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\n \n \n\n \n \n \n \n \n \n Triphenylphosphonium Analogs of Short Peptide Related to Bactenecin 7 and Oncocin 112 as Antimicrobial Agents.\n \n \n \n \n\n\n \n Tereshchenkov, A. G.; Khairullina, Z. Z.; Volynkina, I. A.; Lukianov, D. A.; Nazarov, P. A.; Pavlova, J. A.; Tashlitsky, V. N.; Razumova, E. A.; Ipatova, D. A.; Timchenko, Y. V.; Senko, D. A.; Efremenkova, O. V.; Paleskava, A.; Konevega, A. L.; Osterman, I. A.; Rodin, I. A.; Sergiev, P. V.; Dontsova, O. A.; Bogdanov, A. A.; and Sumbatyan, N. V.\n\n\n \n\n\n\n Pharmaceutics, 16(1): 148. 01 2024.\n \n\n\n\n
\n\n\n\n \n \n![\"Triphenylphosphonium](\"//bibbase.org/img/filetypes/link.svg\"\n\t "\\"Paper\\"\n\t")
Paper\n \n \n\n \n \n doi\n \n \n\n \n link\n \n \n\n bibtex\n \n\n \n \n \n abstract \n \n\n \n\n \n \n \n \n \n \n \n\n \n \n \n \n \n \n \n \n \n \n \n \n \n \n \n\n\n\n
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\n\n\n@Article{Tereshchenkov2024,\n author = {Andrey G. Tereshchenkov and Zimfira Z. Khairullina and Inna A. Volynkina and Dmitrii A. Lukianov and Pavel A. Nazarov and Julia A. Pavlova and Vadim N. Tashlitsky and Elizaveta A. Razumova and Daria A. Ipatova and Yury V. Timchenko and Dmitry A. Senko and Olga V. Efremenkova and Alena Paleskava and Andrey L. Konevega and Ilya A. Osterman and Igor A. Rodin and Petr V. Sergiev and Olga A. Dontsova and Alexey A. Bogdanov and Natalia V. Sumbatyan},\n journal = {Pharmaceutics},\n title = {Triphenylphosphonium Analogs of Short Peptide Related to Bactenecin 7 and Oncocin 112 as Antimicrobial Agents},\n year = {2024},\n issn = {1999-4923},\n month = {01},\n number = {1},\n pages = {148},\n volume = {16},\n abstract = {Antimicrobial peptides (AMPs) have recently attracted attention as promising antibacterial agents capable of acting against resistant bacterial strains. In this work, an approach was applied, consisting of the conjugation of a peptide related to the sequences of bactenecin 7 (Bac7) and oncocin (Onc112) with the alkyl(triphenyl)phosphonium (alkyl-TPP) fragment in order to improve the properties of the AMP and introduce new ones, expand the spectrum of antimicrobial activity, and reduce the inhibitory effect on the eukaryotic translation process. Triphenylphosphonium (TPP) derivatives of a decapeptide RRIRPRPPYL were synthesized. It was comprehensively studied how the modification of the AMP affected the properties of the new compounds. It was shown that while the reduction in the Bac7 length to 10 a.a. residues dramatically decreased the affinity to bacterial ribosomes, the modification of the peptide with alkyl-TPP moieties led to an increase in the affinity. New analogs with structures that combined a decapeptide related to Bac7 and Onc112—Bac(1–10, R/Y)—and TPP attached to the C-terminal amino acid residue via alkylamide linkers, inhibited translation in vitro and were found to be more selective inhibitors of bacterial translation compared with eukaryotic translation than Onc112 and Bac7. The TPP analogs of the decapeptide related to Bac7 and Onc112 suppressed the growth of both Gram-negative bacteria, similar to Onc112 and Bac7, and Gram-positive ones, similar to alkyl-TPP derivatives, and also acted against some resistant laboratory strains. Bac(1–10, R/Y)-C2-TPP, containing a short alkylamide linker between the decapeptide and TPP, was transferred into the <i>E. coli</i> cells via the SbmA transporter protein. TPP derivatives of the decapeptide Bac(1–10, R/Y) containing either a decylamide or ethylamide linker caused <i>B. subtilis</i> membrane depolarization, similar to alkyl-TPP. The Bac(1–10, R/Y)-C2-TPP analog was proven to be non-toxic for mammalian cells using the MTT test.},\n doi = {10.3390/pharmaceutics16010148},\n file = {:Tereshchenkov2024 - Triphenylphosphonium Analogs of Short Peptide Related to Bactenecin 7 and Oncocin 112 As Antimicrobial Agents.pdf:PDF},\n keywords = {alkyl(triphenyl)phosphonium, proline–arginine-rich antimicrobial peptides, bactenecin 7, oncocin 112, bacterial ribosome, bacterial membrane potential},\n publisher = {MDPI AG},\n url = {https://www.mdpi.com/1999-4923/16/1/148},\n}\n\n\n\n Antimicrobial peptides (AMPs) have recently attracted attention as promising antibacterial agents capable of acting against resistant bacterial strains. In this work, an approach was applied, consisting of the conjugation of a peptide related to the sequences of bactenecin 7 (Bac7) and oncocin (Onc112) with the alkyl(triphenyl)phosphonium (alkyl-TPP) fragment in order to improve the properties of the AMP and introduce new ones, expand the spectrum of antimicrobial activity, and reduce the inhibitory effect on the eukaryotic translation process. Triphenylphosphonium (TPP) derivatives of a decapeptide RRIRPRPPYL were synthesized. It was comprehensively studied how the modification of the AMP affected the properties of the new compounds. It was shown that while the reduction in the Bac7 length to 10 a.a. residues dramatically decreased the affinity to bacterial ribosomes, the modification of the peptide with alkyl-TPP moieties led to an increase in the affinity. New analogs with structures that combined a decapeptide related to Bac7 and Onc112—Bac(1–10, R/Y)—and TPP attached to the C-terminal amino acid residue via alkylamide linkers, inhibited translation in vitro and were found to be more selective inhibitors of bacterial translation compared with eukaryotic translation than Onc112 and Bac7. The TPP analogs of the decapeptide related to Bac7 and Onc112 suppressed the growth of both Gram-negative bacteria, similar to Onc112 and Bac7, and Gram-positive ones, similar to alkyl-TPP derivatives, and also acted against some resistant laboratory strains. Bac(1–10, R/Y)-C2-TPP, containing a short alkylamide linker between the decapeptide and TPP, was transferred into the E. coli cells via the SbmA transporter protein. TPP derivatives of the decapeptide Bac(1–10, R/Y) containing either a decylamide or ethylamide linker caused B. subtilis membrane depolarization, similar to alkyl-TPP. The Bac(1–10, R/Y)-C2-TPP analog was proven to be non-toxic for mammalian cells using the MTT test.\n
\n\n\n\n \n\n \n \n \n \n \n \n OCT4 Expression in Gliomas Is Dependent on Cell Metabolism.\n \n \n \n \n\n\n \n Volnitskiy, A.; Shabalin, K.; Pantina, R.; Varfolomeeva, E.; Kovalev, R.; Burdakov, V.; Emelianova, S.; Garaeva, L.; Yakimov, A.; Sogoyan, M.; Filatov, M.; Konevega, A. L.; and Shtam, T.\n\n\n \n\n\n\n Current Issues in Molecular Biology, 46(2): 1107–1120. January 2024.\n \n\n\n\n
\n\n\n\n \n \nPaper\n \n \n\n \n \n doi\n \n \n\n \n link\n \n \n\n bibtex\n \n\n \n \n \n abstract \n \n\n \n\n \n \n \n \n \n \n \n\n \n \n \n\n\n\n
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\n\n\n@Article{Volnitskiy2024,\n author = {Andrey Volnitskiy and Konstantin Shabalin and Rimma Pantina and Elena Varfolomeeva and Roman Kovalev and Vladimir Burdakov and Svetlana Emelianova and L. Garaeva and Alexander Yakimov and Marina Sogoyan and Michael Filatov and Andrey L. Konevega and Tatiana Shtam},\n journal = {Current Issues in Molecular Biology},\n title = {OCT4 Expression in Gliomas Is Dependent on Cell Metabolism},\n year = {2024},\n issn = {1467-3045},\n month = jan,\n number = {2},\n pages = {1107--1120},\n volume = {46},\n abstract = {The OCT4 transcription factor is necessary to maintain cell stemness in the early stages of embryogenesis and is involved in the formation of induced pluripotent stem cells, but its role in oncogenesis is not yet entirely clear. In this work, OCT4 expression was investigated in malignant gliomas. Twenty glioma cell lines and a sample of normal adult brain tissue were used. OCT4 expression was found in all studied glioma cell lines but was not detected in normal adult brain tissue. For one of these lines, OCT4 knockdown caused tumor cell death. By varying the culture conditions of these cells, we unexpectedly found that OCT4 expression increased when cells were incubated in serum-free medium, and this effect was significantly enhanced in serum-free and L-glutamine-free medium. L-glutamine and the Krebs cycle, which is slowed down in serum-free medium according to our NMR data, are sources of α-KG. Thus, our data indicate that OCT4 expression in gliomas may be regulated by the α-KG-dependent metabolic reprogramming of cells.},\n doi = {10.3390/cimb46020070},\n file = {:Volnitskiy2024 - OCT4 Expression in Gliomas Is Dependent on Cell Metabolism.pdf:PDF},\n publisher = {MDPI AG},\n url = {https://www.semanticscholar.org/paper/00ec355fc4cde8aca73f6a5d389342e2028c7bfb},\n venue = {Current Issues in Molecular Biology},\n}\n\n\n\n The OCT4 transcription factor is necessary to maintain cell stemness in the early stages of embryogenesis and is involved in the formation of induced pluripotent stem cells, but its role in oncogenesis is not yet entirely clear. In this work, OCT4 expression was investigated in malignant gliomas. Twenty glioma cell lines and a sample of normal adult brain tissue were used. OCT4 expression was found in all studied glioma cell lines but was not detected in normal adult brain tissue. For one of these lines, OCT4 knockdown caused tumor cell death. By varying the culture conditions of these cells, we unexpectedly found that OCT4 expression increased when cells were incubated in serum-free medium, and this effect was significantly enhanced in serum-free and L-glutamine-free medium. L-glutamine and the Krebs cycle, which is slowed down in serum-free medium according to our NMR data, are sources of α-KG. Thus, our data indicate that OCT4 expression in gliomas may be regulated by the α-KG-dependent metabolic reprogramming of cells.\n
\n\n\n\n \n\n \n \n \n \n \n \n Hybrid Molecules of Azithromycin with Chloramphenicol and Metronidazole: Synthesis and Study of Antibacterial Properties.\n \n \n \n \n\n\n \n Volynkina, I. A.; Bychkova, E. N.; Karakchieva, A. O.; Tikhomirov, A. S.; Zatonsky, G. V.; Solovieva, S. E.; Martynov, M. M.; Grammatikova, N. E.; Tereshchenkov, A. G.; Paleskava, A.; Konevega, A. L.; Sergiev, P. V.; Dontsova, O. A.; Osterman, I. A.; Shchekotikhin, A. E.; and Tevyashova, A. N.\n\n\n \n\n\n\n Pharmaceuticals, 17(2). 2024.\n \n\n\n\n
\n\n\n\n \n \nPaper\n \n \n\n \n \n doi\n \n \n\n \n link\n \n \n\n bibtex\n \n\n \n \n \n abstract \n \n\n \n\n \n \n \n \n \n \n \n\n \n \n \n\n\n\n
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Paper\n \n \n\n \n \n doi\n \n \n\n \n link\n \n \n\n bibtex\n \n\n \n \n \n abstract \n \n\n \n\n \n \n \n \n \n \n \n\n \n \n \n\n\n\n\n
\n\n\n@Article{Volynkina2024,\n author = {Volynkina, Inna A. and Bychkova, Elena N. and Karakchieva, Anastasiia O. and Tikhomirov, Alexander S. and Zatonsky, George V. and Solovieva, Svetlana E. and Martynov, Maksim M. and Grammatikova, Natalia E. and Tereshchenkov, Andrey G. and Paleskava, Alena and Konevega, Andrey L. and Sergiev, Petr V. and Dontsova, Olga A. and Osterman, Ilya A. and Shchekotikhin, Andrey E. and Tevyashova, Anna N.},\n journal = {Pharmaceuticals},\n title = {Hybrid Molecules of Azithromycin with Chloramphenicol and Metronidazole: Synthesis and Study of Antibacterial Properties},\n year = {2024},\n issn = {1424-8247},\n number = {2},\n volume = {17},\n abstract = {The sustained rise of antimicrobial resistance (AMR) causes a strong need to develop new antibacterial agents. One of the methods for addressing the problem of antibiotic resistance is through the design of hybrid antibiotics. In this work, we proposed a synthetic route for the conjugation of an azithromycin derivative with chloramphenicol and metronidazole hemisuccinates and synthesized two series of new hybrid molecules 4a–g and 5a–g. While a conjugation did not result in tangible synergy for wild-type bacterial strains, new compounds were able to overcome AMR associated with the inducible expression of the ermC gene on a model E. coli strain resistant to macrolide antibiotics. The newly developed hybrids demonstrated a tendency to induce premature ribosome stalling, which might be crucial since they will not induce a macrolide-resistant phenotype in a number of pathogenic bacterial strains. In summary, the designed structures are considered as a promising direction for the further development of hybrid molecules that can effectively circumvent AMR mechanisms to macrolide antibiotics.},\n article-number = {187},\n doi = {10.3390/ph17020187},\n url = {https://www.mdpi.com/1424-8247/17/2/187},\n}\n\n\n\n The sustained rise of antimicrobial resistance (AMR) causes a strong need to develop new antibacterial agents. One of the methods for addressing the problem of antibiotic resistance is through the design of hybrid antibiotics. In this work, we proposed a synthetic route for the conjugation of an azithromycin derivative with chloramphenicol and metronidazole hemisuccinates and synthesized two series of new hybrid molecules 4a–g and 5a–g. While a conjugation did not result in tangible synergy for wild-type bacterial strains, new compounds were able to overcome AMR associated with the inducible expression of the ermC gene on a model E. coli strain resistant to macrolide antibiotics. The newly developed hybrids demonstrated a tendency to induce premature ribosome stalling, which might be crucial since they will not induce a macrolide-resistant phenotype in a number of pathogenic bacterial strains. In summary, the designed structures are considered as a promising direction for the further development of hybrid molecules that can effectively circumvent AMR mechanisms to macrolide antibiotics.\n
