeutic for NAFLD.
- Published
- 2023
5. Tunneling spectroscopy of few-monolayer NbSe2 in high magnetic fields: Triplet superconductivity and Ising protection
- Author
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Council for Higher Education (Israel), Agence Nationale de la Recherche (France), European Commission, European Research Council, Israel Science Foundation, Azrieli Foundation, Kuzmanović, Marko, Dvir, T., LeBoeuf, D., Ilić, Stefan, Haim, Menashe, Möckli, David, Krämer, Steffen, Khodas, M., Houzet, Manuel, Meyer, Julia S., Aprili, M., Steinberger, Hadar, Quay, C.H.L., Council for Higher Education (Israel), Agence Nationale de la Recherche (France), European Commission, European Research Council, Israel Science Foundation, Azrieli Foundation, Kuzmanović, Marko, Dvir, T., LeBoeuf, D., Ilić, Stefan, Haim, Menashe, Möckli, David, Krämer, Steffen, Khodas, M., Houzet, Manuel, Meyer, Julia S., Aprili, M., Steinberger, Hadar, and Quay, C.H.L.
- Abstract
In conventional Bardeen-Cooper-Schrieffer superconductors, Cooper pairs of electrons of opposite spin (i.e., singlet structure) form the ground state. Equal-spin triplet pairs (ESTPs), as in superfluid 3He, are of great interest for superconducting spintronics and topological superconductivity, yet remain elusive. Recently, odd-parity ESTPs were predicted to arise in (few-)monolayer superconducting NbSe2, from the noncollinearity between the out-of-plane Ising spin-orbit field (due to the lack of inversion symmetry in monolayer NbSe2) and an applied in-plane magnetic field. These ESTPs couple to the singlet order parameter at finite field. Using van der Waals tunnel junctions, we perform spectroscopy of superconducting NbSe2 flakes, of 2–25 monolayer thickness, measuring the quasiparticle density of states (DOS) as a function of applied in-plane magnetic field up to 33 T. In flakes ≲15 monolayers thick the DOS has a single superconducting gap. In these thin samples, the magnetic field acts primarily on the spin (vs orbital) degree of freedom of the electrons, and superconductivity is further protected by the Ising field. The superconducting energy gap, extracted from our tunneling spectra, decreases as a function of the applied magnetic field. However, in bilayer NbSe2, close to the critical field (up to 30 T, much larger than the Pauli limit), superconductivity appears to be more robust than expected from Ising protection alone. Our data can be explained by the above-mentioned ESTPs.
- Published
- 2022
6. The emerging landscape of single-molecule protein sequencing technologies
- Author
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Swiss National Science Foundation, National Institutes of Health (US), Welch Foundation, US Army Research Office, Erisyon, National Institute of General Medical Sciences (US), Wyss Institute of Biologically Inspired Engineering, Harvard Medical School, Peter and Traudl Engelhorn Foundation, Netherlands Organization for Scientific Research, Azrieli Foundation, Paul G. Allen Family Foundation, National Science Foundation (US), Human Frontier Science Program, Polish National Agency for Academic Exchange, European Commission, European Research Council, Fonds National de la Recherche Luxembourg, Adolphe Merkle Foundation, Michael J. Fox Foundation for Parkinson's Research, Swiss National Supercomputing Centre, Foundation for Polish Science, Genome British Columbia, Genome Canada, Alfaro, Javier Antonio [0000-0002-5553-6991], Dai, Mingjie [0000-0002-8665-4966], Filius, Mike [0000-0002-5434-8358], Pomorski, Adam [0000-0002-0669-3421], Schmid, Sonja [0000-0002-3710-5602], Aksimentiev, Aleksei [0000-0002-6042-8442], Anslyn, Eric V. [0000-0002-5137-8797], Cao, Chan [0000-0003-2592-0690], Hentz, Sébastien [0000-0003-0479-9027], Kalathiya, Umesh [0000-0001-7757-6962], Kelleher, Neil L. [0000-0002-8815-3372], Kuster, Bernhard [0000-0002-9094-1677], Rodríguez-Larrea, David [0000-0002-5580-7413], Maglia, Giovanni [0000-0003-2784-0811], Marino, John P. [0000-0002-6860-5853], Masselon, Christophe [0000-0003-0117-2480], Samaras, Patroklos [0000-0001-6042-1585], Stein, Derek [0000-0001-5917-4986], Wilhelm, Mathias [0000-0002-9224-3258], Yin, Peng [0000-0002-2769-6357], Meller, Amit [0000-0001-7082-0985], Joo, Chirlmin [0000-0003-2803-0335], Alfaro, Javier Antonio, Bohländer, Peggy, Dai, Mingjie, Filius, Mike, Howard, Cecil J., Kooten, Xander F. van, Ohayon, Shilo, Pomorski, Adam, Schmid, Sonja, Aksimentiev, Aleksei, Anslyn, Eric V., Bedran, Georges, Cao, Chan, Chinappi, Mauro, Coyaud, Etienne, Dekker, Cees, Dittmar, Gunnar, Drachman, Nicholas, Eelkema, Rienk, Goodlett, David, Hentz, Sébastien, Kalathiya, Umesh, Kelleher, Neil L., Kelly, Ryan T., Kelman, Zvi, Kim, Sung Hyun, Kuster, Bernhard, Rodríguez-Larrea, David, Lindsay, Stuart, Maglia, Giovanni, Marcotte, Edward M., Marino, John P., Masselon, Christophe, Mayer, Michael, Samaras, Patroklos, Sarthak, Kumar, Sepiashvili, Lusia, Stein, Derek, Wanunu, Meni, Wilhelm, Mathias, Yin, Peng, Meller, Amit, Joo, Chirlmin, Swiss National Science Foundation, National Institutes of Health (US), Welch Foundation, US Army Research Office, Erisyon, National Institute of General Medical Sciences (US), Wyss Institute of Biologically Inspired Engineering, Harvard Medical School, Peter and Traudl Engelhorn Foundation, Netherlands Organization for Scientific Research, Azrieli Foundation, Paul G. Allen Family Foundation, National Science Foundation (US), Human Frontier Science Program, Polish National Agency for Academic Exchange, European Commission, European Research Council, Fonds National de la Recherche Luxembourg, Adolphe Merkle Foundation, Michael J. Fox Foundation for Parkinson's Research, Swiss