EMBL Seminars

Abstract
The molecular mechanisms causing neuronal death in many neurodegenerative diseases, such as amyotrophic lateral sclerosis (ALS), frontotemporal dementia (FTD) and Charcot Marie Tooth (CMT) disease, are poorly understood. The key consequence of our incomplete understanding of disease pathogenesis is that there is a complete dearth of effective symptomatic treatments for these widespread global disorders, prompting the necessity for a step-change in treatment strategies to fight these pathologies.

In this view, we are investigating ALS and CMT as disease paradigms to identify new, common targets for pharmacological intervention in these devastating pathologies. Recently, we uncovered alterations in axonal transport of several cytoplasmic organelles, such as mitochondria and signalling endosomes, at pre-symptomatic stages of ALS and CMT pathogenesis, suggesting that these impairments may play a causative role in disease onset and progression. Crucially, we have restored axonal transport to physiological levels at early symptomatic stages of disease, thus demonstrating that these pathological changes are fully reversible. 

In light of these promising results, our main goal is identifying novel signalling nodes that modulate axonal transport in healthy and diseased neurons. This will allow us to test the hypothesis that counteracting axonal transport deficits observed in ALS, CMT and other neurodegenerative diseases, represents a novel, effective therapeutic strategy towards treating these pathologies.

Abstract
Highly entangled polymers—a topic that has been extensively studied in the realm of equilibrium polymer physics. Adding an active component to drive the system far from equilibrium represents a significant advancement in exploring the interplay between entanglement and activity in polymer-like entities [1,2,3]. This exploration is crucial for establishing a comprehensive understanding of living systems across various scales. Examples include cell cytoskeletons, bacterial colonies, and worms, where entanglement and activity profoundly influence their behavior and responses to environmental cues. Furthermore, this extends to the field of bio-inspired engineering, where soft robotic grippers strategically deploy active filaments for object capture.

In my talk, I will present the transport and elastic properties of such systems. First, we explore the intricate interplay of crowding and self-propulsion in stiff filaments via Brownian dynamics simulations. Contrary to the well-studied 'crowded is slower' phenomenon observed in various fields, such as colloidal glasses and crowd evacuation, we discover a remarkable enhancement in the diffusivity of self-propelled anisotropic agents like biofilaments and elongated bacteria due to crowding [1]. To explain this behavior, we extend the Doi and Edwards' tube concept to active systems, establishing a crucial link through our scaling theory between effective diffusivity, the Péclet number, and filament density.

Second, we delve into the viscoelastic properties of highly entangled, flexible, self-propelled polymers through simulations. Our findings reveal a novel scaling law for elasticity, $G_0 \sim L$, where $L$ represents the polymer length, challenging conventional understandings of polymer behavior [2]. These insights into activity-enhanced elasticity hold significant promise for collective life forms, including bacterial colonies and California blackworms, potentially providing resistance to environmental stresses.

[1] S. Mandal, C. Kurzthaler, T. Franosch, and H. Löwen, Physical Review Letters, 125, 138002 (2020).

[2] D. Breoni, C. Kurzthaler, B. Liebchen, and H. Löwen, and S. Mandal, arXiv:2310.02929 (2023).

[3] C. Kurzthaler, S. Mandal, T. Bhattacharjee, H. Löwen, S. S. Datta, and H. Stone, Nature Communications, 12, 7088 (2021).

About the speaker
Researcher at the Institute for Condensed Matter Physics (IPKM) in TU Darmstadt

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Attachments
[Link to a file (for example a pdf of the seminar’s programme) - the file can be uploaded on the intranet]

Connection details
Zoom*: [link] (Meeting ID: [XXXXXXXXX], Password: [XXXXXXX])

Please note that the talk will yes/not be recorded.
*For the FAQ section, as a zoom participant, please use either the chat function (the host will read out your question) or the “raise your hand” function and turn on your microphone.

Abstract
It is becoming increasingly clear that alternative mRNA processing is a major factor underlying human phenotypes, disease etiology, and cellular responses to external stimuli. Though we have begun to unravel the genetic factors involved in regulating alternative isoform usage, we do not yet understand the temporal dynamics of RNA processing decisions. The development of high-throughput sequencing approaches to systematically capture and analyze nascent pre-mRNA molecules at defined time-scales has opened the door for genome-wide kinetic profiling of RNA maturation. Many steps of RNA maturation – including mRNA splicing and cleavage – are thought to occur primarily co-transcriptionally, with substantial interplay between the rate of transcription elongation and choices involved in isoform variability. Furthermore, there is increasing evidence that these steps are often co-regulated to ensure expression of precise full length isoforms. Thus, measuring the speed, accuracy, and coordination of mRNA processing decisions is central to understanding the regulation of initial gene regulatory decisions and mRNA biogenesis. Previous methods to do so have imaged single loci, studied dynamics in mutated or heavily altered genes, or used chemical treatments that affect cellular metabolisms. I will describe our ongoing development and application of computational genomics approaches to estimate genome-wide kinetics, fidelity, and coupling of transcription elongation, mRNA splicing, and mRNA cleavage decisions in eukaryotic cells.

