Publications by authors named "Sergey Larin"

30 Publications

  • Page 1 of 1

Effects of Amino Acid Side-Chain Length and Chemical Structure on Anionic Polyglutamic and Polyaspartic Acid Cellulose-Based Polyelectrolyte Brushes.

Polymers (Basel) 2021 May 28;13(11). Epub 2021 May 28.

Institute of Macromolecular Compounds, Russian Academy of Sciences, Bolshoy pr. 31, 199004 Petersburg, Russia.

We used atomistic molecular dynamics (MD) simulations to study polyelectrolyte brushes based on anionic α,L-glutamic acid and α,L-aspartic acid grafted on cellulose in the presence of divalent CaCl salt at different concentrations. The motivation is to search for ways to control properties such as sorption capacity and the structural response of the brush to multivalent salts. For this detailed understanding of the role of side-chain length, the chemical structure and their interplay are required. It was found that in the case of glutamic acid oligomers, the longer side chains facilitate attractive interactions with the cellulose surface, which forces the grafted chains to lie down on the surface. The additional methylene group in the side chain enables side-chain rotation, enhancing this effect. On the other hand, the shorter and more restricted side chains of aspartic acid oligomers prevent attractive interactions to a large degree and push the grafted chains away from the surface. The difference in side-chain length also leads to differences in other properties of the brush in divalent salt solutions. At a low grafting density, the longer side chains of glutamic acid allow the adsorbed cations to be spatially distributed inside the brush resulting in a charge inversion. With an increase in grafting density, the difference in the total charge of the aspartic and glutamine brushes disappears, but new structural features appear. The longer sides allow for ion bridging between the grafted chains and the cellulose surface without a significant change in main-chain conformation. This leads to the brush structure being less sensitive to changes in salt concentration.
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http://dx.doi.org/10.3390/polym13111789DOI Listing
May 2021

Relative expansion of CD19-negative very-early normal B-cell precursors in children with acute lymphoblastic leukaemia after CD19 targeting by blinatumomab and CAR-T cell therapy: implications for flow cytometric detection of minimal residual disease.

Br J Haematol 2021 May 14;193(3):602-612. Epub 2021 Mar 14.

National Research and Clinical Center for Pediatric Hematology, Oncology and Immunology, Moscow, Russian Federation.

CD19-directed treatment in B-cell precursor acute lymphoblastic leukaemia (BCP-ALL) frequently leads to the downmodulation of targeted antigens. As multicolour flow cytometry (MFC) application for minimal/measurable residual disease (MRD) assessment in BCP-ALL is based on B-cell compartment study, CD19 loss could hamper MFC-MRD monitoring after blinatumomab or chimeric antigen receptor T-cell (CAR-T) therapy. The use of other antigens (CD22, CD10, CD79a, etc.) as B-lineage gating markers allows the identification of CD19-negative leukaemia, but it could also lead to misidentification of normal very-early CD19-negative BCPs as tumour blasts. In the current study, we summarized the results of the investigation of CD19-negative normal BCPs in 106 children with BCP-ALL who underwent CD19 targeting (blinatumomab, n = 64; CAR-T, n = 25; or both, n = 17). It was found that normal CD19-negative BCPs could be found in bone marrow after CD19-directed treatment more frequently than in healthy donors and children with BCP-ALL during chemotherapy or after stem cell transplantation. Analysis of the antigen expression profile revealed that normal CD19-negative BCPs could be mixed up with residual leukaemic blasts, even in bioinformatic analyses of MFC data. The results of our study should help to investigate MFC-MRD more accurately in patients who have undergone CD19-targeted therapy, even in cases with normal CD19-negative BCP expansion.
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http://dx.doi.org/10.1111/bjh.17382DOI Listing
May 2021

Abnormal promoter DNA hypermethylation of the integrin, nidogen, and dystroglycan genes in breast cancer.

Sci Rep 2021 Jan 26;11(1):2264. Epub 2021 Jan 26.

Molecular Genetic Diagnostics Laboratory 2, Research Centre for Medical Genetics, Moskvorechie St 1, 115522, Moscow, Russia.

Cell transmembrane receptors and extracellular matrix components play a pivotal role in regulating cell activity and providing for the concerted integration of cells in the tissue structures. We have assessed DNA methylation in the promoter regions of eight integrin genes, two nidogen genes, and the dystroglycan gene in normal breast tissues and breast carcinomas (BC). The protein products of these genes interact with the basement membrane proteins LAMA1, LAMA2, and LAMB1; abnormal hypermethylation of the LAMA1, LAMA2, and LAMB1 promoters in BC has been described in our previous publications. In the present study, the frequencies of abnormal promoter hypermethylation in BC were 13% for ITGA1, 31% for ITGA4, 4% for ITGA7, 39% for ITGA9, 38% for NID1, and 41% for NID2. ITGA2, ITGA3, ITGA6, ITGB1, and DAG1 promoters were nonmethylated in normal and BC samples. ITGA4, ITGA9, and NID1 promoter hypermethylation was associated with the HER2 positive tumors, and promoter hypermethylation of ITGA1, ITGA9, NID1 and NID2 was associated with a genome-wide CpG island hypermethylated BC subtype. Given that ITGA4 is not expressed in normal breast, one might suggest that its abnormal promoter hypermethylation in cancer is non-functional and is thus merely a passenger epimutation. Yet, this assumption is not supported by our finding that it is not associated with a hypermethylated BC subtype. ITGA4 acquires expression in a subset of breast carcinomas, and methylation of its promoter may be preventive against expression in some tumors. Strong association of abnormal ITGA4 hypermethylation with the HER2 positive tumors (p = 0.0025) suggests that simultaneous presence of both HER2 and integrin α4 receptors is not beneficial for tumor cells. This may imply HER2 and integrin α4 signaling pathways interactions that are yet to be discovered.
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http://dx.doi.org/10.1038/s41598-021-81851-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7838398PMC
January 2021

Ionic liquids: prospects for nucleic acid handling and delivery.