National Supercomputing Centre, Foundation for Polish Science, Genome British Columbia, Genome Canada, Alfaro, Javier Antonio [0000-0002-5553-6991], Dai, Mingjie [0000-0002-8665-4966], Filius, Mike [0000-0002-5434-8358], Pomorski, Adam [0000-0002-0669-3421], Schmid, Sonja [0000-0002-3710-5602], Aksimentiev, Aleksei [0000-0002-6042-8442], Anslyn, Eric V. [0000-0002-5137-8797], Cao, Chan [0000-0003-2592-0690], Hentz, Sébastien [0000-0003-0479-9027], Kalathiya, Umesh [0000-0001-7757-6962], Kelleher, Neil L. [0000-0002-8815-3372], Kuster, Bernhard [0000-0002-9094-1677], Rodríguez-Larrea, David [0000-0002-5580-7413], Maglia, Giovanni [0000-0003-2784-0811], Marino, John P. [0000-0002-6860-5853], Masselon, Christophe [0000-0003-0117-2480], Samaras, Patroklos [0000-0001-6042-1585], Stein, Derek [0000-0001-5917-4986], Wilhelm, Mathias [0000-0002-9224-3258], Yin, Peng [0000-0002-2769-6357], Meller, Amit [0000-0001-7082-0985], Joo, Chirlmin [0000-0003-2803-0335], Alfaro, Javier Antonio, Bohländer, Peggy, Dai, Mingjie, Filius, Mike, Howard, Cecil J., Kooten, Xander F. van, Ohayon, Shilo, Pomorski, Adam, Schmid, Sonja, Aksimentiev, Aleksei, Anslyn, Eric V., Bedran, Georges, Cao, Chan, Chinappi, Mauro, Coyaud, Etienne, Dekker, Cees, Dittmar, Gunnar, Drachman, Nicholas, Eelkema, Rienk, Goodlett, David, Hentz, Sébastien, Kalathiya, Umesh, Kelleher, Neil L., Kelly, Ryan T., Kelman, Zvi, Kim, Sung Hyun, Kuster, Bernhard, Rodríguez-Larrea, David, Lindsay, Stuart, Maglia, Giovanni, Marcotte, Edward M., Marino, John P., Masselon, Christophe, Mayer, Michael, Samaras, Patroklos, Sarthak, Kumar, Sepiashvili, Lusia, Stein, Derek, Wanunu, Meni, Wilhelm, Mathias, Yin, Peng, Meller, Amit, and Joo, Chirlmin
- Abstract
Single-cell profiling methods have had a profound impact on the understanding of cellular heterogeneity. While genomes and transcriptomes can be explored at the single-cell level, single-cell profiling of proteomes is not yet established. Here we describe new single-molecule protein sequencing and identification technologies alongside innovations in mass spectrometry that will eventually enable broad sequence coverage in single-cell profiling. These technologies will in turn facilitate biological discovery and open new avenues for ultrasensitive disease diagnostics.
- Published
- 2021
7. Focal accumulation of aromaticity at the CDRH3 loop mitigates 4E10 polyreactivity without altering its HIV neutralization profile
- Author
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European Commission, National Institutes of Health (US), James B. Pendleton Charitable Trust, Japan Society for the Promotion of Science, Ministerio de Ciencia, Innovación y Universidades (España), Agencia Estatal de Investigación (España), Eusko Jaurlaritza, Medical Research Council (UK), Wolfson Foundation, German Research Foundation, Leibniz Association, Wellcome Trust, John Fell Fund, Japan Agency for Medical Research and Development, Universidad del País Vasco, Azrieli Foundation, Canada Research Chairs, Ontario Research Fund, Carravilla, Pablo [0000-0001-6592-7630], Iloro, Ibon [0000-0002-9537-1714], Elortza, Félix [0000-0001-8839-5438], Julien, Jean-Philippe [0000-0001-7602-3995], Caaveiro, José M. M. [0000-0001-5568-2369], Rujas, Edurne, Leaman, Daniel P., Insausti, Sara, Carravilla, Pablo, García-Porras, Miguel, Largo, Eneko, Morillo, Izaskun, Sánchez-Eugenia, Rubén, Zhang, Lei, Cui, Hong, Iloro, Ibon, Elortza, Félix, Julien, Jean-Philippe, Eggeling, Christian, Zwick, Michael B., Caaveiro, José M. M., Nieva, José Luis, European Commission, National Institutes of Health (US), James B. Pendleton Charitable Trust, Japan Society for the Promotion of Science, Ministerio de Ciencia, Innovación y Universidades (España), Agencia Estatal de Investigación (España), Eusko Jaurlaritza, Medical Research Council (UK), Wolfson Foundation, German Research Foundation, Leibniz Association, Wellcome Trust, John Fell Fund, Japan Agency for Medical Research and Development, Universidad del País Vasco, Azrieli Foundation, Canada Research Chairs, Ontario Research Fund, Carravilla, Pablo [0000-0001-6592-7630], Iloro, Ibon [0000-0002-9537-1714], Elortza, Félix [0000-0001-8839-5438], Julien, Jean-Philippe [0000-0001-7602-3995], Caaveiro, José M. M. [0000-0001-5568-2369], Rujas, Edurne, Leaman, Daniel P., Insausti, Sara, Carravilla, Pablo, García-Porras, Miguel, Largo, Eneko, Morillo, Izaskun, Sánchez-Eugenia, Rubén, Zhang, Lei, Cui, Hong, Iloro, Ibon, Elortza, Félix, Julien, Jean-Philippe, Eggeling, Christian, Zwick, Michael B., Caaveiro, José M. M., and Nieva, José Luis
- Abstract
Broadly neutralizing antibodies (bnAbs) against HIV-1 are frequently associated with the presence of autoreactivity/polyreactivity, a property that can limit their use as therapeutic agents. The bnAb 4E10, targeting the conserved Membrane proximal external region (MPER) of HIV-1, displays almost pan-neutralizing activity across globally circulating HIV-1 strains but exhibits nonspecific off-target interactions with lipid membranes. The hydrophobic apex of the third complementarity-determining region of the heavy chain (CDRH3) loop, which is essential for viral neutralization, critically contributes to this detrimental effect. Here, we have replaced the aromatic/hydrophobic residues from the apex of the CDRH3 of 4E10 with a single aromatic molecule through chemical modification to generate a variant that preserves the neutralization potency and breadth of 4E10 but with reduced autoreactivity. Collectively, our study suggests that the localized accumulation of aromaticity by chemical modification provides a pathway to ameliorate the adverse effects triggered by the CDRH3 of anti-HIV-1 MPER bnAbs.
