Seminars 2020/2021

09.04.21 [online] Fully bioresorbable, leadless, battery-free cardiac pacemaker

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Presenter: Igor Efimov, PhD, FNAI, FAIMBE, FAHA, FHRS Alisann and Terry Collins Professor, Department of Biomedical Engineering The George Washington University, Washington DC Editor-in-Chief, Cardiovascular Engineering & Technology

Temporary cardiac pacemakers provide critical functions in pacing through periods of need during post-surgical recovery.  The percutaneous leads and externalized hardware associated with these systems present, however, risks of infection and constraints on patient mobility.  Furthermore, the pacing leads can become enveloped in fibrotic tissue at the electrode-myocardium interface, which thereby increases the potential for myocardial damage and perforation during lead removal.  Here, we report a bioresorbable, leadless, and fully implantable cardiac pacemaker for post-operative control of cardiac rate and rhythm during a stable operating timeframe that subsequently undergoes complete dissolution and clearance via natural biological processes.  A combined set of in vitro, ex vivo, and in vivo studies across mouse, rat, rabbit, canine, and human cardiac models demonstrates that these devices provide an effective, battery-free means for pacing hearts of various sizes with tailored geometries and timescales for operation and bioresorption. These features enable programmable cardiac pacing in a manner that overcomes all of the key disadvantages of traditional temporary pacing devices.  As such, this novel cardiac pacemaker may serve as the basis for the next generation of post-operative temporary pacing technology.

02.04.21 [online] Molecular mechanisms of oncogenesis through the lens of nucleosomes and histones

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Presenter: Anna Gribkova, Gupta Shubhangi; Shaytan Alexey (after the publication Espiritu, Daniel; Gribkova, Anna; Gupta, Shubhangi; Shaytan, Alexey; Panchenko, Anna; The Journal of Physical Chemistry B).

At the cellular level cancer is the disease of both the genome and the epigenome, and the interplay between genetic mutations and epigenetic states may occur at the level of elementary chromatin units, the nucleosomes. They are formed by a segment of DNA wrapped around an octamer of histone proteins. In this review we survey various mechanisms of cancer etiology and progression mediated by histones and nucleosomes. In particular, we discuss the effects of mutations in histones, changes in their expression and slicing on epigenetic dysregulation and carcinogenesis. The links between cancer phenotypes and differential expression of histones variants and isoforms are summarized. Finally, we discourse the geometric and steric effects of DNA compaction in nucleosomes on DNA mutation rate, interactions with transcription factors, including pioneer transcription factors, and prospects of cancer cells’ genome and epigenome editing.

26.03.21 [online] ZBP1: Innate sensor regulating cell death and inflammation

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Presenter: Maria Poptsova, head of the International Bioinformatics Laboratory

Review of the publication Teneema Kuriakose and Thirumala-Devi Kanneganti, Trends Immunol. 2018 February ; 39(2): 123–134

Z-DNA binding protein 1 (ZBP1), initially reported as an IFN-inducible, tumor-associated protein, harbors nucleic acid binding domains for left handed helix (Z-form) and RHIM domains for protein homotypic interactions. Recent studies have identified ZBP1 as an innate sensor of viral infections and a target of viral evasion strategies, regulating cell death, inflammasome activation and proinflammatory responses. ZBP1 also functions during development and can trigger perinatal lethality when its RHIM-dependent interactions are not restricted. Here, we review the history and emergence of ZBP1 as a pathogen sensor and a central regulator of cell death and inflammatory responses. We also discuss the gaps in our knowledge regarding the regulation and functions of ZBP1 and highlight potential avenues for future research.

19.03.21 [online] Integrative modeling of structure and dynamics of biomacromolecular complexes

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Presenter: Alexey K. Shaytan, Ph.D., Researcher, International Laboratory of Bioinformatics, Faculty of Computer Science, Lead Investigator, Integrative Biology Group, Faculty of Biology, Moscow State Lomonosov University

The presentation will cover the materials of the dissertation submitted for the degree of Doctor of Science in mathematical biology and bioinformatics. We will discuss the application of computer modeling and simulations techniques for the study of large biomolecular complexes. In particular supercomputer simulations of nucleosomes - elementary units of DNA compaction in eukaryotic genomes - using molecular dynamics simulations method will be presented. We will show how integration of molecular modeling techniques together with various experimental data allows to study DNA compactions in cell nucleus and the structure of amyloid-fibrils.