About the speaker
Athma Pai is an RNA systems geneticist working at the interface of RNA biology, functional genomics, and computational biology. Athma received her Ph.D. in Human Genetics from the University of Chicago, completed a Jane Coffin Childs postdoctoral fellowship in the Department of Biology at MIT, and assumed her current position as an Assistant Professor in the RNA Therapeutics Institute at the University of Massachusetts Chan Medical School in January 2018. Her lab works on developing and applying methods to study the kinetics of RNA processing and understanding how various steps in RNA maturation are efficiently coordinated through the lifecycle of an RNA molecule. Her work has been recognized with professional awards and grants such as the NIH Maximizing Investigators Research Award, NSF CAREER Award, and the UMass Chan Early Career Achievement in Science and Health Award

Connection details
Zoom*: https://embl-org.zoom.us/j/94006407995?pwd=OEVERXRPbkhLWngvZUV3RnZPeDFaUT09

(Meeting ID:985 8784 8976, Password:694582)

Please note that the talk will not be recorded.
*For the FAQ section, as a zoom participant, please use either the chat function (the host will read out your question) or the “raise your hand” function and turn on your microphone.

Abstract
The discovery of RNA editing in trypanosomes in 1986 challenged the central dogma of molecular biology and introduced fundamental biological entities, such as gRNA and the editosome. Although trans-acting RNAs underpin most modern genome and transcriptome-altering technologies, the structural basis of gRNA-programmed mitochondrial mRNA recoding has remained elusive. In Trypanosoma brucei, the ~1.2 MDa editosome consists of RNA editing substrate-binding (RESC) and catalytic (RECC) complexes. I will describe the structures and functions of macromolecular complexes responsible for gRNA stabilization, gRNA-mRNA interaction, U-deletion and U-insertion sites selection, and mRNA strand cleavage. Our findings illuminate the temporal and spatial order of the editosome assembly from substrate-binding and catalytic complexes, the structural organization of U-deletion and U-insertion enzymatic cascades, and the mechanism of mRNA scission.

About the speaker
Ruslan Afasizhev received BS and MS from the Department of Molecular Biology at the Division of Biology, Moscow State University, under the mentorship of Prof. Alexander Spirin, and completed PhD studies at the Institute of Molecular Biology, Russian Academy of Sciences with Prof. Lev Kisselev. After a short-term EMBO post at the Institut de Biologie Moléculaire et Cellulaire in Strasbourg, he was awarded an HHMI Postdoctoral Fellowship to study RNA editing in Prof. Larry Simpson's laboratory at UCLA. In his postdoctoral work, Dr. Afasizhev discovered the first RNA editing enzymes and complexes, which he continued to study as a faculty member at the University of California Irvine Medical School and currently at Boston University.

Connection details
Zoom Meeting https://embl-org.zoom.us/j/94006407995?pwd=OEVERXRPbkhLWngvZUV3RnZPeDFaUT09 

Meeting ID: 940 0640 7995 

Password: 694582

Please note that the talk will not be recorded.
*For the FAQ section, as a zoom participant, please use either the chat function (the host will read out your question) or the “raise your hand” function and turn on your microphone.

Abstract
DNA methylation occurs on CpGs in mammalian genomes and catalyzed by DNA methyltransferases (DNMTs). It is dynamically reprogrammed during embryonic development and is essential to establish long term repression of evolutionarily young retrotransposons and CpG-rich promoters of germline genes in embryos. A second wave of DNA methylation reprogramming occurs in primordial germ cells (PGCs). PGCs undergo global erasure of DNA methylation with delayed demethylation of germline genes and selective retention of DNA methylation at retrotransposons. However, the molecular mechanisms of persistent DNA methylation in PGCs remain unclear. I will present evidence that the resistance to DNA methylation reprogramming in PGCs requires DNMT1 and UHRF2, the paralog of the DNMT1 cofactor UHRF1. PGCs from Uhrf2 knock-out mice show loss of retrotransposon DNA methylation. Furthermore, Uhrf2-deficient PGCs show precocious demethylation of germline genes and overexpress meiotic genes in females. Subsequently, Uhrf2-deficient mice show impaired oocyte development and female-specific infertility. These findings reveal a crucial function for the UHRF1 paralog UHRF2 in controlling DNA methylation in the germline.
 

