Second semester 2019/2020

28/02/2020 Patterns of promoter quadruplexes associated with different epigenetic marks

Arina Nostaeva, Lab Research Assistant

Based on materials presented at the conference "Applied Bioinformatics in Life Sciences (3rd edition)" (Leuven, Belgium, February 13-14).

Quadruplexes (G4) are Tuesday structures of DNA and RNA, formed as a result of two donor and two acceptor bonds of four Gs between themselves. Experimental proof of the formation of G4 in each specific place is a very complex task that requires a lot of resources and time. Therefore, an important approach in the study of G4 is bioinformatic analysis of their connections and the search for patterns of interactions with different parts of the genome based on the predicted G4 sequences. This work is devoted to the search for patterns of interaction between G4 and histone labels.

Pokrovsky Boulevard, 11, D509

18:10-19:30

20/02/2020 Systemic Autoimmune Diseases: Genetic Associations, Contribution of Rare SNVs, and Regulation of Gene Expression

Nina Oparina, Gothenburg University, also affiliated as a collaborator at Karolinska University

Human autoimmune diseases, characterized by the production of pathological autoantibodies or the multiplication of auto-aggressive killer T cells, are an extremely diverse group of pathologies, with the obvious complexity of their differential diagnosis and classification. Nina Oparina and her colleagues studied systemic autoimmune diseases (SAZ), for which there is no pronounced organ-specific lesion. Analysis of the genetic predisposition to them makes it possible to identify common associated loci and markers and to simulate some of the mechanisms of pathogenesis. But with such a heterogeneity of the material and the complexity of making a diagnosis, classification tasks come to the fore, including, ideally, unsupervised learning based on molecular data. We also studied data on genome-wide associations, exomes, and targeted resequencing for different SAZ, primarily for systemic lupus erythematosus. In addition, the work included functional studies - for example, analysis of gene expression, splicing, eQTL, sQTL, etc.

Pokrovsky Boulevard, 11, R408

18:10-19:30

13/02/2020 Transformer neural network for protein specific de novo drug generation as machine translation problem

Daria Grechishnikova, Candidate of Physical and Mathematical Sciences, Faculty of Physics, Moscow State University

Drug discovery for the protein target is a very laborious, long and costly process. Machine learning approaches, and deep generative networks in particular, can substantially reduce development time and costs. However, the majority of methods imply prior knowledge of protein binders, their physicochemical characteristics or three-dimensional structure of the protein. The method proposed
in this work generates novel molecules with predicted ability to bind target protein relying on its amino acid sequence only. We consider target specific de novo drug design as a translational problem between amino acid “language” and SMILE (Simplified Molecular Input Line Entry System) representation of the molecule. To tackle this problem, we apply Transformer neural network architecture, the state-of-the-art approach in sequence transduction tasks. The Transformer is based on a self-attention technique which allows capturing long-range dependencies between
items in sequence. The model generates realistic diverse compounds with structural novelty. The computed physicochemical properties and common metrics used in drug discovery fall within the plausible drug-like range of values.

Pokrovsky Boulevard, 11, R506

18:10-19:30

28/01/2020 Genomic and transcriptomic correlates of immunotherapy within the tumor microenvironment of leptomeningeal metastases

 Dr. Samuel Markson, postdoctoral research in the group of Dr. Scott Carter at the Dana-Farber Cancer Institute (affiliated with Harvard Medical School)

Abstract: Over the past decade, the incidence of leptomeningeal disease (LMD) has steadily increased without the development of effective treatment options. To potentially address clinical demand, we completed two phase II trials of immune checkpoint inhibitor (ICI) immunotherapy in patients with LMD. Here, we apply single-cell RNA and cell-free DNA profiling of clinical cerebrospinal draws from patients enrolled in both trials to investigate the cellular and molecular features underpinning observed clinical trajectories. We recover immune and malignant cell types in the CSF, characterize changes in T cell behavior following immunotherapy, and identify genomic features coincident with relevant clinical phenomena. Overall, our study describes, for the first time, cellular behaviors in the liquid LMD tumor microenvironment following immunotherapy, demonstrates the potential for cell-free and single-cell genomic measurements to better understand clinical phenomena, and describes potential mechanisms underlying the promise of intravenously (IV) administered immunotherapy for the treatment of LMD.

Seminar working language – English

Pokrovsky Boulevard, 11, T907

17:15-18:00

28/01/2020 Mechanisms of remodeling in human heart failure

Igor R. Efimov, The Alisann and Terry Collins Professor, Department of Biomedical Engineering, George Washington University, Washington, DC

Animal models of cardiac diseases have been studied for decades to investigate the mechanisms of arrhythmia initiation and maintenance with the aim to develop life-saving prevention and therapy. However, few clinical advances resulted from these investigations so far.  Many mechanistic discoveries made by cardiac electrophysiologists using animal models failed to translate to humans. For example, despite significant efforts of the generations of scientists, we do not have effective pharmacological agents preventing or aborting sudden cardiac death caused by ventricular fibrillation. To address this problem our laboratory conducted for more than a decade experimental investigations of arrhythmia mechanisms in explanted human hearts procured from patients undergoing transplant or donors whose hearts were not used for transplantation. “Omics” studies employing genome, proteome, transcriptome and other molecular biology approaches revealed that pathological mechanisms usually multifactorial and often cannot be reduced to a single gene or protein defect. Furthermore, pro-arrhythmic SNPs identified by GWAS studies are predominantly located in the regulatory but not in the protein-coding regions of DNA. Moreover, individual SNPs in the regulatory elements could have impact on transcription of multiple genes. Optical and electrical mapping studies revealed the mechanisms of normal and pathological electrophysiology specific to human, which often differ from those previously discovered in animal models. However, arrhythmias in the human heart follow fundamental principles of arrhythmia initiation and maintenance conceptually described by non-linear dynamics theory during the last century.  

Pokrovsky Boulevard, 11, G114

16:00-17:30

28/01/2020 Global burden of disease project. International collaboration in modelling the morbidity and mortality goes into the subnational data

Professor Mohsen Naghavi (University of Washington, Washington, USA).

Professor will talk about the development of the most advanced project on assessing world morbidity and mortality, influence of risk factors (including economical) on human health. The project results lie in the basis of modern statistics of the UN/WHO. In the framework of the project the unique technologies on data correction and modeling were developed as a result of refinement of national and subnational data.

Seminar working language – English

Pokrovsky Boulevard, 11, Building Z, Small Hall

18: 10-20: 00