Molecular Bases of Proteinopathies

2020-2021 virtual meeting of talks and discussion on "protein multimerization: the bad and the good"

The goal of this event is to bring scientific leaders working in the field of 'Amyloid Research' together from across the globe

Registration is required to secure a zoom link (Registration)

The ZOOMinar series on “Molecular Basis of Proteinopathies” will cover recent breakthroughs in this exciting multidisciplinary area of research from experts in the field. When conferences have been canceled around the world, these virtual presentations and discussions will provide unique opportunities for everyone to learn about recent findings, new topics, and cutting-edge techniques. The live presentations are on Tuesdays (August 2020) and Saturdays (from September 2020 to August 2021) from 10:00 AM to ~11:00 AM (EDT); and Mondays (from October 2021) from 12:00 noon EST/EDT. This virtual seminar includes a ~35 minutes presentation and ~15 minutes for questions and answers. We expect that there will be about 450 to 500 researchers participating from all over the world. The virtual presentations will be recorded and made available on a YouTube channel.

The Organizers

Ayyalusamy (Rams) RamamoorthyBiophysics and Chemistry, University of Michigan

Email: ramamoor@umich.edu


Joan Shea, Chemistry and Biochemistry & Physics, University of California Santa Barbara

Email: shea@ucsb.edu

Magda Ivanova, Department of Neurology, University of Michigan

Email: mivanova@umich.edu

Bikash R. Sahoo, Biophysics and Chemistry, University of Michigan

Email: bsahoo@umich.edu

*For general inquiry please write us at amyloidsymposium@gmail.com

Invited Speakers

The invited lectures on Proteinopathies will take place via Zoom from 10:00 - 11:30 AM (EST) on Tuesdays in August (and shifted to Saturdays from September). After a brief introduction of the speaker by a moderator (~2 minutes), the invited speaker will present the lecture for 30-35 minutes followed by a question-and-answer session led by the moderator (for ~10 minutes). Lectures will be recorded to allow off-line viewing, but recording will be turned off at the speaker's preference. To facilitate the question-and-answer session, the audience will be invited to submit questions during the lecture using the Q&A folder in Zoom. After the lecture, the moderator will read the questions to the speaker (or a subset of related questions) and if needed unmute a participant for follow-up discussion. Depending on the availability of the speaker, informal discussion may continue for ~20 minutes after the formal session.

October 04, 2021 Dr. Dennis J. Selkoe

August 21, 2021

Gary Lorigan

Professor, Miami University, Ohio

https://blogs.miamioh.edu/lorigan-research-group/

Annelise E. Barron

Associate Professor

Department of Bioengineering

Stanford University

August 4, 2020

A Hypothesis for How Innate Immune Dysregulation May Cause Alzheimer’s Dementia;

and How We May Be Able to Prevent It

We are investigating the early-stage etiology of sporadic Alzheimer's Disease (AD), for which 420+ clinical trials by Pharma have failed over the past 15 years to produce an effective drug. What causes the accumulation of Aβ peptide-rich fibrils and plaques in an aging brain? What are Aβ's physiological functions? We focus on Aβ's interactions with the human cathelicidin peptide, LL-37, an antibacterial and antiviral innate immune system effector and modulator that is ubiquitous in tissues and expressed by myriad cell types, yet unique in the human proteome. Recently, evidence has built that chronic Herpesvirus or P. gingivalis infections of human brain tissue may precipitate many cases of sporadic dementia labeled as Alzheimer’s Disease. We present experimental evidence and discuss our developing hypothesis that the antiviral and antibacterial peptide LL-37, which can be chronically under-expressed in humans based on dietary and lifestyle factors or degraded by P. gingivalis virulence factors, is a natural binding partner of Aβ that inhibits formation of AD fibrils and plaques, such that LL-37 and Aβ have a toxin/antitoxin relationship. We demonstrate binding between LL-37 and Aβ by Transmission Electron Microscopy (TEM), Surface Plasmon Resonance Imaging (SPRi), and circular dichroism (CD) spectroscopy. TEM shows that LL-37 inhibits the fibrillization of Aβ, especially the formation of long, straight fibrils characteristic of AD, while CD spectroscopy reveals that LL-37 binding prevents Aβ from adopting β-type secondary structure. Analytical Ultracentrifugation (AUC) and Small-Angle X-ray Scattering (SAXS) prove that LL-37 and Aβ form a unique, water-soluble, 1:1 complex. In vitro cell culture studies using primary human microglia and neuronal cells indicates that these two peptides neutralize each other’s cytotoxic effects on these cells. Finally, studies in 5XFAD and wildtype transgenic mice, and Drosophila Melanogaster, support these findings. We discuss what all of this means in the context of the prevention and treatment of Alzheimer’s dementia.