Nucleic Acids Res 2021 02;49(3):1201-1234

N.D. Zelinsky Institute of Organic Chemistry, Russian Academy of Sciences, Leninsky prospect 47, Moscow 119991, Russia.

Operations with nucleic acids are among the main means of studying the mechanisms of gene function and developing novel methods of molecular medicine and gene therapy. These endeavours usually imply the necessity of nucleic acid storage and delivery into eukaryotic cells. In spite of diversity of the existing dedicated techniques, all of them have their limitations. Thus, a recent notion of using ionic liquids in manipulations of nucleic acids has been attracting significant attention lately. Due to their unique physicochemical properties, in particular, their micro-structuring impact and tunability, ionic liquids are currently applied as solvents and stabilizing media in chemical synthesis, electrochemistry, biotechnology, and other areas. Here, we review the current knowledge on interactions between nucleic acids and ionic liquids and discuss potential advantages of applying the latter in delivery of the former into eukaryotic cells.
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http://dx.doi.org/10.1093/nar/gkaa1280DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7897475PMC
February 2021

Human Short Peptidoglycan Recognition Protein PGLYRP1/Tag-7/PGRP-S Inhibits Intracellular Survival in Macrophages.

Front Cell Infect Microbiol 2020 23;10:582803. Epub 2020 Dec 23.

Laboratory of Molecular Immunology, Dmitry Rogachev National Medical Research Center of Pediatric Hematology, Oncology and Immunology, Russian Ministry of Health, Moscow, Russia.

PGLYRP1/Tag-7/PGRP-S is one of mammalian peptidoglycan recognition proteins (PGRPs). Here, we demonstrate that human recombinant PGLYRP1/Tag-7/PGRP-S potentiates the response of murine macrophage-like ANA-1 cells and human macrophages to facultative intracellular pathogen . PGLYRP1/Tag-7/PGRP-S binds to the surface of and other bacterial cells but has no effect on their growth in culture. While PGLYRP1/Tag-7/PGRP-S treatment modestly enhanced phagocytosis of bacteria by ANA-1 cells, the intracellular survival of PGLYRP1/Tag-7/PGRP-S treated was strongly inhibited 2 h after internalization. PGLYRP1/Tag-7/PGRP-S treatment of bacteria boosted oxidative burst induction and increased the level of proinflammatory cytokine IL-6 produced by ANA-1, however, these effects happened too late to be responsible for decreased intracellular survival of bacteria. Our results thus suggest that PGLYRP1/Tag-7/PGRP-S acts as a molecular sensor for detection of infection of mammalian cells that leads to increased killing through a mechanism(s) that remains to be defined.
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http://dx.doi.org/10.3389/fcimb.2020.582803DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7785527PMC
June 2021

Branched linear lactide chains for cellulose nanoparticle modification: an atomistic molecular dynamics study.

Phys Chem Chem Phys 2021 Jan;23(1):457-469

Institute of Macromolecular Compounds, Russian Academy of Sciences, Bolshoj pr. 31 (V.O.), St. Petersburg 199004, Russia.

We studied the structure of brushes consisting of branched oligolactide (OLA) chains grafted onto the surface of cellulose nanoparticles (CNPs) in polylactide (PLA) and compared the outcomes to the case of grafting linear OLA chains using atomistic molecular dynamics simulations. The systems were considered in a melt state. The branched model OLA chains comprised one branching point and three branches, while the linear OLA chains examined had a molecular weight similar to the branched chains. It was shown that free branches of the branched OLA chains tend to fold back toward the CNPs due to dipole-dipole interactions within the grafted layer, in contrast to the well-established behavior of the grafted uncharged branched chains. This result, however, is in qualitative agreement with the conformational behavior known for linear OLA chains. At the same time, no significant difference in the effectiveness of covering the filler surface with grafted branched or linear OLA chains was found. In terms of the expelling ability of the grafted chains and the interaction between PLA and CNP or OLA, the linear chains were broadly similar (sparse grafting) or better (intermediate or dense grafting) compared to the branched ones. Thus, the grafted lactide chains with a linear architecture, rather than their branched counterpart, may be preferable for the covalent modification of cellulose nanoparticles.
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http://dx.doi.org/10.1039/d0cp04556jDOI Listing
January 2021

Efficacy of romiplostim in treatment of thrombocytopenia in children with Wiskott-Aldrich syndrome.

Br J Haematol 2021 01 31;192(2):366-374. Epub 2020 Oct 31.

Department of Immunology, Dmitry Rogachev National Medical Center of Pediatric Hematology, Oncology and Immunology, Moscow, Russia.

Wiskott-Aldrich syndrome (WAS) is a life-threatening primary immunodeficiency associated with bleeding of variable severity due to thrombocytopenia. Correction of the thrombocytopenia is of paramount importance for most WAS patients. We report a retrospective analysis of the safety and efficacy of romiplostim treatment in reducing thrombocytopenia and bleeding tendency in 67 children (median age 1·3 years) with genetically confirmed WAS, followed in eight months (range, 1-12 months). Complete or partial primary responses regarding platelet counts were observed in 22 (33%) and 18 (27%) subjects, respectively. Yet, even in the non-responder group, the risk of haemorrhagic events decreased significantly, to 21%, after the first month of treatment. The responses tended to be durable and stable over time, with no significant fluctuations in platelets counts. The results of this retrospective study of a large cohort of WAS patients demonstrates that romiplostim can be used to increase platelet counts and reduce the risks of life-threatening bleeding in WAS patients awaiting haematopoietic stem cell transplantation or forgoing the procedure for various reasons.
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http://dx.doi.org/10.1111/bjh.17174DOI Listing
January 2021

Abnormal Hypermethylation of CpG Dinucleotides in Promoter Regions of Matrix Metalloproteinases Genes in Breast Cancer and Its Relation to Epigenomic Subtypes and HER2 Overexpression.