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\n \n \n\n \n \n \n \n \n Photonuclear production of medical radioisotopes , jakarta.xml.bind.JAXBElement@582d48f0, Tb and , jakarta.xml.bind.JAXBElement@25392b14, Tb.\n \n \n \n\n\n \n Fedotova, А. О.; Aliev, R. A.; Egorova, B. V.; Kormazeva, Е. S.; Konevega, А. L.; Belyshev, S. S.; Khankin, V. V.; Kuznetsov, А. А.; and Kalmykov, S. N.\n\n\n \n\n\n\n Applied radiation and isotopes : including data, instrumentation and methods for use in agriculture, industry and medicine, 198: 110840. August 2023.\n \n\n\n\n
\n\n\n\n \n\n \n \n doi\n \n \n\n \n link\n \n \n\n bibtex\n \n\n \n \n \n abstract \n \n\n \n\n \n \n \n \n \n \n \n\n \n \n \n \n \n \n \n \n \n\n\n\n
\n\n\n \n\n\n\n \n\n \n \n doi\n \n \n\n \n link\n \n \n\n bibtex\n \n\n \n \n \n abstract \n \n\n \n\n \n \n \n \n \n \n \n\n \n \n \n \n \n \n \n \n \n\n\n\n
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\n\n\n@Article{Fedotova2023,\n author = {Fedotova, А. О. and Aliev, R. A. and Egorova, B. V. and Kormazeva, Е. S. and Konevega, А. L. and Belyshev, S. S. and Khankin, V. V. and Kuznetsov, А. А. and Kalmykov, S. N.},\n journal = {Applied radiation and isotopes : including data, instrumentation and methods for use in agriculture, industry and medicine},\n title = {Photonuclear production of medical radioisotopes , jakarta.xml.bind.JAXBElement@582d48f0, Tb and , jakarta.xml.bind.JAXBElement@25392b14, Tb.},\n year = {2023},\n issn = {1872-9800},\n month = aug,\n pages = {110840},\n volume = {198},\n abstract = {The production possibility of Tb and Tb by irradiating of natural dysprosium with gamma rays obtained by decelerating an electron beam with an energy of 55 MeV has been demonstrated experimentally. The yield of Tb was 14.4 × 10 Bq × μA × h × cm × g . Simultaneously, upon irradiation, Dy is formed with the yield of 25 × 10 Bq × μA × h × cm × g , which leads to the formation of 1.6 × 10 Bq × μA × h × cm × g of Tb. It has been shown that the isolation of terbium radioisotopes from tens of mg of dysprosium target can be achieved by extraction chromatography, and final separation yield was 39%. The impurity of Tb is 7.3% of the Tb activity at EOB.},\n chemicals = {Dysprosium, Radioisotopes, Terbium},\n citation-subset = {IM},\n completed = {2023-06-12},\n country = {England},\n doi = {10.1016/j.apradiso.2023.110840},\n issn-linking = {0969-8043},\n keywords = {Dysprosium, chemistry; Radioisotopes; Terbium, chemistry},\n nlm-id = {9306253},\n owner = {NLM},\n pii = {S0969-8043(23)00193-8},\n pmid = {37156063},\n pubmodel = {Print-Electronic},\n pubstate = {ppublish},\n revised = {2023-06-12},\n}\n\n\n\n The production possibility of Tb and Tb by irradiating of natural dysprosium with gamma rays obtained by decelerating an electron beam with an energy of 55 MeV has been demonstrated experimentally. The yield of Tb was 14.4 × 10 Bq × μA × h × cm × g . Simultaneously, upon irradiation, Dy is formed with the yield of 25 × 10 Bq × μA × h × cm × g , which leads to the formation of 1.6 × 10 Bq × μA × h × cm × g of Tb. It has been shown that the isolation of terbium radioisotopes from tens of mg of dysprosium target can be achieved by extraction chromatography, and final separation yield was 39%. The impurity of Tb is 7.3% of the Tb activity at EOB.\n
\n\n\n\n \n\n \n \n \n \n \n Inside and outside of virus-like particles HBc and HBc/4M2e: A comprehensive study of the structure.\n \n \n \n\n\n \n Egorov, V. V.; Shvetsov, A. V.; Pichkur, E. B.; Shaldzhyan, A. A.; Zabrodskaya, Y. A.; Vinogradova, D. S.; Nekrasov, P. A.; Gorshkov, A. N.; Garmay, Y. P.; Kovaleva, A. A.; Stepanova, L. A.; Tsybalova, L. M.; Shtam, T. A.; Myasnikov, A. G.; and Konevega, A. L.\n\n\n \n\n\n\n Biophysical chemistry, 293: 106943. February 2023.\n \n\n\n\n
\n\n\n\n \n\n \n \n doi\n \n \n\n \n link\n \n \n\n bibtex\n \n\n \n \n \n abstract \n \n\n \n\n \n \n \n \n \n \n \n\n \n \n \n \n \n \n \n \n \n \n \n \n \n\n\n\n
\n\n\n \n\n\n\n \n\n \n \n doi\n \n \n\n \n link\n \n \n\n bibtex\n \n\n \n \n \n abstract \n \n\n \n\n \n \n \n \n \n \n \n\n \n \n \n \n \n \n \n \n \n \n \n \n \n\n\n\n
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\n\n\n@Article{Egorov2023,\n author = {Egorov, V. V. and Shvetsov, A. V. and Pichkur, E. B. and Shaldzhyan, A. A. and Zabrodskaya, Ya A. and Vinogradova, D. S. and Nekrasov, P. A. and Gorshkov, A. N. and Garmay, Yu P. and Kovaleva, A. A. and Stepanova, L. A. and Tsybalova, L. M. and Shtam, T. A. and Myasnikov, A. G. and Konevega, A. L.},\n journal = {Biophysical chemistry},\n title = {Inside and outside of virus-like particles HBc and HBc/4M2e: A comprehensive study of the structure.},\n year = {2023},\n issn = {1873-4200},\n month = feb,\n pages = {106943},\n volume = {293},\n abstract = {Hepatitis B virus core antigen (HBc) with the insertion of four external domains of the influenza A M2 protein (HBc/4M2e) form virus-like particles whose structure was studied using a combination of molecular modeling and cryo-electron microscopy (cryo-EM). It was also shown that self-assembling of the particles occurs inside bacterial cells, but despite the big inner volume of the core shell particle, purified HBc/4M2e contain an insignificant amount of bacterial proteins. It was shown that a fragment of the M2e corresponding to 4M2e insertion is prone to formation of amyloid-like fibrils. However, as the part of the immunodominant loop, M2e insertion does not show a tendency to intermolecular interaction. A full-atomic HBc-4M2e model with the resolution of about 3 Å (3.13 Å for particles of Т = 4 symmetry, 3.7 Å for particles of Т = 3 symmetry) was obtained by molecular modeling methods based on cryo-EM data.},\n chemicals = {Hepatitis B Core Antigens, M2 protein, Influenza A virus, Viral Matrix Proteins},\n citation-subset = {IM},\n completed = {2023-01-18},\n country = {Netherlands},\n doi = {10.1016/j.bpc.2022.106943},\n issn-linking = {0301-4622},\n keywords = {Cryoelectron Microscopy; Hepatitis B Core Antigens, chemistry; Hepatitis B virus, chemistry; Models, Molecular; Viral Matrix Proteins, chemistry; Cryo-electron microscopy; Hepatitis B virus core antigen; Influenza virus; Molecular modeling; Structural analysis; Virus-like particles},\n nlm-id = {0403171},\n owner = {NLM},\n pii = {S0301-4622(22)00185-5},\n pmid = {36495688},\n pubmodel = {Print-Electronic},\n pubstate = {ppublish},\n revised = {2023-03-22},\n}\n\n\n\n Hepatitis B virus core antigen (HBc) with the insertion of four external domains of the influenza A M2 protein (HBc/4M2e) form virus-like particles whose structure was studied using a combination of molecular modeling and cryo-electron microscopy (cryo-EM). It was also shown that self-assembling of the particles occurs inside bacterial cells, but despite the big inner volume of the core shell particle, purified HBc/4M2e contain an insignificant amount of bacterial proteins. It was shown that a fragment of the M2e corresponding to 4M2e insertion is prone to formation of amyloid-like fibrils. However, as the part of the immunodominant loop, M2e insertion does not show a tendency to intermolecular interaction. A full-atomic HBc-4M2e model with the resolution of about 3 Å (3.13 Å for particles of Т = 4 symmetry, 3.7 Å for particles of Т = 3 symmetry) was obtained by molecular modeling methods based on cryo-EM data.\n
\n\n\n\n \n\n \n \n \n \n \n Experimental validation of proton boron capture therapy for glioma cells.\n \n \n \n\n\n \n Shtam, T.; Burdakov, V.; Garina, A.; Garaeva, L.; Tran, N. H.; Volnitskiy, A.; Kuus, E.; Amerkanov, D.; Pack, F.; Andreev, G.; Lubinskiy, A.; Shabalin, K.; Verlov, N.; Ivanov, E.; Ezhov, V.; Lebedev, D.; and Konevega, A. L.\n\n\n \n\n\n\n Scientific reports, 13: 1341. January 2023.\n \n\n\n\n
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\n\n\n@Article{Shtam2023,\n author = {Shtam, Tatiana and Burdakov, Vladimir and Garina, Alina and Garaeva, Luiza and Tran, Nhan Hau and Volnitskiy, Andrey and Kuus, Eva and Amerkanov, Dmitry and Pack, Fedor and Andreev, Georgy and Lubinskiy, Andrey and Shabalin, Konstantin and Verlov, Nicolay and Ivanov, Evgeniy and Ezhov, Victor and Lebedev, Dmitry and Konevega, Andrey L.},\n journal = {Scientific reports},\n title = {Experimental validation of proton boron capture therapy for glioma cells.},\n year = {2023},\n issn = {2045-2322},\n month = jan,\n pages = {1341},\n volume = {13},\n abstract = {Proton boron capture therapy (PBCT) has emerged from particle acceleration research for enhancing the biological effectiveness of proton therapy. The mechanism responsible for the dose increase was supposed to be related to proton-boron fusion reactions ( B + p → 3α + 8.7 MeV). There has been some experimental evidence that the biological efficiency of protons is significantly higher for boron-11-containing prostate or breast cancer cells. The aim of this study was to evaluate the sensitizing potential of sodium borocaptate (BSH) under proton irradiation at the Bragg peak of cultured glioma cells. To address this problem, cells of two glioma lines were preincubated with 80 or 160 ppm boron-11, irradiated both at the middle of 200 MeV beam Spread-Out Bragg Peak (SOBP) and at the distal end of the 89.7 MeV beam SOBP and assessed for the viability, as well as their ability to form colonies. Our results clearly show that BSH provides for only a slight, if any, enhancement of the effect of proton radiation on the glioma cells in vitro. In addition, we repeated the experiments using the Du145 prostate cancer cell line, for which an increase in the biological efficiency of proton irradiation in the presence of sodium borocaptate was demonstrated previously. The data presented add new argument against the efficiency of proton boron capture therapy when based solely on direct dose-enhancement effect by the proton capture nuclear reaction, underlining the need to investigate the indirect effects of the secondary alpha irradiation depending on the state and treatment conditions of the irradiated tissue.},\n chemicals = {Protons, Boron, Sodium},\n citation-subset = {IM},\n completed = {2023-01-26},\n country = {England},\n doi = {10.1038/s41598-023-28428-z},\n file = {:Shtam2023 - Experimental Validation of Proton Boron Capture Therapy for Glioma Cells..pdf:PDF},\n issn-linking = {2045-2322},\n issue = {1},\n keywords = {Male; Humans; Protons; Boron, pharmacology; Proton Therapy; Glioma, radiotherapy, metabolism; Sodium},\n nlm-id = {101563288},\n owner = {NLM},\n pii = {1341},\n pmc = {PMC9873635},\n pmid = {36693879},\n pubmodel = {Electronic},\n pubstate = {epublish},\n revised = {2023-03-16},\n}\n\n\n\n Proton boron capture therapy (PBCT) has emerged from particle acceleration research for enhancing the biological effectiveness of proton therapy. The mechanism responsible for the dose increase was supposed to be related to proton-boron fusion reactions ( B + p → 3α + 8.7 MeV). There has been some experimental evidence that the biological efficiency of protons is significantly higher for boron-11-containing prostate or breast cancer cells. The aim of this study was to evaluate the sensitizing potential of sodium borocaptate (BSH) under proton irradiation at the Bragg peak of cultured glioma cells. To address this problem, cells of two glioma lines were preincubated with 80 or 160 ppm boron-11, irradiated both at the middle of 200 MeV beam Spread-Out Bragg Peak (SOBP) and at the distal end of the 89.7 MeV beam SOBP and assessed for the viability, as well as their ability to form colonies. Our results clearly show that BSH provides for only a slight, if any, enhancement of the effect of proton radiation on the glioma cells in vitro. In addition, we repeated the experiments using the Du145 prostate cancer cell line, for which an increase in the biological efficiency of proton irradiation in the presence of sodium borocaptate was demonstrated previously. The data presented add new argument against the efficiency of proton boron capture therapy when based solely on direct dose-enhancement effect by the proton capture nuclear reaction, underlining the need to investigate the indirect effects of the secondary alpha irradiation depending on the state and treatment conditions of the irradiated tissue.\n
\n\n\n\n \n\n \n \n \n \n \n Current State and Prospectives for Proton Boron Capture Therapy.\n \n \n \n\n\n \n Tran, N. H.; Shtam, T.; Marchenko, Y. Y.; Konevega, A. L.; and Lebedev, D.\n\n\n \n\n\n\n Biomedicines, 11. June 2023.\n \n\n\n\n