Rakez Kayed

Professor

Department of Neurology,

University of Texas Medical Branch


August 11, 2020

“Polymorphism of Protein Aggregates in Alzheimer’s Disease and Related Dementias”

Andrew P. Lieberman

Professor

Director of Neuropathology

University of Michigan Medical School


August 18, 2020

Polyglutamine-mediated proteotoxicity in SBMA"

Amy Gladfelter

Professor

Department of Biology

University of North Carolina

August 25, 2020

“Specific viral RNA drives the SARS CoV-2 nucleocapsid to phase separate "



A mechanistic understanding of the SARS-CoV-2 viral replication cycle is essential to develop new therapies for the COVID-19 global health crisis. In this study, we show that the SARS-CoV-2 nucleocapsid protein (N-protein) undergoes liquid-liquid phase separation (LLPS) with the viral genome, and propose a model of viral packaging through LLPS. N-protein condenses with specific RNA sequences in the first 1000 nts (5’-End) under physiological conditions and is enhanced at human upper airway temperatures. N-protein condensates exclude non-packaged RNA sequences. We comprehensively map sites bound by N-protein in the 5’-End and find preferences for single-stranded RNA flanked by stable structured elements. Liquid-like N-protein condensates form in mammalian cells in a concentration-dependent manner and can be altered by small molecules. Condensation of N-protein is sequence and structure specific, sensitive to human body temperature, and manipulatable with small molecules thus presenting screenable processes for identifying antiviral compounds effective against SARS-CoV-2.

Silvia Marchesan

Professor

Chemical & Pharmaceutical Sciences Department, University of Trieste

September 12, 2020

“Entry to peptide Wonderland through the rabbit-hole”

Aphrodite Kapurniotu

Professor

TUM School of Life Sciences,

Technical University of Munich (TUM)

September 19, 2020

“IAPP cross interactions: from discovery to exploitation"

Marc Diamond

Professor

Center for Alzheimer's and Neurodegenerative Diseases, University of Texas Southwestern Medical Center

September 26, 2020

New insights into tau prion propagation

David Eisenberg

Professor

Department of Chemistry and Biochemistry and Biological Chemistry

University of California, Los Angeles

October 3, 2020

Pathogenic vs Reversible Functional Amyloid"

Samrat Mukhopadhyay

Professor

Centre for Protein Science, Design & Engineering,

Indian Institute of Science Education and Research



October 10, 2020

"The Role of Intrinsic Disorder and Dynamics in Biological Phase Transitions "

Martin Muschol

Associate Professor & Graduate Director

Department of Physics

University of South Florida

October 17, 2020

“Distinct species of amyloid oligomers and their biological activities”

Jennifer Lee

Senior Investigator

Laboratory of Protein Conformation and Dynamics

NHLBI, NIH, USA

October 24, 2020

The complex landscape of α-synuclein

Markus Zweckstetter

Professor

German Center for Neurodegenerative Diseases (DZNE)

Max Planck Institute for Biophysical Chemistry

University Medical Centre Göttingen



October 31, 2020

Molecular underpinnings of the life and death of Tau"

Birgit Strodel

Professor

Research Centre Jülich

Institute for Structural Biochemistry



November 7, 2020

“Computational studies on the effects of in vivo conditions on amyloid-β aggregation”

Cong Liu

Principal Investigator

Interdisciplinary Research Center on Biology & Chemistry

Shanghai Institute of Organic Chemistry

Chinese Academy of Sciences

November 14, 2020

“How chaperones regulate protein phase transition and its role in neurodegenerative disease”

Songi Han

Professor

Department of Chemistry & Biochemistry

Department of Chemical Engineering

University of California Santa Barbara

E-mail: shea@ucsb.edu

November 21, 2020

"Tracking the dynamic conformation ensemble of tau along its aggregation pathway"