Biomedicines 2020 May 10;8(5). Epub 2020 May 10.

Epigenetics Laboratory, Research Centre for Medical Genetics, Moskvorechie St 1, 115522 Moscow, Russia.

Matrix metalloproteinases (MMPs) and their tissue inhibitors (TIMPs) substantially contribute to the regulation of intercellular interactions and thereby play a role in maintaining the tissue structure and function. We examined methylation of a subset of 5'-cytosine-phosphate-guanine-3' (CpG) dinucleotides in promoter regions of the , , and genes by methylation-sensitive restriction enzyme digestion PCR. In our collection of 183 breast cancer samples, abnormal hypermethylation was observed for CpGs in , and promoter regions. The non-methylated status of the examined CpGs in promoter regions of , and in tumors was associated with low HER2 expression, while the group of samples with abnormal hypermethylation of at least two of these MMP genes was significantly enriched with HER2-positive tumors. Abnormal methylation of and was significantly associated with a CpG island hypermethylated breast cancer subtype discovered by genome-wide DNA bisulfite sequencing. Our results indicate that abnormal hypermethylation of at least several MMP genes promoters is a secondary event not directly functional in breast cancer (BC) pathogenesis. We suggest that it is elevated and/or ectopic expression, rather than methylation-driven silencing, that might link MMPs to tumorigenesis.
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http://dx.doi.org/10.3390/biomedicines8050116DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7277193PMC
May 2020

Grafting-Induced Structural Ordering of Lactide Chains.

Polymers (Basel) 2019 Dec 11;11(12). Epub 2019 Dec 11.

Institute of Macromolecular Compounds, Russian Academy of Sciences, Bolshoj pr. 31 (V.O.), 199004 St. Petersburg, Russia.

The structure of a grafted layer of lactide chains in the "dry brush" regime immersed in a melt of chemically similar polymer was examined while varying graft lengths. To this end, microsecond atomistic molecular dynamics simulations were performed. Almost no influence of graft length on the fraction of the grafted chains backfolded to the grafting surface was found. However, a structural ordering was unexpectedly observed in the system when the length of the grafted lactide chains was close to approximately 10 Kuhn segments. This ordering of the grafts is characterized by the formation of helical fragments whose structure is in good agreement with the experimental data for the crystal of the lactide chains. Both the backfolding and the structural ordering may be viewed as the initial stage of the crystallization of the layer of grafted lactide chains. In contrast to the known behavior for conventional polymer brushes in the "dry brush" regime, the structure of the grafted lactide chains can be either amorphous or ordered, depending on the graft length and the grafting density when their product is fixed.
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http://dx.doi.org/10.3390/polym11122056DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6961058PMC
December 2019

Toward Predictive Molecular Dynamics Simulations of Asphaltenes in Toluene and Heptane.

ACS Omega 2019 Nov 12;4(22):20005-20014. Epub 2019 Nov 12.

Institute of Macromolecular Compounds, Russian Academy of Sciences, Bolshoi pr. 31 (V.O.), 199004 St. Petersburg, Russia.

The conventional definition of asphaltenes is based on their solubility in toluene and their insolubility in heptane. We have utilized this definition to study the influence of partial charge parametrization on the aggregation behavior of asphaltenes using classical atomistic molecular dynamics simulations performed on the microsecond time scale. Under consideration here are toluene- and heptane-based systems with different partial charges parametrized using the general AMBER force field (GAFF). Systems with standard GAFF partial charges calculated by the AM1-BCC and HF/6-31G*(RESP) methods were simulated alongside systems without partial charges. The partial charges implemented differ in terms of the resulting electrical negativity of the asphaltene polyaromatic core, with the AM1-BCC method giving the greatest magnitude of the total core charge. Based on our analysis of the molecular relaxation and orientation, and on the aggregation behavior of asphaltenes in toluene and heptane, we proposed to use the partial charges obtained by the AM1-BCC method for the study of asphaltene aggregates. A good agreement with available experimental data was observed on the sizes of the aggregates, their fractal dimensions, and the solvent entrainment for the model asphaltenes in toluene and heptane. From the results obtained, we conclude that for a better predictive ability, simulation parameters must be carefully chosen, with particular attention paid to the partial charges owing to their influence on the electrical negativity of the asphaltene core and on the asphaltenes aggregation.
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http://dx.doi.org/10.1021/acsomega.9b02992DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6882142PMC
November 2019

Gene- and Disease-Based Expansion of the Knowledge on Inborn Errors of Immunity.

Front Immunol 2019 21;10:2475. Epub 2019 Oct 21.

The Laboratory of Molecular Immunology, Rogachev National Research Center of Pediatric Hematology, Oncology and Immunology, Moscow, Russia.