12.02.21 [online] Genome-wide analysis of DNA G-quadruplex motifs across 37 species provides insights into G4 evolution

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Presenter: Yulia Terentieva (researcher at Bioinformatics Lab).

Presentation of the publication:  Wu, F., Niu, K., Cui, Y. et al. Commun Biol 4, 98 (2021).

Genome-wide analysis of DNA G-quadruplex motifs across 37 species provides insights into G4 evolution G-quadruplex (G4) structures have been predicted in the genomes of many organisms and proven to play regulatory roles in diverse cellular activities. However, there is little information on the evolutionary history and distribution characteristics of G4s. Here, whole-genome characteristics of potential G4s were studied in 37 evolutionarily representative species. During evolution, the number, length, and density of G4s generally increased. Immunofluorescence in seven species confirmed G4s’ presence and evolutionary pattern. G4s tended to cluster in chromosomes and were enriched in genetic regions. Short-loop G4s were conserved in most species, while loop-length diversity also existed, especially in mammals. The proportion of G4-bearing genes and orthologue genes, which appeared to be increasingly enriched in transcription factors, gradually increased. The antagonistic relationship between G4s and DNA methylation sites was detected. These findings imply that organisms may have evolutionarily developed G4 into a novel reversible and elaborate transcriptional regulatory mechanism benefiting multiple physiological activities of higher organisms.

05.02.21 [online] Various aspects of RNA biology: from programmed frameshifting to long non-coding RNAs

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Presenter: Ivan Antonov, PhD, Postdoctoral research scientist, International Laboratory of Bioinformatics, HSE University, Lecturer, Faculty of Computer Science, HSE University, Postdoctoral research scientist, Research Center of Biotechnology RAS

In his report, Ivan Antonov will give a brief overview of projects on various projects aimed at studying the role of RNA in molecular biology. He will present the main results obtained over more than 10 years of his experience in this field. In the first part of the report he will present the new ASSA algorithm for predicting intermolecular RNA-RNA interactions, as well as the application of this algorithm to the data of the FANTOM6 project. As a result of this work, more than 10 long noncoding RNAs (lncRNAs) were found that can regulate the expression of other genes in the nucleus of human cells co-transcriptionally. We will also talk about a large-scale analysis of the predicted RNA-DNA triplexes where the existence of so-called "universal triplex target sites" was predicted. Finally, the preliminary results on the host-pathogen interactions between the M.tuberculosis bacteria and the human macrophage will be briefly presented. The second part of the report will be devoted to the discovery of new cases of programmed ribosomal frameshifting (PRF) in prokaryotic genes. To identify such cases, the GeneTack tool for ab initio prediction of genes with potential frameshiftis was developed. GeneTack predicted frameshifted genes in more than 1000 prokaryotic genomes, and using comparative genomics methods, the most promising candidates were identified for further experimental verification. The most interesting experimental results were obtained for the magnesium / cobalt chelatase gene chlD, which was studied in detail in a separate analysis.

29.01.21 [online] Extensive editing of cellular and viral double-stranded RNA structures accounts for innate immunity suppression and the proviral activity of ADAR1p150

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Presenter: Nazar Beknazarov (researcher at Bioinformatics Lab).