Meytal Landau

Associate Professor

Department of Biology

Technion - Israel Institute of Technology

December 5, 2020

"Virulent and Antibacterial Fibrils in Infectious and Aggregation Diseases"

Christian Griesinger & Leif Antonchmidt

Professor (Dr. Christian Griesinger)

Researcher (Dr. Leif Antonchmidt)

Dept. of NMR based structural biology, Max Planck Institute for Biophysical Chemistry, Göttingen, Germany

December 12, 2020

"Interference with protein aggregation at the membrane: structural biology and therapy"

Vladimir Uversky

Professor

College of Medicine Molecular Medicine

University of South Florida


December 19, 2020

"From polyfunctionality to multipathogenicity with intrinsic disorder"

Elisar Barbar & Heather Forsythe

Professor (Dr. Elisar Barbar)

Graduate Student (Heather Forsythe)

Faculty Director of the Oregon State University Biomolecular NMR Facility, and Department Head

January 09, 2020

"Multivalency and protein disorder in virus protein interactions: Common themes among Rabies virus and SARS-CoV2"

Mei Hong

Professor

Department of Chemistry

Massachusetts Institute of Technology

January 16, 2021

"Molecular structures of glucagon and tau fibrils from NMR "

Elizabeth Rhoades

Associate Professor

Department of Chemistry

University of Pennsylvania

January 23, 2021

"Investigating the role of N-terminal acetylation on alpha-synuclein structure and function"


Laura P.W. Ranum

Director of Center for NeuroGenetics

University of Florida

E-mail: ranum@ufl.edu

January 30, 2021

"Repeat associated non-AUG (RAN) translation in neurodegenerative disease: molecular insights and therapeutic opportunities"

Ehud Gazit

Professor

Tel Aviv University,

February 06, 2021

"Metabolite Self-Assembly: Extension of the amyloid hypothesis"

Dieter Willbold

Professor

Institute of Complex Systems & Forschungszentrum Juelich GmbH

February 13, 2021

"Aβ oligomer disassembly into monomers is beneficial for cognition and memory in transgenic and non-transgenic Alzheimer animal models"


Stephen Meredith

Professor

University of Chicago

February 20, 2021

"Heterogeneity of Aβ Aggregates"

Yuji Sugita

Chief Scientist

RIKEN

February 27, 2021

"Replica-exchange simulations on the conformational dynamics of spike protein on the surface of SARS-CoV-2"

March 06, 2021

Alemayehu Gorfe

Associate Professor

University of Texas, Houston

"The intrinsically disordered membrane anchor of Ras proteins sorts membrane lipids"

March 13, 2021

Samir Maji

Professor,

Biosciences and Bioengineering,

"p53 amyloid formation associated with cancer"

March 20, 2021

John Straub

Professor, Boston University

straub@bu.edu

"The roles of monomer and membrane in Aβ-protein genesis and aggregation"

Communications Biology volume 4, Article number: 120 (2021).

The thermodynamic hypothesis of protein folding, known as the “Anfinsen’s dogma” states that the native structure of a protein represents a free energy minimum determined by the amino acid sequence. However, inconsistent with the Anfinsen’s dogma, globular proteins can misfold to form amyloid fibrils, which are ordered aggregates associated with diseases such as Alzheimer’s and Parkinson’s diseases. Here, we present a general concept for the link between folding and misfolding. We tested the accessibility of the amyloid state for various proteins upon heating and agitation. Many of them showed Anfinsen-like reversible unfolding upon heating, but formed amyloid fibrils upon agitation at high temperatures. We show that folding and amyloid formation are separated by the supersaturation barrier of a protein. Its breakdown is required to shift the protein to the amyloid pathway. Thus, the breakdown of supersaturation links the Anfinsen’s intramolecular folding universe and the intermolecular misfolding universe.

No ZOOMinar

on March 27th and April 3rd

Enjoy the break!