The recent report of the International Union of Immunological Societies (IUIS) has provided the categorized list of 354 inborn errors of immunity. We performed a systematic analysis of genes and diseases from the IUIS report with the use of the OMIM, ORPHANET, and HPO resources. To measure phenotypic similarity we applied the Jaccard/Tanimoto (J/T) coefficient for HPO terms and top-level categories. Low J/T coefficients for HPO terms for OMIM or ORPHANET disease pairs associated with the same genes indicated high pleiotropy of these genes. Gene ORGANizer enrichment analysis demonstrated that gene sets related to HPO top-level categories were most often enriched in immune, lymphatic, and corresponding body systems (for example, genes from the category "Cardiovascular" were enriched in cardiovascular system). We presented available data on frequent and very frequent clinical signs and symptoms in inborn errors of immunity. With the use of DisGeNET, we generated the list of 25 IUIS/OMIM diseases with two or more relatively high score gene-disease associations, found for unrelated genes and/or for clusters of genes coding for interacting proteins. Our study showed the enrichment of gene sets related to several IUIS categories with neoplastic and autoimmune diseases from the GWAS Catalog and reported individual genes with phenotypic overlap between inborn errors of immunity and GWAS diseases/traits. We concluded that genetic background may play a role in phenotypic diversity of inborn errors of immunity.
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http://dx.doi.org/10.3389/fimmu.2019.02475DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6816315PMC
October 2020

Transport Properties of Thermoplastic R-BAPB Polyimide: Molecular Dynamics Simulations and Experiment.

Polymers (Basel) 2019 Oct 29;11(11). Epub 2019 Oct 29.

Institute of Macromolecular Compounds, Russian Academy of Sciences, Bolshoy pr. V.O., 31, 199004 St. Petersburg, Russia.

The present work evaluates the transport properties of thermoplastic R-BAPB polyimide based on 1,3-bis(3,3',4,4'-dicarboxyphenoxy)benzene (dianhydride R) and 4,4'-bis(4-aminophenoxy)biphenyl (diamine BAPB). Both experimental studies and molecular dynamics simulations were applied to estimate the diffusion coefficients and solubilities of various gases, such as helium (He), oxygen (O), nitrogen (N), and methane (CH). The validity of the results obtained was confirmed by studying the correlation of the experimental solubilities and diffusion coefficients of He, O, and N in R-BAPB, with their critical temperatures and the effective sizes of the gas molecules, respectively. The solubilities obtained in the molecular dynamics simulations are in good quantitative agreement with the experimental data. A good qualitative relationship between the simulation results and the experimental data is also observed when comparing the diffusion coefficients of the gases. Analysis of the Robeson plots shows that R-BAPB has high selectivity for He, N, and CO separation from CH, which makes it a promising polymer for developing gas-separation membranes. From this point of view, the simulation models developed and validated in the present work may be put to effective use for further investigations into the transport properties of R-BAPB polyimide and nanocomposites based on it.
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http://dx.doi.org/10.3390/polym11111775DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6918166PMC
October 2019

Structural Ordering in SWCNT-Polyimide Nanocomposites and Its Influence on Their Mechanical Properties.

Polymers (Basel) 2018 Nov 10;10(11). Epub 2018 Nov 10.

Institute of Macromolecular Compounds, Russian Academy of Sciences, St. Petersburg 199004, Russia.

Using fully-atomistic models, tens-microseconds-long molecular-dynamic modelling was carried out for the first time to simulate the kinetics of polyimides ordering induced by the presence of single-walled carbon nanotube (SWCNT) nanofillers. Three polyimides (PI) were considered with different dianhydride fragments, namely 3,3',4,4'-biphenyltetracarboxylic dianhydride (BPDA), 2,3',3,4'-biphenyltetracarboxylic dianhydride (aBPDA), and 3,3',4,4'-oxidiphthalic dianhydride (ODPA) and same diamine 1,4-bis[4-(4-aminophenoxy)phenoxy]benzene (diamine P3). Both crystallizable PI BPDA-P3 and two amorphous polyimides ODPA-P3 and aBPDA-P3 reinforced by SWCNTs were studied. The structural properties of the nanocomposites at temperature close to the bulk polymer melting point were studied. The mechanical properties were determined for the nanocomposites cooled down to the glassy state. It was found that the SWCNT nanofiller initiates' structural ordering not only in the crystallizable BPDA-P3 but also in the amorphous ODPA-P3 samples were in agreement with previously obtained experimental results. Two stages of the structural ordering were detected in the presence of SWCNTs, namely the orientation of the planar moieties followed by the elongation of whole polymer chains. The first type of local ordering was observed on the microsecond time scale and did not lead to the change of the mechanical properties of a polymer binder in considered nanocomposites. At the end of the second stage, both BPDA-P3 and ODPA-P3 PI chains extended completely along the SWCNT surface, which in turn led to enhanced mechanical characteristics in their glassy state.
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http://dx.doi.org/10.3390/polym10111245DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6401868PMC
November 2018

Genome-wide methylotyping resolves breast cancer epigenetic heterogeneity and suggests novel therapeutic perspectives.

Epigenomics 2019 05 7;11(6):605-617. Epub 2019 Feb 7.

Epigenetics Laboratory, Research Centre for Medical Genetics, Moscow, Russia.

To provide a breast cancer (BC) methylotype classification by genome-wide CpG islands bisulfite DNA sequencing. XmaI-reduced representation bisulfite sequencing DNA methylation sequencing method was used to profile DNA methylation of 110 BC samples and 6 normal breast samples. Intrinsic DNA methylation BC subtypes were elicited by unsupervised hierarchical cluster analysis, and cluster-specific differentially methylated genes were identified. Overall, six distinct BC methylotypes were identified. BC cell lines constitute a separate group extremely highly methylated at the CpG islands. In turn, primary BC samples segregate into two major subtypes, highly and moderately methylated. Highly and moderately methylated superclusters, each incorporate three distinct epigenomic BC clusters with specific features, suggesting novel perspectives for personalized therapy.
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http://dx.doi.org/10.2217/epi-2018-0213DOI Listing
May 2019

Proteogenomics of Malignant Melanoma Cell Lines: The Effect of Stringency of Exome Data Filtering on Variant Peptide Identification in Shotgun Proteomics.