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\n\n\n@Article{Tran2023,\n author = {Tran, Nhan Hau and Shtam, Tatiana and Marchenko, Yaroslav Yu and Konevega, Andrey L. and Lebedev, Dmitry},\n journal = {Biomedicines},\n title = {Current State and Prospectives for Proton Boron Capture Therapy.},\n year = {2023},\n issn = {2227-9059},\n month = jun,\n volume = {11},\n abstract = {The development of new methods increasing the biological effectiveness of proton therapy (PT) is of high interest in radiation oncology. The use of binary technologies, in which the damaging effect of proton radiation is further enhanced by the selective accumulation of the radiosensitizer in the target tissue, can significantly increase the effectiveness of radiation therapy. To increase the absorbed dose in a tumor target, proton boron capture therapy (PBCT) was proposed based on the reaction of proton capture on the B isotope with the formation of three α-particles. This review summarizes data on theoretical and experimental studies on the effectiveness and prospects of proton boron capture therapy.},\n country = {Switzerland},\n doi = {10.3390/biomedicines11061727},\n issn-linking = {2227-9059},\n issue = {6},\n keywords = {proton boron capture therapy; proton therapy; radiotherapy; sensitization},\n nlm-id = {101691304},\n owner = {NLM},\n pii = {1727},\n pmc = {PMC10296516},\n pmid = {37371822},\n pubmodel = {Electronic},\n pubstate = {epublish},\n revised = {2023-07-01},\n}\n\n\n\n The development of new methods increasing the biological effectiveness of proton therapy (PT) is of high interest in radiation oncology. The use of binary technologies, in which the damaging effect of proton radiation is further enhanced by the selective accumulation of the radiosensitizer in the target tissue, can significantly increase the effectiveness of radiation therapy. To increase the absorbed dose in a tumor target, proton boron capture therapy (PBCT) was proposed based on the reaction of proton capture on the B isotope with the formation of three α-particles. This review summarizes data on theoretical and experimental studies on the effectiveness and prospects of proton boron capture therapy.\n
\n\n\n\n \n\n \n \n \n \n \n Insights into the molecular mechanism of translation inhibition by the ribosome-targeting antibiotic thermorubin.\n \n \n \n\n\n \n Paranjpe, M. N.; Marina, V. I.; Grachev, A. A.; Maviza, T. P.; Tolicheva, O. A.; Paleskava, A.; Osterman, I. A.; Sergiev, P. V.; Konevega, A. L.; Polikanov, Y. S.; and Gagnon, M. G.\n\n\n \n\n\n\n Nucleic acids research, 51: 449–462. January 2023.\n \n\n\n\n
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\n\n\n@Article{Paranjpe2023,\n author = {Paranjpe, Madhura N. and Marina, Valeria I. and Grachev, Aleksandr A. and Maviza, Tinashe P. and Tolicheva, Olga A. and Paleskava, Alena and Osterman, Ilya A. and Sergiev, Petr V. and Konevega, Andrey L. and Polikanov, Yury S. and Gagnon, Matthieu G.},\n journal = {Nucleic acids research},\n title = {Insights into the molecular mechanism of translation inhibition by the ribosome-targeting antibiotic thermorubin.},\n year = {2023},\n issn = {1362-4962},\n month = jan,\n pages = {449--462},\n volume = {51},\n abstract = {Thermorubin (THR) is an aromatic anthracenopyranone antibiotic active against both Gram-positive and Gram-negative bacteria. It is known to bind to the 70S ribosome at the intersubunit bridge B2a and was thought to inhibit factor-dependent initiation of translation and obstruct the accommodation of tRNAs into the A site. Here, we show that thermorubin causes ribosomes to stall in vivo and in vitro at internal and termination codons, thereby allowing the ribosome to initiate protein synthesis and translate at least a few codons before stalling. Our biochemical data show that THR affects multiple steps of translation elongation with a significant impact on the binding stability of the tRNA in the A site, explaining premature cessation of translation. Our high-resolution crystal and cryo-EM structures of the 70S-THR complex show that THR can co-exist with P- and A-site tRNAs, explaining how ribosomes can elongate in the presence of the drug. Remarkable is the ability of THR to arrest ribosomes at the stop codons. Our data suggest that by causing structural re-arrangements in the decoding center, THR interferes with the accommodation of tRNAs or release factors into the ribosomal A site.},\n chemicals = {Anti-Bacterial Agents, Codon, Terminator, thermorubin, Anthraquinones},\n citation-subset = {IM},\n completed = {2023-01-20},\n country = {England},\n doi = {10.1093/nar/gkac1189},\n issn-linking = {0305-1048},\n issue = {1},\n keywords = {Anti-Bacterial Agents, pharmacology; Codon, Terminator, metabolism; Gram-Negative Bacteria, drug effects; Gram-Positive Bacteria, drug effects; Ribosomes, metabolism; Protein Biosynthesis, drug effects; Anthraquinones, pharmacology},\n nlm-id = {0411011},\n owner = {NLM},\n pii = {6956352},\n pmc = {PMC9841432},\n pmid = {36546783},\n pubmodel = {Print},\n pubstate = {ppublish},\n revised = {2023-01-27},\n}\n\n\n\n Thermorubin (THR) is an aromatic anthracenopyranone antibiotic active against both Gram-positive and Gram-negative bacteria. It is known to bind to the 70S ribosome at the intersubunit bridge B2a and was thought to inhibit factor-dependent initiation of translation and obstruct the accommodation of tRNAs into the A site. Here, we show that thermorubin causes ribosomes to stall in vivo and in vitro at internal and termination codons, thereby allowing the ribosome to initiate protein synthesis and translate at least a few codons before stalling. Our biochemical data show that THR affects multiple steps of translation elongation with a significant impact on the binding stability of the tRNA in the A site, explaining premature cessation of translation. Our high-resolution crystal and cryo-EM structures of the 70S-THR complex show that THR can co-exist with P- and A-site tRNAs, explaining how ribosomes can elongate in the presence of the drug. Remarkable is the ability of THR to arrest ribosomes at the stop codons. Our data suggest that by causing structural re-arrangements in the decoding center, THR interferes with the accommodation of tRNAs or release factors into the ribosomal A site.\n
\n\n\n\n \n\n \n \n \n \n \n Cryo-electron microscopy of adipose tissue extracellular vesicles in obesity and type 2 diabetes mellitus.\n \n \n \n\n\n \n Miroshnikova, V. V.; Dracheva, K. V.; Kamyshinsky, R. A.; Yastremsky, E. V.; Garaeva, L. A.; Pobozheva, I. A.; Landa, S. B.; Anisimova, K. A.; Balandov, S. G.; Hamid, Z. M.; Vasilevsky, D. I.; Pchelina, S. N.; Konevega, A. L.; and Shtam, T. A.\n\n\n \n\n\n\n PloS one, 18: e0279652. 2023.\n \n\n\n\n
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\n\n\n@Article{Miroshnikova2023,\n author = {Miroshnikova, Valentina V. and Dracheva, Kseniya V. and Kamyshinsky, Roman A. and Yastremsky, Evgeny V. and Garaeva, Luiza A. and Pobozheva, Irina A. and Landa, Sergey B. and Anisimova, Kristina A. and Balandov, Stanislav G. and Hamid, Zarina M. and Vasilevsky, Dmitriy I. and Pchelina, Sofya N. and Konevega, Andrey L. and Shtam, Tatiana A.},\n journal = {PloS one},\n title = {Cryo-electron microscopy of adipose tissue extracellular vesicles in obesity and type 2 diabetes mellitus.},\n year = {2023},\n issn = {1932-6203},\n pages = {e0279652},\n volume = {18},\n abstract = {Extracellular vesicles (EVs) are cell-derived membrane vesicles which play an important role in cell-to-cell communication and physiology. EVs deliver biological information from producing to recipient cells by transport of different cargo such as proteins, mRNAs, microRNAs, non-coding RNAs and lipids. Adipose tissue EVs could regulate metabolic and inflammatory interactions inside adipose tissue depots as well as distal tissues. Thus, adipose tissue EVs are assumed to be implicated in obesity-associated pathologies, notably in insulin resistance and type 2 diabetes mellitus (T2DM). In this study we for the first time characterize EVs secreted by visceral (VAT) and subcutaneous adipose tissue (SAT) of patients with obesity and T2DM with standard methods as well as analyze their morphology with cryo-electron microscopy. Cryo-electron microscopy allowed us to visualize heterogeneous population of EVs of various size and morphology including single EVs and EVs with internal membrane structures in samples from obese patients as well from the control group. Single vesicles prevailed (up to 85% for SAT, up to 75% for VAT) and higher proportion of EVs with internal membrane structures compared to SAT was typical for VAT. Decreased size of single and double SAT EVs compared to VAT EVs, large proportion of multilayered EVs and all EVs with internal membrane structures secreted by VAT distinguished obese patients with/without T2DM from the control group. These findings could support the idea of modified biogenesis of EVs during obesity and T2DM.},\n citation-subset = {IM},\n completed = {2023-02-28},\n country = {United States},\n doi = {10.1371/journal.pone.0279652},\n issn-linking = {1932-6203},\n issue = {2},\n keywords = {Humans; Diabetes Mellitus, Type 2, pathology; Cryoelectron Microscopy; Intra-Abdominal Fat, metabolism; Adipose Tissue, metabolism; Obesity, metabolism; Subcutaneous Fat, metabolism; Extracellular Vesicles, metabolism},\n nlm-id = {101285081},\n owner = {NLM},\n pii = {e0279652},\n pmc = {PMC10045588},\n pmid = {36827314},\n pubmodel = {Electronic-eCollection},\n pubstate = {epublish},\n revised = {2023-03-30},\n}\n\n\n\n Extracellular vesicles (EVs) are cell-derived membrane vesicles which play an important role in cell-to-cell communication and physiology. EVs deliver biological information from producing to recipient cells by transport of different cargo such as proteins, mRNAs, microRNAs, non-coding RNAs and lipids. Adipose tissue EVs could regulate metabolic and inflammatory interactions inside adipose tissue depots as well as distal tissues. Thus, adipose tissue EVs are assumed to be implicated in obesity-associated pathologies, notably in insulin resistance and type 2 diabetes mellitus (T2DM). In this study we for the first time characterize EVs secreted by visceral (VAT) and subcutaneous adipose tissue (SAT) of patients with obesity and T2DM with standard methods as well as analyze their morphology with cryo-electron microscopy. Cryo-electron microscopy allowed us to visualize heterogeneous population of EVs of various size and morphology including single EVs and EVs with internal membrane structures in samples from obese patients as well from the control group. Single vesicles prevailed (up to 85% for SAT, up to 75% for VAT) and higher proportion of EVs with internal membrane structures compared to SAT was typical for VAT. Decreased size of single and double SAT EVs compared to VAT EVs, large proportion of multilayered EVs and all EVs with internal membrane structures secreted by VAT distinguished obese patients with/without T2DM from the control group. These findings could support the idea of modified biogenesis of EVs during obesity and T2DM.\n
\n\n\n\n \n\n \n \n \n \n \n Potential of Plant Exosome Vesicles from Grapefruit (, jakarta.xml.bind.JAXBElement@62006753, ) and Tomato (, jakarta.xml.bind.JAXBElement@232b9744, ) Juices as Functional Ingredients and Targeted Drug Delivery Vehicles.\n \n \n \n\n\n \n Kilasoniya, A.; Garaeva, L.; Shtam, T.; Spitsyna, A.; Putevich, E.; Moreno-Chamba, B.; Salazar-Bermeo, J.; Komarova, E.; Malek, A.; Valero, M.; and Saura, D.\n\n\n \n\n\n\n Antioxidants (Basel, Switzerland), 12. April 2023.\n \n\n\n\n