April 10, 2021

Sudipta Maiti

Tata Institute of Fundamental Research,

Mumbai 400005, INDIA

Email: maiti@tifr.res.in, URL: biophotonics.co.in

“Probing toxic protein oligomers: From test tubes to patient-derived neurons”


Understanding how amyloid aggregates actually become toxic is one of the challenges in developing a treatment for diseases such as Alzheimer’s and Parkinson’s. One of the major possibilities is that the small oligomeric aggregates incorporate into the cell membrane and make specific functional structures which ultimately cause toxicity. However, very little is known about the structure of the oligomers, the stoichiometry of the toxic oligomer, its insertion into the membrane, and subsequent cellular interactions. Perhaps the hardest problem is to establish the correlation of all these parameters with the actual disease. Here we address these issues for Amyloid-beta, which is associated with Alzheimer’s disease. Nature has provided some clues for Alzheimer’s in terms of the location of disease-accelerating mutations, correlations with other protein isoforms, and neuron-type specific vulnerabilities. However, they have been hard to interpret. Using tools such as nanosecond FCS, time resolved FRET, solid state NMR, membrane-mediated SERS, single molecule photobleaching, and Alzheimer’s patient-derived neurons, we are finally making sense of some of these clues.

References:

1) Dey et al., Chem. Eur. J., (2021), https://doi.org/10.1002/chem.202100328

2) Dey et al., Physical Chemistry Chemical Physics (2020) 22 (26), 14613

3) Chandra et al., Chemical Communications (2018) 54 (56), 7750-7753

4) Bhowmik et al., ACS Nano (2015), 9 (9), 9070-9077

5) Sarkar et al., Angewandte Chemie (2014) 126 (27), 6948-6948.

April 17, 2021

Sheena Radford

Professor

Structural Molecular Biology, Univ. of Leeds

"Seeing the molecular details of amyloid formation"

April 17, 2021

Sabine Ulamec

"A short motif in the N-terminal region of alpha-synuclein is critical for aggregation"

April 24, 2021

Omar El-Agnaf

Executive Director

Qatar Biomedical Research Institute

Joint Professor

College of Health and Life Sciences

“Role of α-synuclein phosphorylation at serine 129 in the pathogenesis of synucleinopathies: an active debate"

Parkinson’s disease (PD) and dementia with Lewy bodies (DLB) are human neurodegenerative diseases characterized neuropathologically by the presence of neuronal α-synuclein inclusions, named as Lewy bodies and Lewy neurites. Increasing number of studies highlighted the aberrant accumulation of phosphorylated α-synuclein at the residue Serine129 (pS129) in the brain of PD and DLB patients, suggesting that phosphorylation may play a vital role in the regulation of α-synuclein aggregation and subsequent neuronal degeneration. However, a comprehensive understating of the exact role of α-synuclein phosphorylation at S129 is still lacking. Here, we study the time-point at which pS129 modification occurs in the process of α-synuclein aggregation and its role in initiation, progression and cellular toxicity of the disease. Therefore, with the collaboration of many international teams we have addressed this issue by designing and executing important in vitro, ex vivo, and in vivo experiments using various models, in addition to post-mortem human brain studies. Contrary to the putative view of pS129-α-synuclein being particularly disease-relevant form of α-synuclein, we suggest that pS129 diminished aggregation-propensity, attenuated cytotoxicity, and occurs subsequent to initial α-synuclein aggregation. Our novel findings have important implications for the design of future neuropathological studies and the development of therapeutic approaches targeting of distinct α-synuclein species.

April 24, 2021

Henrike Heise

Forschungszentrum Juelich GmbH

h.heise@fz-juelich.de

"Protein (mis)folding at high sensitivity and resolution as seen by solid-state NMR"

May 01, 2021

Louise Serpell

Professor

University of Sussex, UK

Proteins at the centre of Alzheimer’s disease"

May 01, 2021

Andisheh Abedini

Research Associate Professor,

SUNY Stony Brook University

andisheh.abedini@stonybrook.edu

"Cellular mechanisms of IAPP-induced islet beta cell dysfunction in diabetes"

May 08, 2021

Lucia Banci

Professor

Magnetic Resonance Center and Department of Chemistry, University of Florence

"In-cell NMR: a powerful approach for studying protein folding and maturation"

David Eliezer

Professor

Weill Cornell Medical College

"Structure-function studies of the Parkinson’s protein alpha-synuclein"

May 15, 2021

Patrick

van der Wel

Professor

p.c.a.van.der.wel@rug.nl

"The structural biology of protein misfolding in Huntington’s disease"

Gareth Morgan

Boston University School of Medicine

"Stabilizing Antibody Light Chains to Prevent Amyloidosis"