J Proteome Res 2018 05 16;17(5):1801-1811. Epub 2018 Apr 16.

Institute of Biomedical Chemistry , Moscow 119121 , Russia.

The identification of genetically encoded variants at the proteome level is an important problem in cancer proteogenomics. The generation of customized protein databases from DNA or RNA sequencing data is a crucial stage of the identification workflow. Genomic data filtering applied at this stage may significantly modify variant search results, yet its effect is generally left out of the scope of proteogenomic studies. In this work, we focused on this impact using data of exome sequencing and LC-MS/MS analyses of six replicates for eight melanoma cell lines processed by a proteogenomics workflow. The main objectives were identifying variant peptides and revealing the role of the genomic data filtering in the variant identification. A series of six confidence thresholds for single nucleotide polymorphisms and indels from the exome data were applied to generate customized sequence databases of different stringency. In the searches against unfiltered databases, between 100 and 160 variant peptides were identified for each of the cell lines using X!Tandem and MS-GF+ search engines. The recovery rate for variant peptides was ∼1%, which is approximately three times lower than that of the wild-type peptides. Using unfiltered genomic databases for variant searches resulted in higher sensitivity and selectivity of the proteogenomic workflow and positively affected the ability to distinguish the cell lines based on variant peptide signatures.
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http://dx.doi.org/10.1021/acs.jproteome.7b00841DOI Listing
May 2018

Gene expression and molecular pathway activation signatures of -amplified neuroblastomas.

Oncotarget 2017 Oct 28;8(48):83768-83780. Epub 2017 Jul 28.

D. Rogachev Federal Research Center of Pediatric Hematology, Oncology and Immunology, Moscow, Russia.

Neuroblastoma is a pediatric cancer arising from sympathetic nervous system. Remarkable heterogeneity in outcomes is one of its widely known features. One of the traits strongly associated with the unfavorable subtype is the amplification of oncogene . Here, we performed cross-platform biomarker detection by comparing gene expression and pathway activation patterns from the two literature reports and from our experimental dataset, combining profiles for the 761 neuroblastoma patients with known amplification status. We identified 109 / 25 gene expression / pathway activation biomarkers strongly linked with the amplification. The marker genes/pathways are involved in the processes of purine nucleotide biosynthesis, ATP-binding, tetrahydrofolate metabolism, building mitochondrial matrix, biosynthesis of amino acids, tRNA aminoacylation and NADP-linked oxidation-reduction processes, as well as in the tyrosine phosphatase activity, p53 signaling, cell cycle progression and the G1/S and G2/M checkpoints. To connect molecular functions of the genes involved in -amplified phenotype, we built a new molecular pathway using known intracellular protein interaction networks. The activation of this pathway was highly selective in discriminating -amplified neuroblastomas in all three datasets. Our data also suggest that the phosphoinositide 3-kinase (PI3K) inhibitors may provide new opportunities for the treatment of the -amplified neuroblastoma subtype.
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http://dx.doi.org/10.18632/oncotarget.19662DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5663553PMC
October 2017

Atomistic Molecular Dynamics Simulations of the Initial Crystallization Stage in an SWCNT-Polyetherimide Nanocomposite.

Polymers (Basel) 2017 Oct 24;9(10). Epub 2017 Oct 24.

Institute of Macromolecular Compounds, Russian Academy of Sciences, Bol'shoi pr. 31 (V.O.), St. Petersburg 199004, Russia.

Crystallization of all-aromatic heterocyclic polymers typically results in an improvement of their thermo-mechanical properties. Nucleation agents may be used to promote crystallization, and it is well known that the incorporation of nanoparticles, and in particular carbon-based nanofillers, may induce or accelerate crystallization through nucleation. The present study addresses the structural properties of polyetherimide-based nanocomposites and the initial stages of polyetherimide crystallization as a result of single-walled carbon nanotube (SWCNT) incorporation. We selected two amorphous thermoplastic polyetherimides ODPA-P3 and aBPDA-P3 based on 3,3',4,4'-oxydiphthalic dianhydride (ODPA), 2,3',3,4'-biphenyltetracarboxylic dianhydride (aBPDA) and diamine 1,4-[4-(4-aminophenoxy)phenoxy]benzene (P3) and simulated the onset of crystallization in the presence of SWCNTs using atomistic molecular dynamics. For ODPA-P3, we found that the planar phthalimide and phenylene moieties show pronounced ordering near the CNT (carbon nanotube) surface, which can be regarded as the initial stage of crystallization. We will discuss two possible mechanisms for ODPA-P3 crystallization in the presence of SWCNTs: the spatial confinement caused by the CNTs and π⁻π interactions at the CNT-polymer matrix interface. Based on our simulation results, we propose that ODPA-P3 crystallization is most likely initiated by favorable π⁻π interactions between the carbon nanofiller surface and the planar ODPA-P3 phthalimide and phenylene moieties.
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http://dx.doi.org/10.3390/polym9100548DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6418835PMC
October 2017

Rapid and affordable genome-wide bisulfite DNA sequencing by XmaI-reduced representation bisulfite sequencing.

Epigenomics 2017 06 10;9(6):833-847. Epub 2017 May 10.

Epigenetics Laboratory, Research Centre for Medical Genetics, Moskvorechie Street 1, Moscow 115478, Russia.

Aim: To develop a reduced representation bisulfite sequencing (RRBS) approach for rapid and affordable genome-wide DNA methylation analysis.

Methods: We have selected restriction endonuclease XmaI to produce RRBS library fragments. After digestion and partial fill-in DNA fragments were ligated to barcoded adapters, bisulfite converted, size-selected, and sequenced on the Ion Torrent Personal Genome Machine. XmaI-RRBS results were compared with the previously published RRBS data.