Presentation of the publication:  Pfaller CK, Donohue RC, Nersisyan S, Brodsky L, Cattaneo R (2018) Extensive editing of cellular and viral double-stranded RNA structures accounts for innate immunity suppression and the proviral activity of ADAR1p150. PLoS Biol 16(11): e2006577

The interferon (IFN)-mediated innate immune response is the first line of defense against viruses. However, an IFN-stimulated gene, the adenosine deaminase acting on RNA 1 (ADAR1), favors the replication of several viruses. ADAR1 binds double-stranded RNA and converts adenosine to inosine by deamination. This form of editing makes duplex RNA unstable, thereby preventing IFN induction. To better understand how ADAR1 works at the cellular level, we generated cell lines that express exclusively either the IFN-inducible, cytoplasmic isoform ADAR1^p150, the constitutively expressed nuclear isoform ADAR1^p110, or no isoform. By comparing the transcriptome of these cell lines, we identified more than 150 polymerase II transcripts that are extensively edited, and we attributed most editing events to ADAR1^p150. Editing is focused on inverted transposable elements, located mainly within introns and untranslated regions, and predicted to form duplex RNA structures. Editing of these elements occurs also in primary human samples, and there is evidence for cross-species evolutionary conservation of editing patterns in primates and, to a lesser extent, in rodents. Whereas ADAR1^p150 rarely edits tightly encapsidated standard measles virus (MeV) genomes, it efficiently edits genomes with inverted repeats accidentally generated by a mutant MeV. We also show that immune activation occurs in fully ADAR1-deficient (ADAR1^KO) cells, restricting virus growth, and that complementation of these cells with ADAR1^p150 rescues virus growth and suppresses innate immunity activation. Finally, by knocking out either protein kinase R (PKR) or mitochondrial antiviral signaling protein (MAVS)—another protein controlling the response to duplex RNA—in ADAR1^KO cells, we show that PKR activation elicits a stronger antiviral response. Thus, ADAR1 prevents innate immunity activation by cellular transcripts that include extensive duplex RNA structures. The trade-off is that viruses take advantage of ADAR1 to elude innate immunity control.

20.11.20 [online] ChIP-seq peak calling: review of the state-of-the art methods and approaches

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Presenter: Alexander Fedorov (researcher at Bioinformatics Lab)

A key step in processing ChIP-seq experiments is to find a region enriched in reads relative to the control. The simplicity of this problem is deceiving, it has no formal definition, and there is no generally accepted solution. Here we will review computational challenges in ChIP-seq data processing, fundamental ideas underlying popular algorithms, and summarize peak-calling quality assessment problems.

Time: 18:00-19:30

06.11.20 [online] The role of G-quadruplexes in differential methylation

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Presenter: Dmitry Konovalov (Bioinformatics Lab, Faculty of Computer Science, HSE, PhD student, Faculty of physics, Lomonosov Moscow State University)

Currently it is not fully understood how methylation level affects stability and dynamic of quadruplexes (G4s). Quadruplexes were found both in hypo- and hypermethylated regions. It was shown that G4s are associated with hypomethylation in the human genome, and it is thought that G4 locally regulates methylation level by binding and inhibiting DNMT1. On the other hand methylation induces formation of quadruplexes with increased stability that can arrest DNA polymerase. Here we explored distribution of quadruplexes with different types of differentially methylated positions (DMPs or DMCs) including associated wth sex, age, tissue type and cell differentiation. We found statistically significant depletion of quadruplexes in hypermethylated DMCs in all types of DMCs. The 28-fold enrichment of quadruplexes in hypomethylated DMC was found for sex-related DMCs. This raises the hypothesis that G4s play a regulatory role in escape from X chromosome inactivation.

Time: 18:00-19:30

28.10.20 [online] Recognition of DNA Secondary Structures as Nucleosome Barriers with Deep Learning Methods.

29.09.20 Drug Development: How Mathematical Modeling is Changing the Paradigm of New Drug Development in Oncology

Presenter - Kirill Peskov – Ph.D. in biology,  director JCS «M&S Decisions», head of the scientific groupd of computer oncology in the Sechenov University.

World practices show that the use of various methods of computer science is becoming an integral part of the process of developing original drugs. For example, mathematical modeling of pharmacological data is widely used in drug registration by the regulatory authorities of the United States and the European Union, the FDA and EMA, and machine learning methods are actively in demand in the search for targets and the optimal structure of chemical compounds. During his lecture Kirill Peskov will give an introduction into pharmacometrics, which is a scientific discipline about the quantitative analysis of data from clinical trials, and will tell how new scientific methods are changing the paradigm of drug development.