May 22, 2021

Michel Goedert

Professor, MRC Laboratory of Molecular Biology, Cambridge, UK

Cryo-EM structures of amyloid filaments from human brain"

May 22, 2021

Bin Xu

Assistant Professor,

Pharmaceutical Sciences,

North Carolina Central University

bxu@nccu.edu

binxulab@weebly.com

"Small Molecule Modifiers of Toxic Protein Aggregation in Neurodegenerative and Aging Diseases: Discovery and Mechanisms"

May 29, 2021

Samuel Kotler

NIH


"Proinsulin misfolding and aggregation:

relevance to beta cell dysfunction in diabetes"

Anoop Arunagiri


University of Michigan

June 05, 2021

Charles Sanders

Professor

Vanderbilt University


"Membrane Protein Super-Trafficking as a Disease Mechanism: The KCNQ1 Potassium Channel and Atrial Fibrillation"

June 05, 2021

Luis del Pozo-Yauner

Assistant Professor, University of South Alabama

"Recombinant protein 6aJL2 as a model for understanding the mechanism of light chain amyloid aggregation"

June 12, 2021

Matthew Chapman

Professor

University of Michigan, Ann Arbor


"Polymerizing the fiber between functional and pathogenic amyloid"





Daniel Otzen

Professor

Aarhus University, Denmark


"Swords to plowshares: The assembly of functional amyloid"

June 19, 2021

Cathy Royer

Professor

Rensselaer Polytechnic Institute

"Pressure-based mapping of protein conformational landscapes"

June 26, 2021

Wenjing Wang

Assistant Professor, University of Michigan

"Designing fibril-specific nanobodies to inhibit alpha-synuclein pathology development"

June 26, 2021

Tessa Sinnige

Assistant Professor, University of Utrecht

"Understanding amyloid formation in vivo using C. elegans models of polyglutamine aggregation"

July 3, 2021: No Zoominar

July 10, 2021

Gunilla Westermark

Professor

Uppsala University, Sweden

"Islet amyloid polypeptide a friend or foe to the beta-cell"

July 10, 2021

Ansgar Siemer

Assistant Professor, USC

"Residual structure and dynamics of framing sequences important for fibril binding, seeding, and toxicity"

July 17, 2021

Fabrizio Chiti

Professor, University of Florence

"Physicochemical basis of the displacement of amyloidogenic proteins and misfolded protein oligomers from biological membranes"

July 17, 2021

Bernd Reif

Professor

Technical University of Munich, Germany

"Conformational properties of immunoglobulin light chain fibrils probed by MAS solid-state NMR"

July 24, 2021

Pete Tessier

Professor

University of Michigan,

Ann Arbor


July 24, 2021

Samuel Gandy

Professor

The Mount Sinai Hospital, NY

"Deregulated immune-inflammatory and neurogenic events contribute to the pathogenesis of Alzheimer's disease"

July 31, 2021

Galia Debelouchina

Assistant Professor, UCSD

"Understanding the molecular basis of protein phase transformations with solid-state NMR and computational approaches"

July 31, 2021


Mi Hee Lim

Professor, KAIST, Korea

"Bioinorganic Strategies to Study Multiple Facets in Alzheimer's Disease"

August 07, 2021

Brandon Ruotolo

Professor, University of Michigan, Ann Arbor

"Untangling the Complexity of Protein Misfolding Diseases with Ion Mobility-Mass Spectrometry"

August 07, 2021

Richard Vachet

Professor

University of Massachusetts, Amherst

"Structural insights into the early stages of protein amyloid formation from mass spectrometry"

August 14, 2021

Ulrich Hartl

Professor, Dr.

Max Planck Institute of Biochemistry, Germany

http://www.biochem.mpg.de/hartl

"Disaggregation of Tau fibrils and possible consequences"

August 21, 2021

Gary Lorigan

Professor, Miami University, Ohio

https://blogs.miamioh.edu/lorigan-research-group/

"Solid-state and EPR Spectroscopic Studies to Probe the Structure and Topology of the Active and Inactive Forms of the Pinholin Membrane Protein"

Kathleen Howard

Professor, Swarthmore College

https://www.swarthmore.edu/profile/kathleen-howard

"Characterization of influenza matrix proteins at membrane surfaces"