Results: We have developed an XmaI-RRBS method for rapid and affordable genome-wide DNA methylation analysis, with library preparation taking only 4 days and sequencing possible within 4 h. We have also addressed several challenges in order to further improve the RRBS technology. XmaI-RRBS may be performed on degraded DNA samples and is compatible with the bench-top next-generation sequencing machines.
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http://dx.doi.org/10.2217/epi-2017-0031DOI Listing
June 2017

Molecular pathway activation features of pediatric acute myeloid leukemia (AML) and acute lymphoblast leukemia (ALL) cells.

Aging (Albany NY) 2016 11;8(11):2936-2947

D. Rogachev Federal Research Center of Pediatric Hematology, Oncology and Immunology, Moscow, 117198, Russia.

Acute lymphoblast leukemia (ALL) is characterized by overproduction of immature white blood cells in the bone marrow. ALL is most common in the childhood and has high (>80%) cure rate. In contrast, acute myeloid leukemia (AML) has far greater mortality rate than the ALL and is most commonly affecting older adults. However, AML is a leading cause of childhood cancer mortality. In this study, we compare gene expression and molecular pathway activation patterns in three normal blood, seven pediatric ALL and seven pediatric AML bone marrow samples. We identified 172/94 and 148/31 characteristic gene expression/pathway activation signatures, clearly distinguishing ALL and AML cells, respectively, from the normal blood. The AML and ALL cells differed by 139/34 gene expression/pathway activation biomarkers. For the 30 AML and 17 normal blood samples, we found 132/33 gene expression/pathway AML-specific features, of which only 7/2 were common for the adult and pediatric AML and, therefore, age-independent. At the pathway level, we found more differences than similarities between the adult and pediatric forms. These findings suggest that the adult and pediatric AMLs may require different treatment strategies.
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http://dx.doi.org/10.18632/aging.101102DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5182073PMC
November 2016

Highly efficient 2  μm CW and Q-switched Tm3+:Lu2O3 ceramics lasers in-band pumped by a Raman-shifted erbium fiber laser at 1670  nm.

Opt Lett 2016 May;41(10):2298-301

Highly efficient laser oscillations at 2 μm were investigated in Tm:Lu2O3 ceramics in-band pumped at 1670 nm by a Raman-shifted erbium fiber laser. Both 23 W CW and 15 W active Q-switched oscillations with 40 ns pulse duration and 15-30 kHz repetition rate were achieved in a high-quality beam. The evolution of two generated waves at 1966 and 2064 nm in dependence on pump power was studied.
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http://dx.doi.org/10.1364/OL.41.002298DOI Listing
May 2016

Hybrid booster at 1940 nm based on Tm:Lu₂O₃ ceramics implementing fiber combined signal and pump sources.

Opt Lett 2014 Jun;39(11):3216-8

A novel concept of a booster amplifier for a pulsed Tm fiber laser at 1940 nm based on Tm:Lu2O3 ceramics and implementing fiber-combined signal and pump was examined. The pumping emission of the ceramics at 1678 nm was obtained from Raman-shifted Er fiber laser radiation. The hybrid fiber-ceramics amplifier with a gain factor of up to 6 dB and a pulse energy of more than 650 μJ with single-mode output was demonstrated.
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http://dx.doi.org/10.1364/OL.39.003216DOI Listing
June 2014

Thermal properties of bulk polyimides: insights from computer modeling versus experiment.

Soft Matter 2014 Feb;10(8):1224-32

Institute of Macromolecular Compounds, Russian Academy of Sciences, Bol'shoi pr. 31 (V.O.), St. Petersburg, 199004 Russia.

Due to the great importance for many industrial applications it is crucial from the point of view of theoretical description to reproduce thermal properties of thermoplastic polyimides as accurate as possible in order to establish "chemical structure-physical properties" relationships of new materials. In this paper we employ differential scanning calorimetry, dilatometry, and atomistic molecular dynamics (MD) simulations to explore whether the state-of-the-art computer modeling can serve as a precise tool for probing thermal properties of polyimides with highly polar groups. For this purpose the polyimide R-BAPS based on dianhydride 1,3-bis(3',4-dicarboxyphenoxy)benzene (dianhydride R) and diamine 4,4'-bis(4''-aminophenoxy)biphenyl sulphone) (diamine BAPS) was synthesized and extensively studied. Overall, our findings show that the widely used glass-transition temperature Tg evaluated from MD simulations should be employed with great caution for verification of the polyimide computational models against experimental data: in addition to the well-known impact of the cooling rate on the glass-transition temperature, correct definition of Tg requires cooling that starts from very high temperatures (no less than 800 K for considered polyimides) and accurate evaluation of the appropriate cooling rate, otherwise the errors in the measured values of Tg become undefined. In contrast to the glass-transition temperature, the volumetric coefficient of thermal expansion (CTE) does not depend on the cooling rate in the low-temperature domain (T < Tg) so that comparison of computational and experimental values of CTE provides a much safer way for proper validation of the theoretical model when electrostatic interactions are taken into account explicitly. Remarkably, this conclusion is most likely of generic nature: we show that it also holds for the commercial polyimide EXTEM, another polyimide with a similar chemical structure.
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http://dx.doi.org/10.1039/c3sm52521jDOI Listing
February 2014

Cooperation of TLR12 and TLR11 in the IRF8-dependent IL-12 response to Toxoplasma gondii profilin.

J Immunol 2013 Nov 27;191(9):4818-27. Epub 2013 Sep 27.