- Published
- 2021
8. Structural characterization of the ICOS/ICOS-L immune complex reveals high molecular mimicry by therapeutic antibodies
- Author
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Canadian Institutes of Health Research, Azrieli Foundation, Julien, Jean-Philippe [0000-0001-7602-3995], Rujas, Edurne, Cui, Hong, Sicard, Taylor, Semesi, Anthony, Julien, Jean-Philippe, Canadian Institutes of Health Research, Azrieli Foundation, Julien, Jean-Philippe [0000-0001-7602-3995], Rujas, Edurne, Cui, Hong, Sicard, Taylor, Semesi, Anthony, and Julien, Jean-Philippe
- Abstract
The inducible co-stimulator (ICOS) is a member of the CD28/B7 superfamily, and delivers a positive co-stimulatory signal to activated T cells upon binding to its ligand (ICOS-L). Dysregulation of this pathway has been implicated in autoimmune diseases and cancer, and is currently under clinical investigation as an immune checkpoint blockade. Here, we describe the molecular interactions of the ICOS/ICOS-L immune complex at 3.3 Å resolution. A central FDPPPF motif and residues within the CC' loop of ICOS are responsible for the specificity of the interaction with ICOS-L, with a distinct receptor binding orientation in comparison to other family members. Furthermore, our structure and binding data reveal that the ICOS N110 N-linked glycan participates in ICOS-L binding. In addition, we report crystal structures of ICOS and ICOS-L in complex with monoclonal antibodies under clinical evaluation in immunotherapy. Strikingly, antibody paratopes closely mimic receptor-ligand binding core interactions, in addition to contacting peripheral residues to confer high binding affinities. Our results uncover key molecular interactions of an immune complex central to human adaptive immunity and have direct implications for the ongoing development of therapeutic interventions targeting immune checkpoint receptors.
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- 2020
9. Affinity for the Interface Underpins Potency of Antibodies Operating In Membrane Environments
- Author
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Eusko Jaurlaritza, Universidad del País Vasco, European Commission, National Institutes of Health (US), James B. Pendleton Charitable Trust, Japan Society for the Promotion of Science, Ministerio de Economía y Competitividad (España), Ministerio de Ciencia, Innovación y Universidades (España), Agencia Estatal de Investigación (España), Medical Research Council (UK), German Research Foundation, Wolfson Foundation, Wellcome Trust, Azrieli Foundation, Canada Research Chairs, Japan Agency for Medical Research and Development, Carravilla, Pablo [0000-0001-6592-7630], Sáez-Cirión, Asier [0000-0003-2406-7536], Eggeling, Christian [0000-0002-3698-5599], Caaveiro, José M. M. [0000-0001-5568-2369], Rujas, Edurne, Insausti, Sara, Leaman, Daniel P., Carravilla, Pablo, González-Resines, Saúl, Monceaux, Valérie, Sánchez-Eugenia, Rubén, García-Porras, Miguel, Iloro, Ibon, Zhang, Lei, Elortza, Félix, Julien, Jean-Philippe, Sáez-Cirión, Asier, Zwick, Michael B., Eggeling, Christian, Ojida, Akio, Domene, Carmen, Caaveiro, José M. M., Nieva, José Luis, Eusko Jaurlaritza, Universidad del País Vasco, European Commission, National Institutes of Health (US), James B. Pendleton Charitable Trust, Japan Society for the Promotion of Science, Ministerio de Economía y Competitividad (España), Ministerio de Ciencia, Innovación y Universidades (España), Agencia Estatal de Investigación (España), Medical Research Council (UK), German Research Foundation, Wolfson Foundation, Wellcome Trust, Azrieli Foundation, Canada Research Chairs, Japan Agency for Medical Research and Development, Carravilla, Pablo [0000-0001-6592-7630], Sáez-Cirión, Asier [0000-0003-2406-7536], Eggeling, Christian [0000-0002-3698-5599], Caaveiro, José M. M. [0000-0001-5568-2369], Rujas, Edurne, Insausti, Sara, Leaman, Daniel P., Carravilla, Pablo, González-Resines, Saúl, Monceaux, Valérie, Sánchez-Eugenia, Rubén, García-Porras, Miguel, Iloro, Ibon, Zhang, Lei, Elortza, Félix, Julien, Jean-Philippe, Sáez-Cirión, Asier, Zwick, Michael B., Eggeling, Christian, Ojida, Akio, Domene, Carmen, Caaveiro, José M. M., and Nieva, José Luis
- Abstract
The contribution of membrane interfacial interactions to recognition of membrane-embedded antigens by antibodies is currently unclear. This report demonstrates the optimization of this type of antibodies via chemical modification of regions near the membrane but not directly involved in the recognition of the epitope. Using the HIV-1 antibody 10E8 as a model, linear and polycyclic synthetic aromatic compounds are introduced at selected sites. Molecular dynamics simulations predict the favorable interactions of these synthetic compounds with the viral lipid membrane, where the epitope of the HIV-1 glycoprotein Env is located. Chemical modification of 10E8 with aromatic acetamides facilitates the productive and specific recognition of the native antigen, partially buried in the crowded environment of the viral membrane, resulting in a dramatic increase of its capacity to block viral infection. These observations support the harnessing of interfacial affinity through site-selective chemical modification to optimize the function of antibodies that target membrane-proximal epitopes.