Presentations from Early Career Researchers

Please join the virtual meeting using the ZOOM link:

https://umich.zoom.us/s/98980924851


June 23, 2021

Eastern time, USA

9:00-9:30 am Emily Byrd, the University of LEEDS, UK

Title: Probing the conformational dynamics of alpha-synuclein by ion mobility mass spectrometry

9:30-10:00 am Dipita Bhattacharyya, Department of Biophysics, Bose Institute, Kolkata, India

Title: Trapping the Invisible Early Intermediates in the Gut-Brain Axis of Parkinson's Disease Pathophysiology

10:00-10:30 am Buyan Pan, Department of Chemistry, University of Pennsylvania, USA

Title: Examining post-translational modifications in alpha-synuclein through semi-synthesis and single molecule spectroscopy

10:30-11:00 am Rashik Ahmed PhD, Department of Chemistry and Chemical Biology, McMaster University, Canada

Title: Atomic resolution map of hierarchical self-assembly for an amyloidogenic protein probed through thermal 15N-R2 correlation matrices

11:00-11:30 am Frederica Scollo, J. Heyrovský Institute of Physical Chemistry (Academy of Sciences of the Czech Republic), Prague, Czech Republic

Carmelo Tempra, Institute of Organic Chemistry and Biochemistry (Czech Academy of Sciences) Prague, Czech Republic

Title: A comprehensive biophysical study on intrinsically disordered proteins: the lipid-chaperone hypothesis

July 14, 2021

Eastern time, USA

9:00-9:30 am Ushasi Pramanik, Department of Chemistry, IISER Bhopal, India

Title: An Intrinsically disordered protein in F127 hydrogel: fluorescence correlation spectroscopy and structural diversity of beta casein

9:30-10:00 am Naiemeh Jafari PhD, Department of Chemistry and Chemical Biology, McMaster University, Canada

Title: Non-Canonical Protein Kinase A Activation by Oligomerization of Regulatory Subunits as Revealed by Inherited Carney Complex Mutations

10:00-10:30 am Debayan Chakraborty Ph D, Department of Chemistry, University of Texas at Austin, USA

Title: Differences in the free energies between the excited states of Aβ40 and Aβ42 monomers encode their aggregation propensities

10:30-11:00 am Vrinda Sant, Materials Science & Engineering, UCSD, United States

Title: Hybrid silica nanobowls scavenge membrane associated Amyloid-β: mechanism and applications for Aβ pathology

11:00-11:30 am Xuemei Zhang PhD, Neuroscience Research Institute, UCSB, USA

Title: Live imaging oligomeric tau cellular phase transitions



Presentations from Early Career Researchers

Organizers of the ZOOMinar series invite early career researchers to present their latest research findings. The goal is to provide opportunities for early-career researchers to present their latest research findings, interact with experts with multidisciplinary expertise, and gain critical feedback and collaborations.

To be considered for a short presentation in the ZOOMinar series, you will need to prepare an abstract (300 words or less) and a short (for ~3 to 5 minutes) video, and submit them by March 10, 2021 (5:00 PM EST) at https://forms.gle/29PfU1TFtSWLuTxGA. The video and the abstract should summarize the significance of the investigated research problem, the major findings, and their impacts in the field. The following groups of early-career researchers are eligible:

A) Early-career trainees (undergraduate, graduate, and postdoctoral researchers). The top four presentations (voted by the audience) will receive monetary awards.

B) Young investigators (tenure and non-tenure track assistant professors).

  • Sponsors: The Journal of Physical Chemistry B, Chemistry and Physics of Lipids, more to come...

A committee will evaluate the video presentations and will finalize the list of candidates for live presentations (~20 minutes, 10 minutes Q&A).

Committee: Dr. Martin Muschol (Chair) (Univ. of South Florida), Yifat Miller Ben Gurion Univ, Israel), Yanzhuang Wang (Univ of Michigan), Anirban Bhunia (Bose Research Institute, India), Michele Sciacca (CNRS, Catania), Sandrine Ongeri (CNRS/Université Paris Saclay).

Presentation Evaluation Committee: Dr. Bikash Sahoo (Chair) (Univ. of Michigan), Dr. Michael Bekier (Univ. of Michigan), Dr. Samuel Kotler (NIH), Anoop Arunagiri (Univ of Michigan), Sunil Kumar (University of Denver), Jose L. Arenas (CNRS/Université Paris Saclay).