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\n\n\n@Article{Kilasoniya2023,\n author = {Kilasoniya, Alina and Garaeva, Luiza and Shtam, Tatiana and Spitsyna, Anastasiia and Putevich, Elena and Moreno-Chamba, Bryan and Salazar-Bermeo, Julio and Komarova, Elena and Malek, Anastasia and Valero, Manuel and Saura, Domingo},\n journal = {Antioxidants (Basel, Switzerland)},\n title = {Potential of Plant Exosome Vesicles from Grapefruit (, jakarta.xml.bind.JAXBElement@62006753, ) and Tomato (, jakarta.xml.bind.JAXBElement@232b9744, ) Juices as Functional Ingredients and Targeted Drug Delivery Vehicles.},\n year = {2023},\n issn = {2076-3921},\n month = apr,\n volume = {12},\n abstract = {Plant-derived extracellular vesicles (PEVs) have gained attention as promising bioactive nutraceutical molecules; their presence in common fruit juices has increased their significance because human interaction is inevitable. The goal of this study was to evaluate the potential of PEVs derived from grapefruit and tomato juices as functional ingredients, antioxidant compounds, and delivery vehicles. PEVs were isolated using differential ultracentrifugation and were found to be similar in size and morphology to mammalian exosomes. The yield of grapefruit exosome-like vesicles (GEVs) was higher than that of tomato exosome-like vesicles (TEVs), despite the latter having larger vesicle sizes. Furthermore, the antioxidant activity of GEVs and TEVs was found to be low in comparison to their juice sources, indicating a limited contribution of PEVs to the juice. GEVs showed a higher efficiency in being loaded with the heat shock protein 70 (HSP70) than TEVs, as well as a higher efficiency than TEV and PEV-free HSP70 in delivering HSP70 to glioma cells. Overall, our results revealed that GEVs present a higher potential as functional ingredients present in juice and that they exert the potential to deliver functional molecules to human cells. Although PEVs showed low antioxidant activity, their role in oxidative response in cells should be further addressed.},\n country = {Switzerland},\n doi = {10.3390/antiox12040943},\n issn-linking = {2076-3921},\n issue = {4},\n keywords = {antioxidant activity; drug delivery; fruit juices; grapefruit exosomes; plant exosomes; tomato exosomes},\n nlm-id = {101668981},\n owner = {NLM},\n pii = {943},\n pmc = {PMC10135875},\n pmid = {37107317},\n pubmodel = {Electronic},\n pubstate = {epublish},\n revised = {2023-04-30},\n}\n\n\n\n Plant-derived extracellular vesicles (PEVs) have gained attention as promising bioactive nutraceutical molecules; their presence in common fruit juices has increased their significance because human interaction is inevitable. The goal of this study was to evaluate the potential of PEVs derived from grapefruit and tomato juices as functional ingredients, antioxidant compounds, and delivery vehicles. PEVs were isolated using differential ultracentrifugation and were found to be similar in size and morphology to mammalian exosomes. The yield of grapefruit exosome-like vesicles (GEVs) was higher than that of tomato exosome-like vesicles (TEVs), despite the latter having larger vesicle sizes. Furthermore, the antioxidant activity of GEVs and TEVs was found to be low in comparison to their juice sources, indicating a limited contribution of PEVs to the juice. GEVs showed a higher efficiency in being loaded with the heat shock protein 70 (HSP70) than TEVs, as well as a higher efficiency than TEV and PEV-free HSP70 in delivering HSP70 to glioma cells. Overall, our results revealed that GEVs present a higher potential as functional ingredients present in juice and that they exert the potential to deliver functional molecules to human cells. Although PEVs showed low antioxidant activity, their role in oxidative response in cells should be further addressed.\n
\n\n\n\n \n\n \n \n \n \n \n \n Correlated Target Search by Vaccinia Virus Uracil–DNA Glycosylase, a DNA Repair Enzyme and a Processivity Factor of Viral Replication Machinery.\n \n \n \n \n\n\n \n Diatlova, E. A.; Mechetin, G. V.; Yudkina, A. V.; Zharkov, V. D.; Torgasheva, N. A.; Endutkin, A. V.; Shulenina, O. V.; Konevega, A. L.; Gileva, I. P.; Shchelkunov, S. N.; and Zharkov, D. O.\n\n\n \n\n\n\n International Journal of Molecular Sciences, 24(9113): 9113. 05 2023.\n \n\n\n\n
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\n\n\n@Article{Diatlova2023,\n author = {Evgeniia A. Diatlova and Grigory V. Mechetin and Anna V. Yudkina and Vasily D. Zharkov and Natalia A. Torgasheva and Anton V. Endutkin and Olga V. Shulenina and Andrey L. Konevega and Irina P. Gileva and Sergei N. Shchelkunov and Dmitry O. Zharkov},\n journal = {International Journal of Molecular Sciences},\n title = {Correlated Target Search by Vaccinia Virus Uracil–DNA Glycosylase, a DNA Repair Enzyme and a Processivity Factor of Viral Replication Machinery},\n year = {2023},\n issn = {1661-6596},\n month = {05},\n number = {9113},\n pages = {9113},\n volume = {24},\n abstract = {The protein encoded by the vaccinia virus <i>D4R</i> gene has base excision repair uracil–DNA <i>N</i>-glycosylase (vvUNG) activity and also acts as a processivity factor in the viral replication complex. The use of a protein unlike PolN/PCNA sliding clamps is a unique feature of orthopoxviral replication, providing an attractive target for drug design. However, the intrinsic processivity of vvUNG has never been estimated, leaving open the question whether it is sufficient to impart processivity to the viral polymerase. Here, we use the correlated cleavage assay to characterize the translocation of vvUNG along DNA between two uracil residues. The salt dependence of the correlated cleavage, together with the similar affinity of vvUNG for damaged and undamaged DNA, support the one-dimensional diffusion mechanism of lesion search. Unlike short gaps, covalent adducts partly block vvUNG translocation. Kinetic experiments show that once a lesion is found it is excised with a probability ~0.76. Varying the distance between two uracils, we use a random walk model to estimate the mean number of steps per association with DNA at ~4200, which is consistent with vvUNG playing a role as a processivity factor. Finally, we show that inhibitors carrying a tetrahydro-2,4,6-trioxopyrimidinylidene moiety can suppress the processivity of vvUNG.},\n doi = {10.3390/ijms24119113},\n keywords = {DNA repair, uracil–DNA glycosylase, protein translocation, viral replication, processivity, correlated cleavage},\n publisher = {MDPI AG},\n url = {https://www.mdpi.com/1422-0067/24/11/9113},\n}\n\n\n\n The protein encoded by the vaccinia virus D4R gene has base excision repair uracil–DNA N-glycosylase (vvUNG) activity and also acts as a processivity factor in the viral replication complex. The use of a protein unlike PolN/PCNA sliding clamps is a unique feature of orthopoxviral replication, providing an attractive target for drug design. However, the intrinsic processivity of vvUNG has never been estimated, leaving open the question whether it is sufficient to impart processivity to the viral polymerase. Here, we use the correlated cleavage assay to characterize the translocation of vvUNG along DNA between two uracil residues. The salt dependence of the correlated cleavage, together with the similar affinity of vvUNG for damaged and undamaged DNA, support the one-dimensional diffusion mechanism of lesion search. Unlike short gaps, covalent adducts partly block vvUNG translocation. Kinetic experiments show that once a lesion is found it is excised with a probability 0.76. Varying the distance between two uracils, we use a random walk model to estimate the mean number of steps per association with DNA at 4200, which is consistent with vvUNG playing a role as a processivity factor. Finally, we show that inhibitors carrying a tetrahydro-2,4,6-trioxopyrimidinylidene moiety can suppress the processivity of vvUNG.\n
\n\n\n\n \n\n \n \n \n \n \n \n Myelin Basic Protein Fragmentation by Engineered Human Proteasomes with Different Catalytic Phenotypes Revealed Direct Peptide Ligands of MS-Associated and Protective HLA Class I Molecules.\n \n \n \n \n\n\n \n Saratov, G. A.; Vladimirov, V. I.; Novoselov, A. L.; Ziganshin, R. H.; Chen, G.; Baymukhametov, T. N.; Konevega, A. L.; Belogurov, A. A.; and Kudriaeva, A. A.\n\n\n \n\n\n\n International Journal of Molecular Sciences, 24(2091): 2091. 01 2023.\n \n\n\n\n
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\n\n\n@Article{Saratov2023,\n author = {George A. Saratov and Vasiliy I. Vladimirov and Alexey L. Novoselov and Rustam H. Ziganshin and Guo Chen and Timur N. Baymukhametov and Andrey L. Konevega and Alexey A. Belogurov and Anna A. Kudriaeva},\n journal = {International Journal of Molecular Sciences},\n title = {Myelin Basic Protein Fragmentation by Engineered Human Proteasomes with Different Catalytic Phenotypes Revealed Direct Peptide Ligands of MS-Associated and Protective HLA Class I Molecules},\n year = {2023},\n issn = {1661-6596},\n month = {01},\n number = {2091},\n pages = {2091},\n volume = {24},\n abstract = {Proteasomes exist in mammalian cells in multiple combinatorial variants due to the diverse regulatory particles and exchange of catalytic subunits. Here, using biotin carboxyl carrier domain of transcarboxylase from <i>Propionibacterium shermanii</i> fused with different proteasome subunits of catalytic and regulatory particles, we report comprehensive characterization of highly homogenous one-step purified human constitutive and immune 20S and 26S/30S proteasomes. Hydrolysis of a multiple sclerosis (MS) autoantigen, myelin basic protein (MBP), by engineered human proteasomes with different catalytic phenotypes, revealed that peptides which may be directly loaded on the HLA class I molecules are produced mainly by immunoproteasomes. We detected at least five MBP immunodominant core regions, namely, LPRHRDTGIL, SLPQKSHGR, QDENPVVHFF, KGRGLSLSRF and GYGGRASDY. All peptides, except QDENPVVHFF, which originates from the encephalitogenic MBP part, were associated with HLA I alleles considered to increase MS risk. Prediction of the affinity of HLA class I to this peptide demonstrated that MS-protective HLA-A*44 and -B*35 molecules are high-affinity binders, whereas MS-associated HLA-A*23, -A*24, -A*26 and -B*51 molecules tend to have moderate to low affinity. The HLA-A*44 molecules may bind QDENPVVHFF and its deamidated form in several registers with unprecedently high affinity, probably linking its distinct protective phenotype with thymic depletion of the repertoire of autoreactive cytotoxic T cells or induction of CD8+ regulatory T cells, specific to the encephalitogenic MBP peptide.},\n doi = {10.3390/ijms24032091},\n keywords = {proteasome, HTBH, immunoproteasome, biotin carboxyl carrier domain, myelin basic protein, HLA class I},\n publisher = {MDPI AG},\n url = {https://www.mdpi.com/1422-0067/24/3/2091},\n}\n\n\n\n Proteasomes exist in mammalian cells in multiple combinatorial variants due to the diverse regulatory particles and exchange of catalytic subunits. Here, using biotin carboxyl carrier domain of transcarboxylase from Propionibacterium shermanii fused with different proteasome subunits of catalytic and regulatory particles, we report comprehensive characterization of highly homogenous one-step purified human constitutive and immune 20S and 26S/30S proteasomes. Hydrolysis of a multiple sclerosis (MS) autoantigen, myelin basic protein (MBP), by engineered human proteasomes with different catalytic phenotypes, revealed that peptides which may be directly loaded on the HLA class I molecules are produced mainly by immunoproteasomes. We detected at least five MBP immunodominant core regions, namely, LPRHRDTGIL, SLPQKSHGR, QDENPVVHFF, KGRGLSLSRF and GYGGRASDY. All peptides, except QDENPVVHFF, which originates from the encephalitogenic MBP part, were associated with HLA I alleles considered to increase MS risk. Prediction of the affinity of HLA class I to this peptide demonstrated that MS-protective HLA-A*44 and -B*35 molecules are high-affinity binders, whereas MS-associated HLA-A*23, -A*24, -A*26 and -B*51 molecules tend to have moderate to low affinity. The HLA-A*44 molecules may bind QDENPVVHFF and its deamidated form in several registers with unprecedently high affinity, probably linking its distinct protective phenotype with thymic depletion of the repertoire of autoreactive cytotoxic T cells or induction of CD8+ regulatory T cells, specific to the encephalitogenic MBP peptide.\n
\n\n\n\n \n\n \n \n \n \n \n Determination of hydrogen bonds in Gromacs: new implementation to overcome the limitation.\n \n \n \n\n\n \n Gorelov, S. V.; Titov, A. I.; Tolicheva, O. A.; Konevega, A. L.; and Shvetsov, A. V.\n\n\n \n\n\n\n September 2023.\n \n\n\n\n
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\n\n\n\n@Misc{Gorelov2023,\n author = {S. V. Gorelov and A. I. Titov and O. A. Tolicheva and A. L. Konevega and A. V. Shvetsov},\n month = sep,\n title = {Determination of hydrogen bonds in Gromacs: new implementation to overcome the limitation},\n year = {2023},\n doi = {10.1101/2023.09.01.555860},\n publisher = {Cold Spring Harbor Laboratory},\n}\n\n\n\n \n\n \n \n \n \n \n DSSP in Gromacs: tool for defining secondary structures of proteins in trajectories.\n \n \n \n\n\n \n Gorelov, S. V.; Titov, A. I.; Tolicheva, O. A.; Konevega, A. L.; and Shvetsov, A. V.\n\n\n \n\n\n\n August 2023.\n \n\n\n\n
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\n\n\n\n@Misc{Gorelov2023a,\n author = {S. V. Gorelov and A. I. Titov and O. A. Tolicheva and A. L. Konevega and A. V. Shvetsov},\n month = aug,\n title = {DSSP in Gromacs: tool for defining secondary structures of proteins in trajectories},\n year = {2023},\n doi = {10.1101/2023.08.21.554196},\n publisher = {Cold Spring Harbor Laboratory},\n}\n\n\n\n \n\n \n \n \n \n \n Theranostics in Nuclear Medicine.\n \n \n \n\n\n \n Rumyantsev, P. O.; Sergunova, K. A.; Konevega, A. L.; and Korenev, S. V.\n\n\n \n\n\n\n Nanobiotechnology Reports, 18(4): 569-576. 2023.\n \n\n\n\n