- Published
- 2020
10. APLF and long non-coding RNA NIHCOLE promote stable DNA synapsis in non-homologous end joining
- Author
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Sara De Bragança, Clara Aicart-Ramos, Raquel Arribas-Bosacoma, Angel Rivera-Calzada, Juan Pablo Unfried, Laura Prats-Mari, Mikel Marin-Baquero, Puri Fortes, Oscar Llorca, Fernando Moreno-Herrero, Ministerio de Ciencia e Innovación (España), Agencia Estatal de Investigación (España), European Commission, Comunidad de Madrid, Consejo Superior de Investigaciones Científicas (España), Asociación Española Contra el Cáncer, Azrieli Foundation, EMBO, and Instituto de Salud Carlos III
- Subjects
Magnetic tweezers ,Molecular biology [CP] ,APLF ,DNA ligase IV ,Ku70-Ku80 ,Single-molecule ,Xrcc4 ,XLF ,General Biochemistry, Genetics and Molecular Biology ,non-homologous end joining ,lncRNA ,single-molecule ,Non-homologous end joining ,magnetic tweezers ,NHEJ - Abstract
The synapsis of DNA ends is a critical step for the repair of double-strand breaks by non-homologous end joining (NHEJ). This is performed by a multicomponent protein complex assembled around Ku70-Ku80 heterodimers and regulated by accessory factors, including long non-coding RNAs, through poorly understood mechanisms. Here, we use magnetic tweezers to investigate the contributions of core NHEJ proteins and APLF and lncRNA NIHCOLE to DNA synapsis. APLF stabilizes DNA end bridging and, together with Ku70-Ku80, establishes a minimal complex that supports DNA synapsis for several minutes under piconewton forces. We find the C-terminal acidic region of APLF to be critical for bridging. NIHCOLE increases the dwell time of the synapses by Ku70-Ku80 and APLF. This effect is further enhanced by a small and structured RNA domain within NIHCOLE. We propose a model where Ku70-Ku80 can simultaneously bind DNA, APLF, and structured RNAs to promote the stable joining of DNA ends., This work was funded by grants PID2020-114429RB-I00 to O.L., PID2020-112998GB-I00 (open access) to F.M.-H., RTI2018-101759-B-I00 to P.F., and PID2021-1287910B-I00 to P.F., funded by Ministerio de Ciencia e Innovación (MICINN)/Agencia Estatal de Investigación (AEI/10.13039/501100011 033)_FEDER, EU, and co-funded by the European Regional Development Fund (ERDF); grants Y2018/BIO4747 and P2018/NMT4443 to both O.L. and F.M.-H., funded by the Autonomous Region of Madrid and co-funded by the European Social Fund (ESF) and the ERDF; grant EUREXCEL ref. 951214 to F. M.-H., funded by the CSIC; grant AECC IDEAS20169FORT to P.F., funded by the Scientific Foundation of the Spanish Association Against Cancer, and by the Instituto de Salud Carlos III (ISCIII), which supports CNIO, CIBEREhd, and TERAV ISCIII, funded by the European Union – NextGenerationEU, Plan de recuperación Transformación y Resiliencia. J.P.U. is a recipient of the Azrieli Foundation International Postdoctoral Fellowship, the Excellence Fellowship Program for International Postdoctoral from Israel CHE/IASH, and an EMBO Postdoctoral Fellowship. L.P.M. is a recipient of a PFIS fellowship (FI20/00074) by the ISCIII and ESF “Investing in Your Future”. M.M.-B. acknowledges support from MICINN as a recipient of an FPI fellowship (PRE2018-083464).