Abstract
Optimal performance, in which a task is completed quickly and accurately, is difficult to achieve and maintain.  Is this because the neural pathways underlying the performance need to be accurately tuned through plasticity, or is it because of variability in the state of the brain?  Here we present evidence that waking mice are constantly in a state of flux – ranging from a state of low arousal and inattentiveness, to high arousal and stress.  The optimal state for performance of sensory detection or discrimination tasks lies in the middle – optimally aroused, attentive, and appropriately activated, but to some degree relaxed.  Rapid variations in the waking state of the animal, which occur on time scales as short as 10s of milliseconds, involve an interaction of the thalamus and cerebral cortex, controlled by neurotransmitter pathways that remain to be clearly delineated  These rapid changes in state can account for a significant portion of on-going activity in the mammalian brain, and therefore need to be fully understood and accounted for.

Abstract
 

Chromosome segregation is performed by the spindle, a dynamic machine composed of microtubules, motors, and other associated proteins (MAPs). We currently know a lot about the protein components what constitute the spindle. However, evolution has tuned these components differently in different organisms. I will present different strategies that yeast, insect, and human cells have evolved to assemble the spindle for chromosome segregation. Understanding these different modes of spindle assembly may help fight cancer.

About the speaker
[Biographical information about the speaker].

Meet the speaker
To meet with the speaker informally after the talks,sign up here [add link]. We especially encourage predocs and postdocs to take advantage of this opportunity.

Attachments
[Link to a file (for example a pdf of the seminar’s programme) - the file can be uploaded on the intranet]

Connection details
Zoom*: [link] (Meeting ID: [XXXXXXXXX], Password: [XXXXXXX])

Please note that the talk will yes/not be recorded.
*For the FAQ section, as a zoom participant, please use either the chat function (the host will read out your question) or the “raise your hand” function and turn on your microphone.

Abstract
The centriole is an evolutionary conserved organelle coordinating fundamental biological processes including cell division, cellular signaling and cell motility. This organelle, of 500 nm long and 250 nm in diameter is composed of about 200 different proteins, some of which have been associated with human diseases. How these proteins are organized at the level of the centriole architecture and how associated mutations could be involved in pathologies is still poorly understood. In this seminar, I will present the latest work from my laboratory, which tackle these fundamental structural cell biology questions using cryo-tomography, cell biology and our newly developed ultrastructure expansion microscopy (U-ExM) method.

About the speaker
Virginie Hamel (previously Hachet) is an expert in Cell Biology and Biochemistry. She completed her PhD under the supervision of Iain Mattaj at EMBL (Heidelberg, Germany, 2004) working on the role of importin alpha in nuclear envelope re-assembly in vitro using Xenopus laevis egg extracts. From 2005 to 2015, she worked as a post-doctoral fellow and then scientist collaborator in the laboratory of Prof. Gönczy at EPFL (Lausanne, Switzerland) where she first studied timing of mitotic entry in C. elegans embryos followed by dissecting the mechanisms of centriole assembly both in vitro and in vivo. Since 2015, she is co-heading the Centriole architecture lab with Prof Paul Guichard in the Molecular and Cellular Biology Department at the University of Geneva. Their lab focuses on deciphering the structural mechanisms governing centriole assembly combining the use of cell biology methods, in vitro reconstitution assays, cryo-microscopy/cryo-tomography and expansion microscopy.

Meet the speaker
To meet with the speaker informally after the talks, please contact administration@embl.fr. We especially encourage predocs and postdocs to take advantage of this opportunity.

Attachments
[Link to a file (for example a pdf of the seminar’s programme) - the file can be uploaded on the intranet]

Connection details
Zoom*: https://embl-org.zoom.us/j/95432724854?pwd=NnJvUWU5dzU0L1NheEM2SFlQM3FPQT09(Meeting ID: 954 3272 4854, Password: Passcode: 765338)

Please note that the talk will yes/not be recorded.
*For the FAQ section, as a zoom participant, please use either the chat function (the host will read out your question) or the “raise your hand” function and turn on your microphone.

About the speaker
Dr. Singh is a Senior Scientist in the Donald K. Johnson Eye Institute and Krembil Research Institute, located with University Health Network (UHN) since 2020. He is an Associate Professor in the Departments of Ophthalmology and Vision Sciences, and Laboratory Medicine and Pathobiology (LMP) at the Faculty of Medicine, University of Toronto. Prior to this, he was at McMaster University from 2012-2020 where he was a Scientist and Neural Program Lead at the Stem Cell and Cancer Research Institute, The David Braley Chair in Stem Cell Research, and an Associate Professor in the Department of Biochemistry and Biomedical Sciences at McMaster University. 

His lab utilizes mouse and patient-derived neural 3D organoid/assembloid models, in combination with multi-omic approaches, to study neurodevelopmental and adult neurological and vision disorders. His program focuses on studying genetic risk factors for neurological and vision disorders, and identifying molecular/cellular mechanisms of disease. The long-term goal is to utilize these platforms to study disease etiology, and develop regenerative medicine approaches such as genetic therapies.