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\n\n\n\n@Article{Rumyantsev2023,\n author = {P. O. Rumyantsev and K. A. Sergunova and A. L. Konevega and S. V. Korenev},\n journal = {Nanobiotechnology Reports},\n title = {Theranostics in Nuclear Medicine},\n year = {2023},\n issn = {2635-1676},\n number = {4},\n pages = {569-576},\n volume = {18},\n doi = {10.1134/s263516762370043x},\n keywords = {Electrical and Electronic Engineering, Engineering (miscellaneous), Condensed Matter Physics, General Materials Science, Biomedical Engineering, Bioengineering},\n publisher = {Pleiades Publishing Ltd},\n}\n\n\n\n \n\n \n \n \n \n \n \n Radiosensitizing Effect of Dextran-Coated Iron Oxide Nanoparticles on Malignant Glioma Cells.\n \n \n \n \n\n\n \n Tran, N. H.; Ryzhov, V.; Volnitskiy, A.; Amerkanov, D.; Pack, F.; Golubev, A. M.; Arutyunyan, A.; Spitsyna, A.; Burdakov, V.; Lebedev, D.; Konevega, A. L.; Shtam, T.; and Marchenko, Y.\n\n\n \n\n\n\n International Journal of Molecular Sciences, 24(20): 15150. 10 2023.\n \n\n\n\n
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\n\n\n@Article{Tran2023a,\n author = {Nhan Hau Tran and Vyacheslav Ryzhov and Andrey Volnitskiy and Dmitry Amerkanov and Fedor Pack and Aleksander M. Golubev and Alexandr Arutyunyan and Anastasiia Spitsyna and Vladimir Burdakov and Dmitry Lebedev and Andrey L. Konevega and Tatiana Shtam and Yaroslav Marchenko},\n journal = {International Journal of Molecular Sciences},\n title = {Radiosensitizing Effect of Dextran-Coated Iron Oxide Nanoparticles on Malignant Glioma Cells},\n year = {2023},\n issn = {1661-6596},\n month = {10},\n number = {20},\n pages = {15150},\n volume = {24},\n abstract = {The potential of standard methods of radiation therapy is limited by the dose that can be safely delivered to the tumor, which could be too low for radical treatment. The dose efficiency can be increased by using radiosensitizers. In this study, we evaluated the sensitizing potential of biocompatible iron oxide nanoparticles coated with a dextran shell in A172 and Gl-Tr glioblastoma cells in vitro. The cells preincubated with nanoparticles for 24 h were exposed to ionizing radiation (X-ray, gamma, or proton) at doses of 0.5–6 Gy, and their viability was assessed by the Resazurin assay and by staining of the surviving cells with crystal violet. A statistically significant effect of radiosensitization by nanoparticles was observed in both cell lines when cells were exposed to 35 keV X-rays. A weak radiosensitizing effect was found only in the Gl-Tr line for the 1.2 MeV gamma irradiation and there was no radiosensitizing effect in both lines for the 200 MeV proton irradiation at the Bragg peak. A slight (ca. 10%) increase in the formation of additional reactive oxygen species after X-ray irradiation was found when nanoparticles were present. These results suggest that the nanoparticles absorbed by glioma cells can produce a significant radiosensitizing effect, probably due to the action of secondary electrons generated by the magnetite core, whereas the dextran shell of the nanoparticles used in these experiments appears to be rather stable under radiation exposure.},\n doi = {10.3390/ijms242015150},\n keywords = {radiosensitization, superparamagnetic iron oxide nanoparticles (SPIONs), glioma cells, radiotherapy},\n publisher = {MDPI AG},\n url = {https://www.mdpi.com/1422-0067/24/20/15150},\n}\n\n\n\n The potential of standard methods of radiation therapy is limited by the dose that can be safely delivered to the tumor, which could be too low for radical treatment. The dose efficiency can be increased by using radiosensitizers. In this study, we evaluated the sensitizing potential of biocompatible iron oxide nanoparticles coated with a dextran shell in A172 and Gl-Tr glioblastoma cells in vitro. The cells preincubated with nanoparticles for 24 h were exposed to ionizing radiation (X-ray, gamma, or proton) at doses of 0.5–6 Gy, and their viability was assessed by the Resazurin assay and by staining of the surviving cells with crystal violet. A statistically significant effect of radiosensitization by nanoparticles was observed in both cell lines when cells were exposed to 35 keV X-rays. A weak radiosensitizing effect was found only in the Gl-Tr line for the 1.2 MeV gamma irradiation and there was no radiosensitizing effect in both lines for the 200 MeV proton irradiation at the Bragg peak. A slight (ca. 10%) increase in the formation of additional reactive oxygen species after X-ray irradiation was found when nanoparticles were present. These results suggest that the nanoparticles absorbed by glioma cells can produce a significant radiosensitizing effect, probably due to the action of secondary electrons generated by the magnetite core, whereas the dextran shell of the nanoparticles used in these experiments appears to be rather stable under radiation exposure.\n
\n\n\n\n \n\n \n \n \n \n \n HER2-specific liposomes loaded with proteinaceous BRET pair as a promising tool for targeted self-excited photodynamic therapy.\n \n \n \n\n\n \n Shramova, E. I.; Filimonova, V. P.; Frolova, A. Y.; Pichkur, E. B.; Fedotov, V. R.; Konevega, A. L.; Deyev, S. M.; and Proshkina, G. M.\n\n\n \n\n\n\n European journal of pharmaceutics and biopharmaceutics : official journal of Arbeitsgemeinschaft fur Pharmazeutische Verfahrenstechnik e.V, 193: 208–217. December 2023.\n \n\n\n\n
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\n\n\n@Article{Shramova2023,\n author = {Shramova, Elena I. and Filimonova, Victoriya P. and Frolova, Anastasiya Yu and Pichkur, Eugene B. and Fedotov, Vlad R. and Konevega, Andrey L. and Deyev, Sergey M. and Proshkina, Galina M.},\n journal = {European journal of pharmaceutics and biopharmaceutics : official journal of Arbeitsgemeinschaft fur Pharmazeutische Verfahrenstechnik e.V},\n title = {HER2-specific liposomes loaded with proteinaceous BRET pair as a promising tool for targeted self-excited photodynamic therapy.},\n year = {2023},\n issn = {1873-3441},\n month = dec,\n pages = {208--217},\n volume = {193},\n abstract = {Photodynamic therapy (PDT) for deep-seated tumors is still challenging due to the limited penetration of visible light through tissues. To resolve this limitation, systems based on bioluminescence resonance energy transfer (BRET), that do not require an external light source are proposed. Herein, for BRET-activated PDT we developed proteinaceous BRET-pair consisting of luciferase NanoLuc, which acts as energy donor upon addition of luciferase specific substrate furimazine, and phototoxic protein SOPP3 as a photosensitizer. We have shown that hybrid protein NanoLuc-SOPP3 is an excellent BRET pair with BRET ratio of 1.12. Targeted delivery of NanoLuc-SOPP3 BRET pair via tumor-specific small liposomes (∼100 nm) to tumors overexpressing the HER2-receptor (human epidermal growth factor receptor 2) was demonstrated in vitro and in vivo. The proposed BRET-activated system has been shown to significantly suppress tumor growth in a model of subcutaneous and, more importantly, deep-seated tumor model. Taking into account the in vivo efficiency of proposed BRET-activated system, we believe that it has great potential for depth-independent PDT and can significantly broaden the application of PDT in the clinic.},\n chemicals = {Liposomes, Luciferases},\n citation-subset = {IM},\n completed = {2023-12-11},\n country = {Netherlands},\n doi = {10.1016/j.ejpb.2023.11.008},\n issn-linking = {0939-6411},\n keywords = {Humans; Liposomes; Luciferases, genetics, metabolism; Energy Transfer; Neoplasms, drug therapy; Photochemotherapy; Bioluminescence resonance energy transfer; NanoLuc; SOPP3; Self-excited photodynamic therapy; Targeted delivery; Tumor-specific liposomes},\n nlm-id = {9109778},\n owner = {NLM},\n pii = {S0939-6411(23)00297-7},\n pmid = {37956784},\n pubmodel = {Print-Electronic},\n pubstate = {ppublish},\n revised = {2023-12-11},\n}\n\n\n\n Photodynamic therapy (PDT) for deep-seated tumors is still challenging due to the limited penetration of visible light through tissues. To resolve this limitation, systems based on bioluminescence resonance energy transfer (BRET), that do not require an external light source are proposed. Herein, for BRET-activated PDT we developed proteinaceous BRET-pair consisting of luciferase NanoLuc, which acts as energy donor upon addition of luciferase specific substrate furimazine, and phototoxic protein SOPP3 as a photosensitizer. We have shown that hybrid protein NanoLuc-SOPP3 is an excellent BRET pair with BRET ratio of 1.12. Targeted delivery of NanoLuc-SOPP3 BRET pair via tumor-specific small liposomes (∼100 nm) to tumors overexpressing the HER2-receptor (human epidermal growth factor receptor 2) was demonstrated in vitro and in vivo. The proposed BRET-activated system has been shown to significantly suppress tumor growth in a model of subcutaneous and, more importantly, deep-seated tumor model. Taking into account the in vivo efficiency of proposed BRET-activated system, we believe that it has great potential for depth-independent PDT and can significantly broaden the application of PDT in the clinic.\n
\n\n\n\n \n\n \n \n \n \n \n An easy tool to monitor the elemental steps of in vitro translation via gel electrophoresis of fluorescently labelled small peptides.\n \n \n \n\n\n \n Marina, V. I.; Bidzhieva, M.; Tereshchenkov, A. G.; Orekhov, D.; Sagitova, V. E.; Sumbatyan, N. V.; Tashlitsky, V. N.; Ferberg, A. S.; Maviza, T. P.; Kasatsky, P.; Tolicheva, O.; Paleskava, A.; Polshakov, V. I.; Osterman, I. A.; Dontsova, O. A.; Konevega, A. L.; and Sergiev, P. V.\n\n\n \n\n\n\n RNA (New York, N.Y.). December 2023.\n \n\n\n\n
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\n\n\n@Article{Marina2023,\n author = {Marina, Valeriya I. and Bidzhieva, Medina and Tereshchenkov, Andrey G. and Orekhov, Dmitry and Sagitova, Vladislava E. and Sumbatyan, Nataliya V. and Tashlitsky, Vadim N. and Ferberg, Artem S. and Maviza, Tinashe P. and Kasatsky, Pavel and Tolicheva, Olga and Paleskava, Alena and Polshakov, Vladimir I. and Osterman, Ilya A. and Dontsova, Olga A. and Konevega, Andrey L. and Sergiev, Petr V.},\n journal = {RNA (New York, N.Y.)},\n title = {An easy tool to monitor the elemental steps of in vitro translation via gel electrophoresis of fluorescently labelled small peptides.},\n year = {2023},\n issn = {1469-9001},\n month = dec,\n abstract = {Several methods are available to visualize and assess the kinetics and efficiency of elemental steps of protein biosynthesis. However, each of these methods has its own limitations. Here, we present a novel, simple and convenient tool for monitoring stepwise in vitro translation initiated by BODIPY-Met-tRNA. Synthesis and release of very short, 1 to 7 amino acids, BODIPY-labelled peptides, can be monitored using urea-polyacrylamide gel electrophoresis. Very short BODIPY-labelled oligopeptides might be resolved this way, in contrast to widely used Tris-tricine gel electrophoresis, which is suitable to separate peptides larger than 1 kDa. The method described in this manuscript allows one to monitor the steps of translation initiation, peptide transfer, translocation, and termination as well as their inhibition at an unprecedented single amino acid resolution.},\n citation-subset = {IM},\n country = {United States},\n doi = {10.1261/rna.079766.123},\n issn-linking = {1355-8382},\n keywords = {BODIPY; peptidyl transferase; ribosome; termination; translation},\n nlm-id = {9509184},\n owner = {NLM},\n pii = {rna.079766.123},\n pmid = {38164606},\n pubmodel = {Print-Electronic},\n pubstate = {aheadofprint},\n revised = {2024-01-02},\n}\n\n\n\n Several methods are available to visualize and assess the kinetics and efficiency of elemental steps of protein biosynthesis. However, each of these methods has its own limitations. Here, we present a novel, simple and convenient tool for monitoring stepwise in vitro translation initiated by BODIPY-Met-tRNA. Synthesis and release of very short, 1 to 7 amino acids, BODIPY-labelled peptides, can be monitored using urea-polyacrylamide gel electrophoresis. Very short BODIPY-labelled oligopeptides might be resolved this way, in contrast to widely used Tris-tricine gel electrophoresis, which is suitable to separate peptides larger than 1 kDa. The method described in this manuscript allows one to monitor the steps of translation initiation, peptide transfer, translocation, and termination as well as their inhibition at an unprecedented single amino acid resolution.\n
\n\n\n\n \n\n \n \n \n \n \n Co-production of (155)Tb and (152)Tb irradiating (155)Gd / (151)Eu tandem target with a medium energy α-particle beam.\n \n \n \n\n\n \n Moiseeva, A. N.; Makoveeva, K. A.; Furkina, E. B.; Artyushova, E. V.; German, M. N.; Khomenko, I. A.; Konevega, A. L.; Kormazeva, E. S.; Novikov, V. I.; Aksenov, N. V.; Gustova, N. S.; and Aliev, R. A.\n\n\n \n\n\n\n Nuclear medicine and biology, 126-127: 108389. 2023.\n \n\n\n\n