- Published
- 2023
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11. Tunneling spectroscopy of few-monolayer NbSe 2 in high magnetic fields: Triplet superconductivity and Ising protection
- Author
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M. Kuzmanović, T. Dvir, D. LeBoeuf, S. Ilić, M. Haim, D. Möckli, S. Kramer, M. Khodas, M. Houzet, J. S. Meyer, M. Aprili, H. Steinberg, C. H. L. Quay, Laboratoire de Physique des Solides (LPS), Université Paris-Saclay-Centre National de la Recherche Scientifique (CNRS), Aalto University School of Science and Technology [Aalto, Finland], The Hebrew University of Jerusalem (HUJ), Delft University of Technology (TU Delft), Laboratoire national des champs magnétiques intenses - Grenoble (LNCMI-G ), Université Toulouse III - Paul Sabatier (UT3), Université de Toulouse (UT)-Université de Toulouse (UT)-Centre National de la Recherche Scientifique (CNRS)-Université Grenoble Alpes (UGA), Laboratory of Quantum Theory (GT), PHotonique, ELectronique et Ingénierie QuantiqueS (PHELIQS), 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)-Université Grenoble Alpes (UGA)-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), Centro de Fisica de Materiales (CFM), Universidad del Pais Vasco / Euskal Herriko Unibertsitatea [Espagne] (UPV/EHU)-Consejo Superior de Investigaciones Científicas [Madrid] (CSIC), Universidade Federal do Rio Grande do Sul [Porto Alegre] (UFRGS), Laboratoire national des champs magnétiques intenses - Toulouse (LNCMI-T), Institut National des Sciences Appliquées - Toulouse (INSA Toulouse), Institut National des Sciences Appliquées (INSA)-Université de Toulouse (UT)-Institut National des Sciences Appliquées (INSA)-Université de Toulouse (UT)-Université Toulouse III - Paul Sabatier (UT3), Université de Toulouse (UT)-Centre National de la Recherche Scientifique (CNRS)-Université Grenoble Alpes (UGA), ANR-10-LABX-0051,LANEF,Laboratory of Alliances on Nanosciences - Energy for the Future(2010), European Project: 637928,H2020,ERC-2014-STG,TUNNEL(2015), Council for Higher Education (Israel), Agence Nationale de la Recherche (France), European Commission, European Research Council, Israel Science Foundation, Azrieli Foundation, Superconducting Qubits and Circuit QED, Hebrew University of Jerusalem, Université Grenoble Alpes, Université Paris-Saclay, Department of Applied Physics, Aalto-yliopisto, and Aalto University
- Subjects
[PHYS]Physics [physics] ,[SPI]Engineering Sciences [physics] - Abstract
In conventional Bardeen-Cooper-Schrieffer superconductors, Cooper pairs of electrons of opposite spin (i.e., singlet structure) form the ground state. Equal-spin triplet pairs (ESTPs), as in superfluid 3He, are of great interest for superconducting spintronics and topological superconductivity, yet remain elusive. Recently, odd-parity ESTPs were predicted to arise in (few-)monolayer superconducting NbSe2, from the noncollinearity between the out-of-plane Ising spin-orbit field (due to the lack of inversion symmetry in monolayer NbSe2) and an applied in-plane magnetic field. These ESTPs couple to the singlet order parameter at finite field. Using van der Waals tunnel junctions, we perform spectroscopy of superconducting NbSe2 flakes, of 2–25 monolayer thickness, measuring the quasiparticle density of states (DOS) as a function of applied in-plane magnetic field up to 33 T. In flakes ≲15 monolayers thick the DOS has a single superconducting gap. In these thin samples, the magnetic field acts primarily on the spin (vs orbital) degree of freedom of the electrons, and superconductivity is further protected by the Ising field. The superconducting energy gap, extracted from our tunneling spectra, decreases as a function of the applied magnetic field. However, in bilayer NbSe2, close to the critical field (up to 30 T, much larger than the Pauli limit), superconductivity appears to be more robust than expected from Ising protection alone. Our data can be explained by the above-mentioned ESTPs., This work was funded by a Maimonides-Israel grant from the Israeli-French High Council for Scientific and Technological Research; JCJC (SPINOES), PIRE (HYBRID), and PRC (TRIPRES) grants from the French Agence Nationale de Recherche; European Research Council Starting Grant No. ERC-2014-STG 637928 (TUNNEL); Israel Science Foundation Grants No. 861/19 and No. 2665/20, and the Laboratoire d’Excellence LANEF in Grenoble (ANR10-LABX-51-01). T.D. is grateful to the Azrieli Foundation for an Azrieli Fellowship. Part of this work has been performed at the Laboratoire National de Champs Magnétiques Intenses (LNCMI), a member of the European Magnetic Field Laboratory (EMFL).
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- 2022
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12. Focal accumulation of aromaticity at the CDRH3 loop mitigates 4E10 polyreactivity without altering its HIV neutralization profile
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José L. Nieva, Eneko Largo, Daniel P. Leaman, Michael B. Zwick, Jean-Philippe Julien, Felix Elortza, Miguel García-Porras, Edurne Rujas, Sara Insausti, Pablo Carravilla, Lei Zhang, Christian Eggeling, Hong Cui, Jose M. M. Caaveiro, Izaskun Morillo, Rubén Sánchez-Eugenia, Ibon Iloro, European Commission, National Institutes of Health (US), James B. Pendleton Foundation, Japan Society for the Promotion of Science, Ministerio de Ciencia, Innovación y Universidades (España), Agencia Estatal de Investigación (España), Eusko Jaurlaritza, Medical Research Council (UK), Wolfson Foundation, Deutsche Forschungsgemeinschaft, Leibniz Association, Wellcome Trust, John Fell Fund, Japan Agency for Medical Research and Development, Universidad del País Vasco, Azrieli Foundation, Canada Research Chairs, Ontario Research Fund, Carravilla, Pablo, Iloro, Ibon, Elortza, Félix, Julien, Jean-Philippe, and Caaveiro, José M. M.