Department of Immunology, University of Texas Southwestern Medical Center, Dallas, TX 75390;

TLRs play a central role in the innate recognition of pathogens and the activation of dendritic cells (DCs). In this study, we establish that, in addition to TLR11, TLR12 recognizes the profilin protein of the protozoan parasite Toxoplasma gondii and regulates IL-12 production by DCs in response to the parasite. Similar to TLR11, TLR12 is an endolysosomal innate immune receptor that colocalizes and interacts with UNC93B1. Biochemical experiments revealed that TLR11 and TLR12 directly bind to T. gondii profilin and are capable of forming a heterodimer complex. We also establish that the transcription factor IFN regulatory factor 8, not NF-κB, plays a central role in the regulation of the TLR11- and TLR12-dependent IL-12 response of DCs. These results suggest a central role for IFN regulatory factor 8-expressing CD8(+) DCs in governing the TLR11- and TLR12-mediated host defense against T. gondii.
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http://dx.doi.org/10.4049/jimmunol.1301301DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3805684PMC
November 2013

Water-soluble nonstoichiometric complexes between sodium poly(styrenesulfonate) and cetylpyridinium chloride in aqueous NaCl solutions. A static and dynamic light scattering study.

J Phys Chem B 2011 Apr 21;115(14):3793-803. Epub 2011 Mar 21.

Department of Chemistry and Biochemistry, Faculty of Chemistry and Chemical Technology, University of Ljubljana, P.O. Box 537, SI-1000, Ljubljana, Slovenia.

Complexes formed between a cationic surfactant cetylpyridinium chloride, CPC, and an anionic polyelectrolyte sodium poly(styrenesulfonate), NaPSS, in aqueous 0.1 M NaCl solutions were studied by static and dynamic light scattering and by ζ-potential measurements in a broad region of surfactant cation, CP(+), to polyanion, PSS(-), charge ratio, S/P. Two NaPSS samples were used, NaPSS-L with a lower molar mass, M(w) = 1.4 × 10(5) g/mol, and NaPSS-H with a considerably higher M(w) (= 2.6 × 10(6) g/mol), to elucidate the effect of the polyion chain length on the behavior of the aggregates. In the polyelectrolyte-rich regime (S/P < 1), CPPSS complexes are soluble up to rather high S/P values (around 0.72, irrespective of the polyion chain length), which is attributed to a specific interaction between the hydrophobic benzene groups on the polyion and the surfactant micelle, which leads to a less efficient charge screening. The addition of surfactant causes chain contraction. The obtained data suggest a pronounced effect of the NaPSS chain length on the structural properties of the CPPSS complexes. The CPPSS-L complexes are small and dense (the radius of gyration, R(g), is 7.3 nm at S/P = 0.7), and their shape is close to spherical. In contrast, the CPPSS-H complexes (R(g) around 73 nm at S/P = 0.7) have no well-defined structure and reveal a stronger tendency toward intermolecular association when the nominal charge of the complex is reduced, although they remain pretty monodisperse. A model of a temporary network-like association in which surfactant micelles serve as cross-links for polyion chains is proposed to explain the behavior in CPPSS-H solutions. The forces responsible for such labile intermolecular association are weak, in contrast to strong specific interaction involved in the formation of the primary complex. The redissolution of the complex by adding excess surfactant (S/P > 1: the surfactant-rich regime) depends strongly on the polyion chain length and is a slow process, taking several days (CPPSS-L) or even weeks (CPPSS-H). It is achieved only at very high S/P values (around 240 and 2400 in the CPPSS-L and CPPSS-H cases, respectively) by hydrophobic binding of surfactant to the CPPSS complex. The predominating species in these solutions are free surfactant micelles. Similarly, a large excess of NaCl (almost 390 and 690 mol per 1 mol of CPPSS-L and CPPSS-H, respectively) is needed to disintegrate the stoichiometric CPPSS (S/P = 1) complex into free polyion chains and free surfactant micelles.
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http://dx.doi.org/10.1021/jp2008336DOI Listing
April 2011

Linker formation in an overcharged complex of two dendrimers and linear polyelectrolyte.

J Phys Chem B 2010 Mar;114(8):2910-9

Institute of Macromolecular Compounds, Russian Academy of Sciences, Bolshoj pr., d. 31, St. Petersburg, Russia.

The complexes formed by two dendrimers with charged terminal groups and oppositely charged long linear polyelectrolyte (LPE) have been studied using Brownian dynamics simulations. The structural properties of the complexes and their dependence on the LPE chain length were investigated. It was observed that dendrimers in the considered complexes are sufficiently overcharged; i.e., the number of adsorbed LPE monomers is larger than required for the neutralization. The degree of overcharging increases with the increase of the LPE length and is accompanied by the linker appearance until saturation in overcharging is reached. Nonmonotonic dependence of the linker size on the LPE length was observed. To describe the structural properties of the complexes formed by two macroions and a polyelectrolyte chain, the correlation theory has been developed.
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http://dx.doi.org/10.1021/jp908196tDOI Listing
March 2010

Tracking Ku antigen levels in cell extracts with DNA containing abasic sites.

Mutat Res 2010 Mar 25;685(1-2):90-6. Epub 2009 Aug 25.

Institute of Chemical Biology and Fundamental Medicine, Siberian Branch of the Russian Academy of Sciences, Prospect Lavrentieva 8, 630090, Novosibirsk, Russia.