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\n\n\n@Article{Moiseeva2023,\n author = {Moiseeva, A. N. and Makoveeva, K. A. and Furkina, E. B. and Artyushova, E. V. and German, M. N. and Khomenko, I. A. and Konevega, A. L. and Kormazeva, E. S. and Novikov, V. I. and Aksenov, N. V. and Gustova, N. S. and Aliev, R. A.},\n journal = {Nuclear medicine and biology},\n title = {Co-production of (155)Tb and (152)Tb irradiating (155)Gd / (151)Eu tandem target with a medium energy α-particle beam.},\n year = {2023},\n issn = {1872-9614},\n pages = {108389},\n volume = {126-127},\n abstract = {Four terbium isotopes (149,152,155,161)Tb emitting various types of radiation can be used for both diagnostics and therapy. (152)Tb emits positrons and is ideal for PET. (155)Tb is considered a promising Auger emitter and a diagnostic pair for other terbium therapeutic isotopes. Several methods for the production of (155)Tb using charged particle accelerators have been proposed, but they all have significant limitations. The restricted availability of this isotope hinders its medical applications. We have proposed a new method for production of (155)Tb, irradiating enriched (155)Gd by alpha particles. The possibility of simultaneous production of two isotopes of terbium, (152,155)Tb, was also studied for more efficient cyclotron beam use. Irradiation of (155)Gd enriched targets and (155)Gd / (151)Eu tandem target with alpha-particles with an energy of 54 MeV was carried out at the U-150 cyclotron at the NRC "Kurchatov Institute". The cross sections of nuclear reactions on (enr-155)Gd were measured by the stack foil technique, detecting the gamma-radiation of the activation products. The separation of rare earth elements was performed by extraction chromatography with the LN Resin. (155)Tb was produced via (155)Dy decay. The cross sections for the (155,156)Tb and (155,157)Dy production were measured by the irradiation of a gadolinium target enriched with the (155)Gd isotope with alpha-particles in an energy range of 54 → 33 MeV. The yield of (155)Dy on a thick target at 54 MeV was 130 MBq/μAh, which makes it possible to obtain 1 GBq of (155)Tb in 11 hour-irradiation with 20 μA beam current. The possibility of simultaneous production of (152,155)Tb by irradiation of (155)Gd and (151)Eu tandem target with medium-energy alpha-particles is implemented. Optimal irradiation energy ranges of alpha -particles as 54 → 42 MeV for (155)Tb and 42 → 34 MeV for (152)Tb were suggested. Product activity and radionuclidic purity were calculated.},\n chemicals = {Terbium, Radioisotopes},\n citation-subset = {IM},\n completed = {2023-12-16},\n country = {United States},\n doi = {10.1016/j.nucmedbio.2023.108389},\n issn-linking = {0969-8051},\n keywords = {Terbium, chemistry; Alpha Particles, therapeutic use; Radioisotopes, chemistry; Electrons; Cross section; Cyclotron; Nuclear reaction; Tandem target; Terbium-152; Terbium-155},\n nlm-id = {9304420},\n owner = {NLM},\n pii = {S0969-8051(23)00077-X},\n pmid = {37783103},\n pubmodel = {Print-Electronic},\n pubstate = {ppublish},\n revised = {2023-12-16},\n season = {Nov-Dec},\n}\n\n\n\n Four terbium isotopes (149,152,155,161)Tb emitting various types of radiation can be used for both diagnostics and therapy. (152)Tb emits positrons and is ideal for PET. (155)Tb is considered a promising Auger emitter and a diagnostic pair for other terbium therapeutic isotopes. Several methods for the production of (155)Tb using charged particle accelerators have been proposed, but they all have significant limitations. The restricted availability of this isotope hinders its medical applications. We have proposed a new method for production of (155)Tb, irradiating enriched (155)Gd by alpha particles. The possibility of simultaneous production of two isotopes of terbium, (152,155)Tb, was also studied for more efficient cyclotron beam use. Irradiation of (155)Gd enriched targets and (155)Gd / (151)Eu tandem target with alpha-particles with an energy of 54 MeV was carried out at the U-150 cyclotron at the NRC \"Kurchatov Institute\". The cross sections of nuclear reactions on (enr-155)Gd were measured by the stack foil technique, detecting the gamma-radiation of the activation products. The separation of rare earth elements was performed by extraction chromatography with the LN Resin. (155)Tb was produced via (155)Dy decay. The cross sections for the (155,156)Tb and (155,157)Dy production were measured by the irradiation of a gadolinium target enriched with the (155)Gd isotope with alpha-particles in an energy range of 54 → 33 MeV. The yield of (155)Dy on a thick target at 54 MeV was 130 MBq/μAh, which makes it possible to obtain 1 GBq of (155)Tb in 11 hour-irradiation with 20 μA beam current. The possibility of simultaneous production of (152,155)Tb by irradiation of (155)Gd and (151)Eu tandem target with medium-energy alpha-particles is implemented. Optimal irradiation energy ranges of alpha -particles as 54 → 42 MeV for (155)Tb and 42 → 34 MeV for (152)Tb were suggested. Product activity and radionuclidic purity were calculated.\n
\n\n\n\n \n\n \n \n \n \n \n \n Anti-tumor activity of radiopharmaceutical medication based on biospecific antibodies to tumor-associated stroma elements and 177lutecium.\n \n \n \n \n\n\n \n Trashkov, A.; Gagloeva, T. D.; Budko, A. I.; Petrovskiy, A. N.; Timaeva, O. I.; Tsygan, N. V.; Stanzhevsky, A.; Vasiliev, A. G.; Maistrenko, D. N.; Sergunova, C. A.; Sysoev, D.; Shatic, S. V.; Antuganov, D.; and Konevega, A. L.\n\n\n \n\n\n\n Pediatrician (St. Petersburg), 13(6): 35–44. February 2023.\n \n\n\n\n
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\n\n\n@Article{Trashkov2023,\n author = {A. Trashkov and T. D. Gagloeva and Alexander I. Budko and Andrey N. Petrovskiy and Olyesya I. Timaeva and N. V. Tsygan and A. Stanzhevsky and A. G. Vasiliev and D. N. Maistrenko and Christina A. Sergunova and D. Sysoev and S. V. Shatic and D. Antuganov and A. L. Konevega},\n journal = {Pediatrician (St. Petersburg)},\n title = {Anti-tumor activity of radiopharmaceutical medication based on biospecific antibodies to tumor-associated stroma elements and 177lutecium},\n year = {2023},\n issn = {2079-7850},\n month = feb,\n number = {6},\n pages = {35--44},\n volume = {13},\n abstract = {Radiopharmaceutical targeted medication based on biospecific antibodies to tumor-associated stroma elements and 177lutecium (177Lu-DOTA-anti-CTLA4-GITR) potential anti-tumor activity was studied in two courses: one-time administration and two injections with a considerable lag. Subcutaneously transplanted experimental colonic carcinoma (AKATOL; cell line CT26 EGFP) with high expression of green fluorescent protein (eGFP) and additional expression of target tumor-associated stroma molecules CTLA4 and GITR was used as a model in BALB/c male mice. The experimental radiopharmaceutical targeted medication proved to possess high pharmacologic activity against the tumor under study. It was apparent in valid increase of experimental animals mean lifespan, tumor debut latent period inhibition and clinically valid tumor growth rate slowdown. Double administration of 177Lu-DOTA-anti-CTLA4-GITR proved to be more effective than one-time one, however neither of them managed to yield statistically valid difference in safety levels.},\n doi = {10.17816/ped13635-44},\n publisher = {ECO-Vector LLC},\n url = {https://www.semanticscholar.org/paper/e163eabcbbeb4e019ff356cf20379b2c467ac983},\n venue = {Pediatrician (St. Petersburg)},\n}\n\n\n\n Radiopharmaceutical targeted medication based on biospecific antibodies to tumor-associated stroma elements and 177lutecium (177Lu-DOTA-anti-CTLA4-GITR) potential anti-tumor activity was studied in two courses: one-time administration and two injections with a considerable lag. Subcutaneously transplanted experimental colonic carcinoma (AKATOL; cell line CT26 EGFP) with high expression of green fluorescent protein (eGFP) and additional expression of target tumor-associated stroma molecules CTLA4 and GITR was used as a model in BALB/c male mice. The experimental radiopharmaceutical targeted medication proved to possess high pharmacologic activity against the tumor under study. It was apparent in valid increase of experimental animals mean lifespan, tumor debut latent period inhibition and clinically valid tumor growth rate slowdown. Double administration of 177Lu-DOTA-anti-CTLA4-GITR proved to be more effective than one-time one, however neither of them managed to yield statistically valid difference in safety levels.\n
\n\n\n\n \n\n \n \n \n \n \n \n Pharmaceutical Development of Innovative Russian Radiopharmaceuticals Based on Bispecific Nanoantibodies to Gitr and Ctla-4 for the Theranostics of Oncological Diseases.\n \n \n \n \n\n\n \n Maystrenko, D.; Stanzhevsky, A. A.; Sergunova, K. A.; Shatik, S. V.; Antuganov, D. O.; Shehadat, R. I. A.; Sysoev, D.; Nadporozhsky, M. S.; Konevega, A. L.; Trashkov, A. P.; Molchanov, O. E.; Chipiga, L. A.; and Vodovatov, A.\n\n\n \n\n\n\n Nanobiotechnology Reports, 18(4): 650–657. August 2023.\n \n\n\n\n
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\n\n\n\n@Article{Maystrenko2023,\n author = {D. Maystrenko and A. A. Stanzhevsky and K. A. Sergunova and S. V. Shatik and D. O. Antuganov and R. I. Al Shehadat and D. Sysoev and M. S. Nadporozhsky and A. L. Konevega and A. P. Trashkov and O. E. Molchanov and L. A. Chipiga and A. Vodovatov},\n journal = {Nanobiotechnology Reports},\n title = {Pharmaceutical Development of Innovative Russian Radiopharmaceuticals Based on Bispecific Nanoantibodies to Gitr and Ctla-4 for the Theranostics of Oncological Diseases},\n year = {2023},\n issn = {2635-1684},\n month = aug,\n number = {4},\n pages = {650--657},\n volume = {18},\n doi = {10.1134/S2635167623600165},\n publisher = {Pleiades Publishing Ltd},\n url = {https://www.semanticscholar.org/paper/2a778eafc64fcf1bdf62cb5919603ae5497ebb4c},\n venue = {Nanobiotechnology Reports},\n}\n\n\n\n \n\n \n \n \n \n \n Magnetic Relaxation Switching Assay Using IFNα-2b-Conjugated Superparamagnetic Nanoparticles for Anti-Interferon Antibody Detection.\n \n \n \n\n\n \n Nikolaev, B.; Yakovleva, L.; Fedorov, V.; Yudintceva, N.; Ryzhov, V.; Marchenko, Y.; Ischenko, A.; Zhakhov, A.; Dobrodumov, A.; Combs, S. E.; Gao, H.; and Shevtsov, M.\n\n\n \n\n\n\n Biosensors, 13. June 2023.\n \n\n\n\n
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\n\n\n@Article{Nikolaev2023,\n author = {Nikolaev, Boris and Yakovleva, Ludmila and Fedorov, Viacheslav and Yudintceva, Natalia and Ryzhov, Vyacheslav and Marchenko, Yaroslav and Ischenko, Alexander and Zhakhov, Alexander and Dobrodumov, Anatoliy and Combs, Stephanie E. and Gao, Huile and Shevtsov, Maxim},\n journal = {Biosensors},\n title = {Magnetic Relaxation Switching Assay Using IFNα-2b-Conjugated Superparamagnetic Nanoparticles for Anti-Interferon Antibody Detection.},\n year = {2023},\n issn = {2079-6374},\n month = jun,\n volume = {13},\n abstract = {Type I interferons, particularly IFNα-2b, play essential roles in eliciting adaptive and innate immune responses, being implicated in the pathogenesis of various diseases, including cancer, and autoimmune and infectious diseases. Therefore, the development of a highly sensitive platform for analysis of either IFNα-2b or anti-IFNα-2b antibodies is of high importance to improve the diagnosis of various pathologies associated with the IFNα-2b disbalance. For evaluation of the anti-IFNα-2b antibody level, we have synthesized superparamagnetic iron oxide nanoparticles (SPIONs) coupled with the recombinant human IFNα-2b protein (SPIONs@IFNα-2b). Employing a magnetic relaxation switching assay (MRSw)-based nanosensor, we detected picomolar concentrations (0.36 pg/mL) of anti-INFα-2b antibodies. The high sensitivity of the real-time antibodies' detection was ensured by the specificity of immune responses and the maintenance of resonance conditions for water spins by choosing a high-frequency filling of short radio-frequency pulses of the generator. The formation of a complex of the SPIONs@IFNα-2b nanoparticles with the anti-INFα-2b antibodies led to a cascade process of the formation of nanoparticle clusters, which was further enhanced by exposure to a strong (7.1 T) homogenous magnetic field. Obtained magnetic conjugates exhibited high negative MR contrast-enhancing properties (as shown by NMR studies) that were also preserved when particles were administered in vivo. Thus, we observed a 1.2-fold decrease of the T2 relaxation time in the liver following administration of magnetic conjugates as compared to the control. In conclusion, the developed MRSw assay based on SPIONs@IFNα-2b nanoparticles represents an alternative immunological probe for the estimation of anti-IFNα-2b antibodies that could be further employed in clinical studies.},\n chemicals = {Interferons, Contrast Media, Magnetite Nanoparticles},\n citation-subset = {IM},\n completed = {2023-06-29},\n country = {Switzerland},\n doi = {10.3390/bios13060624},\n issn-linking = {2079-6374},\n issue = {6},\n keywords = {Humans; Interferons; Magnetic Resonance Imaging; Nanoparticles; Contrast Media; Magnetic Iron Oxide Nanoparticles; Magnetic Phenomena; Magnetite Nanoparticles, chemistry; IFNα-2b; SPIONs; anti-INFα-2b antibodies; interferon; magnetic relaxation switching assay; magnetic resonance imaging; nanoparticles; nanosensor},\n nlm-id = {101609191},\n owner = {NLM},\n pii = {624},\n pmc = {PMC10296438},\n pmid = {37366989},\n pubmodel = {Electronic},\n pubstate = {epublish},\n revised = {2023-07-01},\n}\n\n\n\n Type I interferons, particularly IFNα-2b, play essential roles in eliciting adaptive and innate immune responses, being implicated in the pathogenesis of various diseases, including cancer, and autoimmune and infectious diseases. Therefore, the development of a highly sensitive platform for analysis of either IFNα-2b or anti-IFNα-2b antibodies is of high importance to improve the diagnosis of various pathologies associated with the IFNα-2b disbalance. For evaluation of the anti-IFNα-2b antibody level, we have synthesized superparamagnetic iron oxide nanoparticles (SPIONs) coupled with the recombinant human IFNα-2b protein (SPIONs@IFNα-2b). Employing a magnetic relaxation switching assay (MRSw)-based nanosensor, we detected picomolar concentrations (0.36 pg/mL) of anti-INFα-2b antibodies. The high sensitivity of the real-time antibodies' detection was ensured by the specificity of immune responses and the maintenance of resonance conditions for water spins by choosing a high-frequency filling of short radio-frequency pulses of the generator. The formation of a complex of the SPIONs@IFNα-2b nanoparticles with the anti-INFα-2b antibodies led to a cascade process of the formation of nanoparticle clusters, which was further enhanced by exposure to a strong (7.1 T) homogenous magnetic field. Obtained magnetic conjugates exhibited high negative MR contrast-enhancing properties (as shown by NMR studies) that were also preserved when particles were administered in vivo. Thus, we observed a 1.2-fold decrease of the T2 relaxation time in the liver following administration of magnetic conjugates as compared to the control. In conclusion, the developed MRSw assay based on SPIONs@IFNα-2b nanoparticles represents an alternative immunological probe for the estimation of anti-IFNα-2b antibodies that could be further employed in clinical studies.\n