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Science ,Immunology ,Human immunodeficiency virus (HIV) ,medicine.disease_cause ,Article ,Neutralization ,03 medical and health sciences ,0302 clinical medicine ,Virology ,medicine ,health care economics and organizations ,030304 developmental biology ,0303 health sciences ,Heavy chain ,Multidisciplinary ,biology ,Chemistry ,Chemical modification ,Aromaticity ,3. Good health ,Membrane ,Biophysics ,biology.protein ,Antibody ,030217 neurology & neurosurgery - Abstract
Summary Broadly neutralizing antibodies (bnAbs) against HIV-1 are frequently associated with the presence of autoreactivity/polyreactivity, a property that can limit their use as therapeutic agents. The bnAb 4E10, targeting the conserved Membrane proximal external region (MPER) of HIV-1, displays almost pan-neutralizing activity across globally circulating HIV-1 strains but exhibits nonspecific off-target interactions with lipid membranes. The hydrophobic apex of the third complementarity-determining region of the heavy chain (CDRH3) loop, which is essential for viral neutralization, critically contributes to this detrimental effect. Here, we have replaced the aromatic/hydrophobic residues from the apex of the CDRH3 of 4E10 with a single aromatic molecule through chemical modification to generate a variant that preserves the neutralization potency and breadth of 4E10 but with reduced autoreactivity. Collectively, our study suggests that the localized accumulation of aromaticity by chemical modification provides a pathway to ameliorate the adverse effects triggered by the CDRH3 of anti-HIV-1 MPER bnAbs., Graphical abstract, Highlights • Aromatic grafting is employed to improve functionality of the HIV antibody 4E10 • Engineering the CDRH3 loop slashes its polyreactivity profile but also its potency • Site-specific chemical modification rescues the activity of the engineered antibody • Collectively, this procedure mitigates the polyreactivity of an MPER antibody, Immunology; Virology
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- 2021
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13. Extensive RNA editing and splicing increase immune self-representation diversity in medullary thymic epithelial cells
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Clotilde Guyon, Erez Y. Levanon, Matthieu Giraud, Miri Danan-Gotthold, Jakub Abramson, The Mina & Everard Goodman Faculty of Life Sciences [Ramat Gan, Israël], Université Bar-Ilan [Israel], [Institut Cochin] Departement Infection, immunité, inflammation, Institut Cochin ( UM3 (UMR 8104 / U1016) ), Université Paris Descartes - Paris 5 ( UPD5 ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Centre National de la Recherche Scientifique ( CNRS ) -Université Paris Descartes - Paris 5 ( UPD5 ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Centre National de la Recherche Scientifique ( CNRS ), Department of Immunology [Rehovot, Israël], Weizmann Institute of Science, This work was supported by EYL: The European Research Council (grant no. 311257), the I-CORE Program of the Planning and Budgeting Committee in Israel (grant nos. 41/11 and 1796/12), and the Israel Science Foundation (1380/14).JA: Israel Science Foundation (1825/10), Sy Syms Foundation, Dr. Celia Zwillenberg-Fridman and Dr. Lutz Fridman Career Development Chair.MGi: The Agence Nationale de Recherche (2011-CHEX-001-R12004KK).MDG is grateful to the Azrieli Foundation for the award of an Azrieli Fellowship., Bos, Mireille, Bar-Ilan University [Israël], Institut Cochin (IC UM3 (UMR 8104 / U1016)), Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), and Weizmann Institute of Science [Rehovot, Israël]
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0301 basic medicine ,Cell type ,RNA editing ,[SDV]Life Sciences [q-bio] ,T-Lymphocytes ,Thymus Gland ,Biology ,Self-tolerance ,Autoantigens ,03 medical and health sciences ,Mice ,Immune system ,Antigen ,Gene expression ,[SDV.BBM] Life Sciences [q-bio]/Biochemistry, Molecular Biology ,Animals ,Humans ,[SDV.BBM]Life Sciences [q-bio]/Biochemistry, Molecular Biology ,Gene ,[ SDV.BBM ] Life Sciences [q-bio]/Biochemistry, Molecular Biology ,[ SDV ] Life Sciences [q-bio] ,Research ,Alternative splicing ,RNA sequencing ,Cell Differentiation ,Epithelial Cells ,Molecular biology ,Cell biology ,Thymus ,Alternative Splicing ,030104 developmental biology ,Self Tolerance ,Medullary thymic epithelial cells (mTECs) ,Gene Expression Regulation ,RNA splicing ,Transcription Factors - Abstract
Background In order to become functionally competent but harmless mediators of the immune system, T cells undergo a strict educational program in the thymus, where they learn to discriminate between self and non-self. This educational program is, to a large extent, mediated by medullary thymic epithelial cells that have a unique capacity to express, and subsequently present, a large fraction of body antigens. While the scope of promiscuously expressed genes by medullary thymic epithelial cells is well-established, relatively little is known about the expression of variants that are generated by co-transcriptional and post-transcriptional processes. Results Our study reveals that in comparison to other cell types, medullary thymic epithelial cells display significantly higher levels of alternative splicing, as well as A-to-I and C-to-U RNA editing, which thereby further expand the diversity of their self-antigen repertoire. Interestingly, Aire, the key mediator of promiscuous gene expression in these cells, plays a limited role in the regulation of these transcriptional processes. Conclusions Our results highlight RNA processing as another layer by which the immune system assures a comprehensive self-representation in the thymus which is required for the establishment of self-tolerance and prevention of autoimmunity. Electronic supplementary material The online version of this article (doi:10.1186/s13059-016-1079-9) contains supplementary material, which is available to authorized users.