Prominent lesions in DNA are abasic (AP) sites arising spontaneously or as intermediates during base excision repair. An AP site can form a Schiff base intermediate with primary amino groups of proteins. This intermediate can be stabilized by NaBH(4) treatment and, therefore, cross-linking of AP site-containing DNA (AP DNA) can be used as a tool in detecting proteins that interact with AP sites. Using AP DNA, we observed in the extracts derived from several human cell lines a predominant cross-linked product with an apparent molecular mass of 95kDa. The cross-linked protein was identified as the p80 subunit of Ku antigen (Ku80) (Ilina et al., Biochem. Biophys. Acta 1784 (2008) 1777-1785 [1]). Because the cross-linking of Ku80 to AP sites is efficient and selective, this approach may be useful to estimate the amount of Ku antigen in cell extracts in the presence of other cellular proteins. We compared levels of Ku80 detected by dot-ELISA with Ku80 antibodies to the levels of Ku80 cross-linked to AP DNA in extracts derived from HeLa cells and several melanoma cell lines. The level of Ku80 trapping varied considerably depending on the cell lines and correlated with the amount of Ku80 in the extracts estimated by the immunochemical approach. This approach, unlike western blot or estimation of the Ku content based on mRNA levels, is more suitable for tracking Ku forms active in DNA binding including those having aberrations in Ku80, but retaining an ability to heterodimerize with Ku70, that provides efficient loading of Ku antigen onto DNA ends. As a routine test, borohydride trapping (BHT) is also less time and reagent consuming than blotting and EMSA.
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http://dx.doi.org/10.1016/j.mrfmmm.2009.08.008DOI Listing
March 2010

Interpolyelectrolyte complexes between starlike and linear macromolecules: a structural model for nonviral gene vectors.

Langmuir 2009 Feb;25(4):1915-8

Institute of Macromolecular Compounds, Russian Academy of Sciences, 199004 St. Petersburg, Russia.

Molecular dynamics simulations are used to probe the structural organization of nonstoichiometric interpolyelectrolyte complexes (IPECs) formed by oppositely charged starlike and linear polyelectrolytes (PEs) in dilute aqueous solution. We demonstrate that undercompensated star-IPEC consists of a denser coacervate core and a charged starlike corona. Two distinctive populations of star branches completely embedded in a coacervate core and stretched in a lyophilizing corona are found. The scaling arguments support the stability of IPEC with partitioned star branches.
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http://dx.doi.org/10.1021/la8037022DOI Listing
February 2009

Structural effects in overcharging in complexes of hyperbranched polymers with linear polyelectrolytes.

Soft Matter 2008 Feb;4(3):453-457

Group Polymer Physics, Eindhoven Polymer Laboratories and Dutch Polymer Institute, Technische Universiteit Eindhoven, P.O. Box 513, MB Eindhoven, 5600, The Netherlands.

New insight is provided by a combined theoretical and simulational approach regarding the effects of structural characteristics of the constituents, on the overcharging phenomena in complexes formed by hyperbranched polymers with linear polyelectrolytes.
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http://dx.doi.org/10.1039/b716647hDOI Listing
February 2008

Immunotherapy with autologous tumor cells engineered to secrete Tag7/PGRP, an innate immunity recognition molecule.

J Gene Med 2004 Jul;6(7):798-808

Institute of Gene Biology, Russian Academy of Sciences, Moscow, Russia.

Background: Recent studies indicate that the innate component of immune defense plays an important role in the establishment of antigen-specific immune response. We have previously isolated a novel mouse gene tag7/PGRP that was shown to be involved in the innate component of the immune system, and its insect homologue is an upstream mediator of Toll signaling in Drosophila.

Methods: Transiently or stably genetically modified mouse tumor cell lines expressing Tag7 were used. Tumor growth rate and animal survival were analyzed. Possible effector cells involved in tumor suppression were detected immunohistochemically.

Results: Transfection of mammary gland adenocarcinoma cells with the tag7 cDNA did not alter their growth rate in vitro but diminished their tumorogenicity in vivo in syngeneic and immunodeficient animals. Increased incidence of apoptosis was registered in the modified tumors. Transient expression of Tag7 by mouse melanoma M3 cells elicited protective immunity against parental tumor cells. Immunohistochemical analysis revealed that tumors after immunization with the genetically modified cells were infiltrated with Mac1(+) cells, B220(+) cells, and NK cells. Using nude mice we observed rejection of modified cells, but did not detect memory formation.

Conclusions: We can conclude that secretion of the Tag7 protein by genetically modified cells can induce mobilization of antigen-presenting cells and innate effectors. Memory mechanisms are mediated by T cell response. For the first time our results demonstrate that local secretion of Tag7-the molecule involved in innate immunity-may play an important role in the induction of effective antitumor response in mice.
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http://dx.doi.org/10.1002/jgm.560DOI Listing
July 2004

Adhesion of Fibroblasts to Immobilized alpha(2)-Macroglobulin.

Russ J Immunol 2000 Apr;5(1):27-32

Russian State Medical University, Moscow, Russia.

This study examines effects of alpha(2)-macroglobulin (alpha(2)M) on adhesion of fibroblasts. Native alpha(2)M and transformed form of alpha(2)M, alpha(2)M-plasmin, were bound to plastic. Adhesion of mouse L929 and human embryo M-19 fibroblasts to immobilized alpha(2)M was estimated under various conditions by counting adherent cells using videomicroscopy and computer-assisted image analysis. alpha(2)M-plasmin, bound to plastic, induced adhesion and spreading of mouse L929 and human M-19 fibroblasts. Neither native alpha(2)M nor plasmin alone did not induce fibroblast adhesion. The adhesion to alpha(2)M-plasmin was undetectable at 4 degrees C, as well as when sodium azide was added or divalent ions were removed. These findings provide novel information on alpha(2)M functions. On the basis of these observations we hypothesized that alpha(2)M, immobilized in the extracellular matrix, can participate in the regulation of microenvironment effects on the cells, and, in particular, influence on fibroblast adhesion.
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April 2000