\n\n\n\n \n\n \n \n \n \n \n Agglomeration of magnetite nanoparticles with citrate shell in an aqueous magnetic fluid.\n \n \n \n\n\n \n Pleshakov, I. V.; Ryzhov, V. A.; Marchenko, Y. Y.; Alekseev, A. A.; Karseeva, E. K.; Nevedomskiy, V. N.; and Prokof'ev, A. V.\n\n\n \n\n\n\n Nanosystems: Physics, Chemistry, Mathematics, 14(3): 334-341. 2023.\n \n\n\n\n
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\n\n\n\n@Article{Pleshakov2023,\n author = {I. V. Pleshakov and V. A. Ryzhov and Ya. Yu. Marchenko and A. A. Alekseev and E. K. Karseeva and V. N. Nevedomskiy and A. V. Prokof'ev},\n journal = {Nanosystems: Physics, Chemistry, Mathematics},\n title = {Agglomeration of magnetite nanoparticles with citrate shell in an aqueous magnetic fluid},\n year = {2023},\n issn = {2220-8054},\n number = {3},\n pages = {334-341},\n volume = {14},\n doi = {10.17586/2220-8054-2023-14-3-334-341},\n keywords = {Physics and Astronomy (miscellaneous), Condensed Matter Physics, Materials Science (miscellaneous), Mathematics (miscellaneous)},\n publisher = {ITMO University},\n}\n\n\n\n \n\n \n \n \n \n \n Feasibility of Transport of 26 Biologically Active Ultrashort Peptides via LAT and PEPT Family Transporters.\n \n \n \n\n\n \n Khavinson, V. K.; Linkova, N. S.; Rudskoy, A. I.; and Petukhov, M. G.\n\n\n \n\n\n\n Biomolecules, 13(3): 552. March 2023.\n \n\n\n\n
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\n\n\n\n@Article{Khavinson2023,\n author = {Vladimir Khatskelevich Khavinson and Natalia Sergeevna Linkova and Andrey Ivanovich Rudskoy and Michael Gennadievich Petukhov},\n journal = {Biomolecules},\n title = {Feasibility of Transport of 26 Biologically Active Ultrashort Peptides via LAT and PEPT Family Transporters},\n year = {2023},\n issn = {2218-273X},\n month = mar,\n number = {3},\n pages = {552},\n volume = {13},\n doi = {10.3390/biom13030552},\n keywords = {Molecular Biology, Biochemistry},\n publisher = {MDPI AG},\n}\n\n\n\n \n\n \n \n \n \n \n The Influence of KE and EW Dipeptides in the Composition of the Thymalin Drug on Gene Expression and Protein Synthesis Involved in the Pathogenesis of COVID-19.\n \n \n \n\n\n \n Linkova, N.; Khavinson, V.; Diatlova, A.; Petukhov, M.; Vladimirova, E.; Sukhareva, M.; and Ilina, A.\n\n\n \n\n\n\n International Journal of Molecular Sciences, 24(17): 13377. August 2023.\n \n\n\n\n
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\n\n\n\n@Article{Linkova2023,\n author = {Natalia Linkova and Vladimir Khavinson and Anastasiia Diatlova and Michael Petukhov and Elizaveta Vladimirova and Maria Sukhareva and Anastasiia Ilina},\n journal = {International Journal of Molecular Sciences},\n title = {The Influence of KE and EW Dipeptides in the Composition of the Thymalin Drug on Gene Expression and Protein Synthesis Involved in the Pathogenesis of COVID-19},\n year = {2023},\n issn = {1422-0067},\n month = aug,\n number = {17},\n pages = {13377},\n volume = {24},\n doi = {10.3390/ijms241713377},\n keywords = {Inorganic Chemistry, Organic Chemistry, Physical and Theoretical Chemistry, Computer Science Applications, Spectroscopy, Molecular Biology, General Medicine, Catalysis},\n publisher = {MDPI AG},\n}\n\n\n\n
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\n \n \n\n \n \n \n \n \n Conjugates of Chloramphenicol Amine and Berberine as Antimicrobial Agents.\n \n \n \n\n\n \n Pavlova, J. A.; Tereshchenkov, A. G.; Nazarov, P. A.; Lukianov, D. A.; Skvortsov, D. A.; Polshakov, V. I.; Vasilieva, B. F.; Efremenkova, O. V.; Kaiumov, M. Y.; Paleskava, A.; Konevega, A. L.; Dontsova, O. A.; Osterman, I. A.; Bogdanov, A. A.; and Sumbatyan, N. V.\n\n\n \n\n\n\n Antibiotics (Basel, Switzerland), 12. December 2022.\n \n\n\n\n
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\n\n\n@Article{Pavlova2022,\n author = {Pavlova, Julia A. and Tereshchenkov, Andrey G. and Nazarov, Pavel A. and Lukianov, Dmitrii A. and Skvortsov, Dmitry A. and Polshakov, Vladimir I. and Vasilieva, Byasilya F. and Efremenkova, Olga V. and Kaiumov, Mikhail Y. and Paleskava, Alena and Konevega, Andrey L. and Dontsova, Olga A. and Osterman, Ilya A. and Bogdanov, Alexey A. and Sumbatyan, Natalia V.},\n journal = {Antibiotics (Basel, Switzerland)},\n title = {Conjugates of Chloramphenicol Amine and Berberine as Antimicrobial Agents.},\n year = {2022},\n issn = {2079-6382},\n month = dec,\n volume = {12},\n abstract = {In order to obtain antimicrobial compounds with improved properties, new conjugates comprising two different biologically active agents within a single chimeric molecule based on chloramphenicol (CHL) and a hydrophobic cation were synthesized and studied. Chloramphenicol amine (CAM), derived from the ribosome-targeting antibiotic CHL, and the plant isoquinoline alkaloid berberine (BER) are connected by alkyl linkers of different lengths in structures of these conjugates. Using competition binding, double reporter system, and toeprinting assays, we showed that synthesized CAM-Cn-BER compounds bound to the bacterial ribosome and inhibited protein synthesis like the parent CHL. The mechanism of action of CAM-C5-BER and CAM-C8-BER on the process of bacterial translations was similar to CHL. Experiments with bacteria demonstrated that CAM-Cn-BERs suppressed the growth of laboratory strains of CHL and macrolides-resistant bacteria. CAM-C8-BER acted against mycobacteria and more selectively inhibited the growth of Gram-positive bacteria than the parent CHL and the berberine derivative lacking the CAM moiety (CH -C8-BER). Using a potential-sensitive fluorescent probe, we found that CAM-C8-BER significantly reduced the membrane potential in cells. Crystal violet assays were used to demonstrate the absence of induction of biofilm formation under the action of CAM-C8-BER on bacteria. Thus, we showed that CAM-C8-BER could act both on the ribosome and on the cell membrane of bacteria, with the alkylated berberine fragment of the compound making a significant contribution to the inhibitory effect on bacterial growth. Moreover, we showed that CAM-Cn-BERs did not inhibit eukaryotic translation in vitro and were non-toxic for eukaryotic cells.},\n country = {Switzerland},\n doi = {10.3390/antibiotics12010015},\n issn-linking = {2079-6382},\n issue = {1},\n keywords = {C-13 derivatives of berberine; antibiotic activity; bacterial membrane potential; bacterial ribosome; berberine; biofilms; chloramphenicol},\n nlm-id = {101637404},\n owner = {NLM},\n pii = {15},\n pmc = {PMC9854996},\n pmid = {36671216},\n pubmodel = {Electronic},\n pubstate = {epublish},\n revised = {2023-01-23},\n}\n\n\n\n In order to obtain antimicrobial compounds with improved properties, new conjugates comprising two different biologically active agents within a single chimeric molecule based on chloramphenicol (CHL) and a hydrophobic cation were synthesized and studied. Chloramphenicol amine (CAM), derived from the ribosome-targeting antibiotic CHL, and the plant isoquinoline alkaloid berberine (BER) are connected by alkyl linkers of different lengths in structures of these conjugates. Using competition binding, double reporter system, and toeprinting assays, we showed that synthesized CAM-Cn-BER compounds bound to the bacterial ribosome and inhibited protein synthesis like the parent CHL. The mechanism of action of CAM-C5-BER and CAM-C8-BER on the process of bacterial translations was similar to CHL. Experiments with bacteria demonstrated that CAM-Cn-BERs suppressed the growth of laboratory strains of CHL and macrolides-resistant bacteria. CAM-C8-BER acted against mycobacteria and more selectively inhibited the growth of Gram-positive bacteria than the parent CHL and the berberine derivative lacking the CAM moiety (CH -C8-BER). Using a potential-sensitive fluorescent probe, we found that CAM-C8-BER significantly reduced the membrane potential in cells. Crystal violet assays were used to demonstrate the absence of induction of biofilm formation under the action of CAM-C8-BER on bacteria. Thus, we showed that CAM-C8-BER could act both on the ribosome and on the cell membrane of bacteria, with the alkylated berberine fragment of the compound making a significant contribution to the inhibitory effect on bacterial growth. Moreover, we showed that CAM-Cn-BERs did not inhibit eukaryotic translation in vitro and were non-toxic for eukaryotic cells.\n
\n\n\n\n \n\n \n \n \n \n \n Ribosomal protein S18 acetyltransferase RimI is responsible for the acetylation of elongation factor Tu.\n \n \n \n\n\n \n Pletnev, P. I.; Shulenina, O.; Evfratov, S.; Treshin, V.; Subach, M. F.; Serebryakova, M. V.; Osterman, I. A.; Paleskava, A.; Bogdanov, A. A.; Dontsova, O. A.; Konevega, A. L.; and Sergiev, P. V.\n\n\n \n\n\n\n The Journal of biological chemistry, 298: 101914. May 2022.\n \n\n\n\n
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\n\n\n@Article{Pletnev2022,\n author = {Pletnev, Philipp I. and Shulenina, Olga and Evfratov, Sergey and Treshin, Vsevolod and Subach, Maksim F. and Serebryakova, Marina V. and Osterman, Ilya A. and Paleskava, Alena and Bogdanov, Alexey A. and Dontsova, Olga A. and Konevega, Andrey L. and Sergiev, Petr V.},\n journal = {The Journal of biological chemistry},\n title = {Ribosomal protein S18 acetyltransferase RimI is responsible for the acetylation of elongation factor Tu.},\n year = {2022},\n issn = {1083-351X},\n month = may,\n pages = {101914},\n volume = {298},\n abstract = {N-terminal acetylation is widespread in the eukaryotic proteome but in bacteria is restricted to a small number of proteins mainly involved in translation. It was long known that elongation factor Tu (EF-Tu) is N-terminally acetylated, whereas the enzyme responsible for this process was unclear. Here, we report that RimI acetyltransferase, known to modify ribosomal protein S18, is likewise responsible for N-acetylation of the EF-Tu. With the help of inducible tufA expression plasmid, we demonstrated that the acetylation does not alter the stability of EF-Tu. Binding of aminoacyl tRNA to the recombinant EF-Tu in vitro was found to be unaffected by the acetylation. At the same time, with the help of fast kinetics methods, we demonstrate that an acetylated variant of EF-Tu more efficiently accelerates A-site occupation by aminoacyl-tRNA, thus increasing the efficiency of in vitro translation. Finally, we show that a strain devoid of RimI has a reduced growth rate, expanded to an evolutionary timescale, and might potentially promote conservation of the acetylation mechanism of S18 and EF-Tu. This study increased our understanding of the modification of bacterial translation apparatus.},\n chemicals = {Peptide Elongation Factors, RNA, Transfer, Amino Acyl, Ribosomal Proteins, ribosomal protein S18, Guanosine Triphosphate, Acetyltransferases, Peptide Elongation Factor Tu},\n citation-subset = {IM},\n completed = {2022-06-03},\n country = {United States},\n doi = {10.1016/j.jbc.2022.101914},\n issn-linking = {0021-9258},\n issue = {5},\n keywords = {Acetylation; Acetyltransferases, genetics, metabolism; Bacteria, metabolism; Guanosine Triphosphate, metabolism; Kinetics; Peptide Elongation Factor Tu, genetics, metabolism; Peptide Elongation Factors, genetics, metabolism; RNA, Transfer, Amino Acyl, metabolism; Ribosomal Proteins; Ribosomes, metabolism; EF-Tu; bacteria; post-translational modification; ribosome},\n nlm-id = {2985121R},\n owner = {NLM},\n pii = {S0021-9258(22)00354-4},\n pmc = {PMC9079301},\n pmid = {35398352},\n pubmodel = {Print-Electronic},\n pubstate = {ppublish},\n revised = {2022-07-16},\n}\n\n\n\n N-terminal acetylation is widespread in the eukaryotic proteome but in bacteria is restricted to a small number of proteins mainly involved in translation. It was long known that elongation factor Tu (EF-Tu) is N-terminally acetylated, whereas the enzyme responsible for this process was unclear. Here, we report that RimI acetyltransferase, known to modify ribosomal protein S18, is likewise responsible for N-acetylation of the EF-Tu. With the help of inducible tufA expression plasmid, we demonstrated that the acetylation does not alter the stability of EF-Tu. Binding of aminoacyl tRNA to the recombinant EF-Tu in vitro was found to be unaffected by the acetylation. At the same time, with the help of fast kinetics methods, we demonstrate that an acetylated variant of EF-Tu more efficiently accelerates A-site occupation by aminoacyl-tRNA, thus increasing the efficiency of in vitro translation. Finally, we show that a strain devoid of RimI has a reduced growth rate, expanded to an evolutionary timescale, and might potentially promote conservation of the acetylation mechanism of S18 and EF-Tu. This study increased our understanding of the modification of bacterial translation apparatus.\n