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- 2016
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14. The excludon: a new concept in bacterial antisense RNA-mediated gene regulation
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Cristel Archambaud, Pascale Cossart, Omri Wurtzel, Nina Sesto, Rotem Sorek, Interactions Bactéries-Cellules (UIBC), Institut National de la Recherche Agronomique (INRA)-Institut Pasteur [Paris]-Institut National de la Santé et de la Recherche Médicale (INSERM), Weizmann Institute of Science [Rehovot, Israël], Pasteur-Weizmann programme, European Research Council [233348, 260432], French Agence Nationale de la Recherche [Bacregrna 09-BLAN-0024-02, BacNet 10-BINF-02-01], Fondation Le Roth Les Mousquetaires, Fondation Louis-Jeantet, German Minerva Foundation, Deutsche Forschungsgemeinschaft, French Institute National de la Recherche Agronomique, Azrieli Foundation, ANR-09-BLAN-0024,BACREGRNA,Régulation ARN-dépendante dans deux bactéries pathogènes gram positive, Listeria monocytogenes et Staphylococcus aureus(2009), ANR-10-BINF-0002,BACNET,Exploring composition and dynamics of bacterial regulatory networks(2010), and Institut National de la Recherche Agronomique (INRA)-Institut Pasteur [Paris] (IP)-Institut National de la Santé et de la Recherche Médicale (INSERM)
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EXPRESSION ,Operon ,[SDV]Life Sciences [q-bio] ,Locus (genetics) ,Biology ,GADY ,Microbiology ,MECHANISMS ,03 medical and health sciences ,Gene expression ,medicine ,TRANSCRIPTOME ,LISTERIA-MONOCYTOGENES ,Gene ,ComputingMilieux_MISCELLANEOUS ,030304 developmental biology ,Genetics ,Regulation of gene expression ,0303 health sciences ,Messenger RNA ,General Immunology and Microbiology ,IDENTIFICATION ,030306 microbiology ,DEGRADATION ,Antisense RNA ,Infectious Diseases ,Mechanism of action ,ESCHERICHIA-COLI ,DEPENDENT SMALL RNA ,medicine.symptom ,MESSENGER-RNA - Abstract
International audience; In recent years, non-coding RNAs have emerged as key regulators of gene expression. Among these RNAs, the antisense RNAs (asRNAs) are particularly abundant, but in most cases the function and mechanism of action for a particular asRNA remains elusive. Here, we highlight a recently discovered paradigm termed the excludon, which defines a genomic locus encoding an unusually long asRNA that spans divergent genes or operons with related or opposing functions. Because these asRNAs can inhibit the expression of one operon while functioning as an mRNA for the adjacent operon, they act as fine-tuning regulatory switches in bacteria.
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- 2013
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15. The emerging landscape of single-molecule protein sequencing technologies
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Patroklos Samaras, Cecil J Howard, Aleksei Aksimentiev, Amit Meller, Derek Stein, Mike Filius, Chan Cao, Rienk Eelkema, Georges Bedran, Adam Pomorski, David R. Goodlett, Zvi Kelman, Nicholas Drachman, Stuart Lindsay, Meni Wanunu, Sonja Schmid, Chirlmin Joo, Etienne Coyaud, Peggy R. Bohländer, Neil L. Kelleher, Giovanni Maglia, Ryan T. Kelly, Michael Mayer, Umesh Kalathiya, Edward M. Marcotte, Eric V. Anslyn, Mingjie Dai, Shilo Ohayon, Kumar Sarthak, Peng Yin, Sebastien Hentz, Sung Hyun Kim, Mauro Chinappi, Javier A. Alfaro, Gunnar Dittmar, John P. Marino, Christophe Masselon, Bernhard Kuster, David Rodriguez-Larrea, Mathias Wilhelm, Xander F. van Kooten, Cees Dekker, Lusia Sepiashvili, Swiss National Science Foundation, National Institutes of Health (US), Welch Foundation, US Army Research Office, Erisyon, National Institute of General Medical Sciences (US), Wyss Institute of Biologically Inspired Engineering, Harvard Medical School, Peter and Traudl Engelhorn Foundation, Netherlands Organization for Scientific Research, Azrieli Foundation, Paul G. Allen Family Foundation, National Science Foundation (US), Human Frontier Science Program, Polish National Agency for Academic Exchange, European Commission, European Research Council, Fonds National de la Recherche Luxembourg, Adolphe Merkle Foundation, Michael J. Fox Foundation for Parkinson's Research, Swiss National Supercomputing Centre, Foundation for Polish Science, Genome British Columbia, Genome Canada, Alfaro, Javier Antonio, Dai, Mingjie, Filius, Mike, Pomorski, Adam, Schmid, Sonja, Aksimentiev, Aleksei, Anslyn, Eric V., Cao, Chan, Hentz, Sébastien, Kalathiya, Umesh, Kelleher, Neil L., Kuster, Bernhard, Rodríguez-Larrea, David, Maglia, Giovanni, Marino, John P., Masselon, Christophe, Samaras, Patroklos, Stein, Derek, Wilhelm, Mathias, Yin, Peng, Meller, Amit, Joo, Chirlmin, University of Gdańsk (UG), Delft University of Technology (TU Delft), Harvard University, Harvard Medical School [Boston] (HMS), University of Texas at Austin [Austin], Technion - Israel Institute of Technology [Haifa], Wageningen University and Research [Wageningen] (WUR), University of Illinois at Urbana-Champaign [Urbana], University of Illinois System, Ecole Polytechnique Fédérale de Lausanne (EPFL), Università degli Studi di Roma Tor Vergata [Roma], CHU Lille, Protéomique, Réponse Inflammatoire, Spectrométrie de Masse (PRISM) - U 1192 (PRISM), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Lille-Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille), Luxembourg Institute of Health (LIH), University of Luxembourg [Luxembourg], Brown University, University of Victoria [Canada] (UVIC), Commissariat à l'énergie atomique et aux énergies alternatives - Laboratoire d'Electronique et de Technologie de l'Information (CEA-LETI), Direction de Recherche Technologique (CEA) (DRT (CEA)), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA), Université Grenoble Alpes (UGA), Northwestern University [Evanston], Brigham Young University (BYU), Institute for Bioscience and Biotechnology Research [Rockville, MD, États-Unis] (IBBR), University of Maryland [College Park], University of Maryland System-University of Maryland System, Technische Universität Munchen - Université Technique de Munich [Munich, Allemagne] (TUM), Universidad del Pais Vasco / Euskal Herriko Unibertsitatea [Espagne] (UPV/EHU), Arizona State University [Tempe] (ASU), University of Groningen [Groningen], Laboratoire de Biologie à Grande Échelle (BGE - UMR S1038), Institut National de la Santé et de la Recherche Médicale (INSERM)-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)-Université Grenoble Alpes (UGA), Université de Fribourg = University of Fribourg (UNIFR), University of Toronto, Northeastern University [Boston], Harvard University [Cambridge], University of Fribourg, Bruley, Christophe, INSERM, Université de Lille, Medical University of Gdańsk, Delft University of Technology [TU Delft], Wageningen University and Research [Wageningen] [WUR], Ecole Polytechnique Fédérale de Lausanne [EPFL], Protéomique, Réponse Inflammatoire, Spectrométrie de Masse (PRISM) - U1192, Technische Universität Munchen - Université Technique de Munich [Munich, Allemagne] [TUM], and Chemical Biology 1
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Proteomics ,Computer science ,[SDV]Life Sciences [q-bio] ,BIOCONJUGATION ,Biophysics ,Settore ING-IND/06 ,Computational biology ,NATIVE PROTEINS ,Biochemistry ,Genome ,Article ,Mass Spectrometry ,03 medical and health sciences ,Protein sequencing ,Single-molecule biophysics ,Sequence Analysis, Protein ,Nanotechnology ,Life Science ,SELECTIVE MODIFICATION ,Molecular Biology ,030304 developmental biology ,Profiling (computer programming) ,0303 health sciences ,IDENTIFICATION ,Sequence Analysis, RNA ,Protein ,RECOGNITION ,Proteins ,PEPTIDES ,Cell Biology ,MASS-SPECTROMETRY ,Single Molecule Imaging ,TRANSLOCATION ,[SDV] Life Sciences [q-bio] ,Biofysica ,Cellular heterogeneity ,DISCRIMINATION ,NANOPORE ,Proteome ,RNA ,Identification (biology) ,Single-Cell Analysis ,Sequence Analysis ,Biotechnology - Abstract
Single-cell profiling methods have had a profound impact on the understanding of cellular heterogeneity. While genomes and transcriptomes can be explored at the single-cell level, single-cell profiling of proteomes is not yet established. Here we describe new single-molecule protein sequencing and identification technologies alongside innovations in mass spectrometry that will eventually enable broad sequence coverage in single-cell profiling. These technologies will in turn facilitate biological discovery and open new avenues for ultrasensitive disease diagnostics., S.S. acknowledges Postdoc Mobility fellowship no. P400PB 180889 from the Swiss National Science Foundation. E.M.M. and E.V.A. acknowledge funding from the NIH (R35 GM122480 and R01 DK110520 to E.M.M.), Welch Foundation (F1515 to E.M.M. and F-0046 to E.V.A.), Army Research Office grant W911NF-12-1-0390 and Erisyon. E.M.M. and E.V.A. are co-founders and shareholders of Erisyon. R.T.K. acknowledges funding from NIGMS (R01 GM138931). P.Y. acknowledges funding from an NIH Director’s New Innovator Award (1DP2OD007292), an NIH Transformative Research Award (1R01EB018659), an NIH Pioneer Award (1DP1GM133052), and the Molecular Robotics Initiative fund at the Wyss Institute for Biologically Inspired Engineering. M.D. acknowledges funding from a Systems Biology Department Fellowship from Harvard Medical School and a Technology Development Fellowship from Wyss Institute for Biologically Inspired Engineering. C.C. acknowledges the Peter and Traudl Engelhorn Foundation. C.D. acknowledges the ERC Advanced Grant Looping DNA (no. 883684) and the NWO programs NanoFront and Basyc., S.O. acknowledges the support of the Azrieli fellowship foundation. N.L.K. acknowledges funding from the Paul G. Allen Frontiers Program (11715), the NIH HuBMAP program (UH3 CA246635) and NIGMS (P41 GM108569). J.P.M. and Z.K. acknowledge internal funding from NIST and are co-inventors on patents relevant to this work. M. Wanunu acknowledges funding from the NIH (HG009186). K.S. and A.A. acknowledge funding from the NSF (PHY-1430124). C.J., C.D. and R.E. acknowledge funding from NWO-I (SMPS). C.J. acknowledges funding from HFSP (RGP0026/2019). A.P. acknowledges Bekker fellowship no. PPN/BEK/2018/1/00296 from the Polish National Agency for Academic Exchange. C.M. and S.H. acknowledge funding from the European Research Council (ERC ‘Enlightened’, GA 616251) and the CEA Transverse Program ‘Instrumentation and Detection’ (PTC-ID VIRIONEMS). Support from the Proteomics French Infrastructure (PROFI) is also gratefully acknowledged. G.D. acknowledges funding from FNR (C17/BM/11642138). M.M. acknowledges funding from the Adolphe Merkle Foundation, the Michael J. Fox Foundation for Parkinson’s Research (grant 17924) and the Swiss National Science Foundation (grant no. 200021-169304). A.M. acknowledges funding from the European Union’s Horizon 2020 research and innovation programme under grant agreement no. 833399-ERC NanoProt-ID and ISF award 3485/19. M.C. acknowledges computational resources from CINECA (NATWE project) and the Swiss National Super-Computing Centre (CSCS), under projects sm11 and s865. E.C. acknowledges funding from I-Site Lille, Région Hauts-de-France, and the European Union’s Horizon 2020 Marie Skłodowska-Curie no. 843052. The study was supported by the project ‘International Centre for Cancer Vaccine Science’ that is carried out within the International Agendas Programme of the Foundation for Polish Science co-financed by the European Union under the European Regional Development Fund. D.G. thanks Genome Canada and Genome British Columbia for financial support for Genomics Technology Platforms (GTP) funding for operations and technology development (264PRO).
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