\n\n\n\n \n\n \n \n \n \n \n Blood Plasma Exosomes Contain Circulating DNA in Their Crown.\n \n \n \n\n\n \n Tutanov, O.; Shtam, T.; Grigor'eva, A.; Tupikin, A.; Tsentalovich, Y.; and Tamkovich, S.\n\n\n \n\n\n\n Diagnostics (Basel, Switzerland), 12. March 2022.\n \n\n\n\n
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\n\n\n@Article{Tutanov2022,\n author = {Tutanov, Oleg and Shtam, Tatiana and Grigor'eva, Alina and Tupikin, Alexey and Tsentalovich, Yuri and Tamkovich, Svetlana},\n journal = {Diagnostics (Basel, Switzerland)},\n title = {Blood Plasma Exosomes Contain Circulating DNA in Their Crown.},\n year = {2022},\n issn = {2075-4418},\n month = mar,\n volume = {12},\n abstract = {It is known that circulating DNA (cirDNA) is protected from nuclease activity by proteins that form macromolecular complexes with DNA. In addition, it was previously shown that cirDNA can bind to the outer surface of exosomes. NTA analysis and real-time PCR show that exosomes from healthy females (HF) or breast cancer patients (BCP) plasma contain less than 1.4 × 10 pg of DNA. Thus, only a minor part of cirDNA is attached to the outer side of the exosome as part of the vesicle crown: the share of exosomal DNA does not exceed 0.025% HF plasma DNA and 0.004% BCP plasma DNA. Treatment of plasma exosomes with DNase I with subsequent dot immunoassay reveals that H2a, H2b, and H3 histones are not part of the exosomal membrane, but are part of the cirDNA-protein macromolecular complex associated with the surface of the exosome either through interaction with DNA-binding proteins or with histone-binding proteins. Using bioinformatics approaches after identification by MALDI-TOF mass spectrometry, 16 exosomal DNA-binding proteins were identified. It was shown that four proteins-AIFM1, IGHM, CHD5, and KCNIP3-are candidates for DNA binding on the outer membrane of exosomes; the crown of exosomes may include five DNA-binding proteins: H2a, H2b, H3, IGHM, and ALB. Of note, AIFM1, IGHM, and CHD5 proteins are found only in HF plasma exosomes; KCNIP3 protein is identified only in BCP plasma exosomes; and H2a, H2b, H3, and ALB are revealed in all samples of plasma exosomes. Two histone-binding proteins, CHD5 and KDM6B, have been found in exosomes from HF plasma. The data obtained indicate that cirDNA preferentially binds to the outer membrane of exosomes by association with DNA-binding proteins.},\n country = {Switzerland},\n doi = {10.3390/diagnostics12040854},\n issn-linking = {2075-4418},\n issue = {4},\n keywords = {DNA-binding proteins; circulating DNA; crown; exosomes; histone-binding proteins},\n nlm-id = {101658402},\n owner = {NLM},\n pii = {854},\n pmc = {PMC9027845},\n pmid = {35453902},\n pubmodel = {Electronic},\n pubstate = {epublish},\n revised = {2022-07-16},\n}\n\n\n\n It is known that circulating DNA (cirDNA) is protected from nuclease activity by proteins that form macromolecular complexes with DNA. In addition, it was previously shown that cirDNA can bind to the outer surface of exosomes. NTA analysis and real-time PCR show that exosomes from healthy females (HF) or breast cancer patients (BCP) plasma contain less than 1.4 × 10 pg of DNA. Thus, only a minor part of cirDNA is attached to the outer side of the exosome as part of the vesicle crown: the share of exosomal DNA does not exceed 0.025% HF plasma DNA and 0.004% BCP plasma DNA. Treatment of plasma exosomes with DNase I with subsequent dot immunoassay reveals that H2a, H2b, and H3 histones are not part of the exosomal membrane, but are part of the cirDNA-protein macromolecular complex associated with the surface of the exosome either through interaction with DNA-binding proteins or with histone-binding proteins. Using bioinformatics approaches after identification by MALDI-TOF mass spectrometry, 16 exosomal DNA-binding proteins were identified. It was shown that four proteins-AIFM1, IGHM, CHD5, and KCNIP3-are candidates for DNA binding on the outer membrane of exosomes; the crown of exosomes may include five DNA-binding proteins: H2a, H2b, H3, IGHM, and ALB. Of note, AIFM1, IGHM, and CHD5 proteins are found only in HF plasma exosomes; KCNIP3 protein is identified only in BCP plasma exosomes; and H2a, H2b, H3, and ALB are revealed in all samples of plasma exosomes. Two histone-binding proteins, CHD5 and KDM6B, have been found in exosomes from HF plasma. The data obtained indicate that cirDNA preferentially binds to the outer membrane of exosomes by association with DNA-binding proteins.\n
\n\n\n\n \n\n \n \n \n \n \n Nanomechanical characterization of exosomes and concomitant nanoparticles from blood plasma by PeakForce AFM in liquid.\n \n \n \n\n\n \n Bairamukov, V. Y.; Bukatin, A. S.; Kamyshinsky, R. A.; Burdakov, V. S.; Pichkur, E. B.; Shtam, T. A.; and Starodubtseva, M. N.\n\n\n \n\n\n\n Biochimica et biophysica acta. General subjects, 1866: 130139. July 2022.\n \n\n\n\n
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\n\n\n@Article{Bairamukov2022,\n author = {Bairamukov, Viktor Yu and Bukatin, Anton S. and Kamyshinsky, Roman A. and Burdakov, Vladimir S. and Pichkur, Evgeny B. and Shtam, Tatiana A. and Starodubtseva, Maria N.},\n journal = {Biochimica et biophysica acta. General subjects},\n title = {Nanomechanical characterization of exosomes and concomitant nanoparticles from blood plasma by PeakForce AFM in liquid.},\n year = {2022},\n issn = {1872-8006},\n month = jul,\n pages = {130139},\n volume = {1866},\n abstract = {To date, EVs characterization techniques are extremely diverse. The contribution of AFM, in particular, is often confined to size distribution. While AFM provides a unique possibility to carry out measurements in situ, nanomechanical characterization of EVs is still missing. Blood plasma EVs were isolated by ultracentrifugation, analyzed by flow cytometry and NTA. Followed by cryo-EM, we applied PeakForce AFM to assess morphological and nanomechanical properties of EVs in liquid. Nanoparticles were subdivided by their size estimated for their suspended state into sub-sets of small S1-EVs (< 30 nm), S2-EVs (30-50 nm), and sub-set of large ones L-EVs (50-170 nm). Non-membranous S1-EVs were distinguished by higher Young's modulus (10.33(7.36;15.25) MPa) and were less deformed by AFM tip (3.6(2.8;4.4) nm) compared to membrane exosomes S2-EVs (6.25(4.52;8.24) MPa and 4.8(4.3;5.9) nm). L-EVs were identified as large membrane exosomes, heterogeneous by their nanomechanical properties (22.43(8.26;53.11) MPa and 3.57(2.07;7.89) nm). Nanomechanical mapping revealed a few non-deformed L-EVs, of which Young's modulus rose up to 300 MPa. Taken together with cryo-EM, these results lead us to the suggestion that two or more vesicles could be contained inside a large one being a multilayer vesicle. We identified particles similar in morphology and showed differences in nanomechanical properties that could be attributed to the features of their inner structure. Our results further elucidate the identification of EVs and concomitant nanoparticles based on their nanomechanical properties.},\n citation-subset = {IM},\n completed = {2022-05-09},\n country = {Netherlands},\n doi = {10.1016/j.bbagen.2022.130139},\n issn-linking = {0304-4165},\n issue = {7},\n keywords = {Elastic Modulus; Exosomes; Microscopy, Atomic Force; Nanoparticles; Plasma; Atomic force microscopy; Extracellular vesicles; Multilayered vesicles; Quantitative nanomechanical mapping exosomes; The Young's modulus},\n nlm-id = {101731726},\n owner = {NLM},\n pii = {S0304-4165(22)00057-5},\n pmid = {35390487},\n pubmodel = {Print-Electronic},\n pubstate = {ppublish},\n revised = {2022-06-17},\n}\n\n\n\n To date, EVs characterization techniques are extremely diverse. The contribution of AFM, in particular, is often confined to size distribution. While AFM provides a unique possibility to carry out measurements in situ, nanomechanical characterization of EVs is still missing. Blood plasma EVs were isolated by ultracentrifugation, analyzed by flow cytometry and NTA. Followed by cryo-EM, we applied PeakForce AFM to assess morphological and nanomechanical properties of EVs in liquid. Nanoparticles were subdivided by their size estimated for their suspended state into sub-sets of small S1-EVs (< 30 nm), S2-EVs (30-50 nm), and sub-set of large ones L-EVs (50-170 nm). Non-membranous S1-EVs were distinguished by higher Young's modulus (10.33(7.36;15.25) MPa) and were less deformed by AFM tip (3.6(2.8;4.4) nm) compared to membrane exosomes S2-EVs (6.25(4.52;8.24) MPa and 4.8(4.3;5.9) nm). L-EVs were identified as large membrane exosomes, heterogeneous by their nanomechanical properties (22.43(8.26;53.11) MPa and 3.57(2.07;7.89) nm). Nanomechanical mapping revealed a few non-deformed L-EVs, of which Young's modulus rose up to 300 MPa. Taken together with cryo-EM, these results lead us to the suggestion that two or more vesicles could be contained inside a large one being a multilayer vesicle. We identified particles similar in morphology and showed differences in nanomechanical properties that could be attributed to the features of their inner structure. Our results further elucidate the identification of EVs and concomitant nanoparticles based on their nanomechanical properties.\n
\n\n\n\n \n\n \n \n \n \n \n \n Erratum to:Neutron Scattering Techniques and Complementary Methods for Structural and Functional Studies of Biological Macromolecules and Large Macromolecular Complexes.\n \n \n \n \n\n\n \n Lebedev, D.; Egorov, V.; Shvetsov, A.; Zabrodskaya, Y.; Isaev-Ivanov, V.; and Konevega, A.\n\n\n \n\n\n\n Crystallography Reports, 67(2): 308-308. April 2022.\n \n\n\n\n
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\n\n\n@Article{Lebedev2022,\n author = {Lebedev, D.~V. and Egorov, V.~V. and Shvetsov, A.~V. and Zabrodskaya, Y.~A. and Isaev-Ivanov, V.~V. and Konevega, A.~L.},\n journal = {Crystallography Reports},\n title = {Erratum to:Neutron Scattering Techniques and Complementary Methods for Structural and Functional Studies of Biological Macromolecules and Large Macromolecular Complexes},\n year = {2022},\n month = apr,\n number = {2},\n pages = {308-308},\n volume = {67},\n abstract = {An Erratum to this paper has been published: https://doi.org/10.1134/S1063774521340034},\n doi = {10.1134/S1063774521340034},\n url = {https://ui.adsabs.harvard.edu/abs/2022CryRp..67..308L},\n}\n\n\n\n An Erratum to this paper has been published: https://doi.org/10.1134/S1063774521340034\n
\n\n\n\n \n\n \n \n \n \n \n Neuroepigenetic Mechanisms of Action of Ultrashort Peptides in Alzheimer’s Disease.\n \n \n \n\n\n \n Ilina, A.; Khavinson, V.; Linkova, N.; and Petukhov, M.\n\n\n \n\n\n\n International Journal of Molecular Sciences, 23(8): 4259. April 2022.\n \n\n\n\n
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\n\n\n\n@Article{Ilina2022,\n author = {Anastasiia Ilina and Vladimir Khavinson and Natalia Linkova and Mikhael Petukhov},\n journal = {International Journal of Molecular Sciences},\n title = {Neuroepigenetic Mechanisms of Action of Ultrashort Peptides in Alzheimer’s Disease},\n year = {2022},\n issn = {1422-0067},\n month = apr,\n number = {8},\n pages = {4259},\n volume = {23},\n doi = {10.3390/ijms23084259},\n keywords = {Inorganic Chemistry, Organic Chemistry, Physical and Theoretical Chemistry, Computer Science Applications, Spectroscopy, Molecular Biology, General Medicine, Catalysis},\n publisher = {MDPI AG},\n}\n\n\n\n \n\n \n \n \n \n \n Transport of Biologically Active Ultrashort Peptides Using POT and LAT Carriers.\n \n \n \n\n\n \n Khavinson, V.; Linkova, N.; Kozhevnikova, E.; Dyatlova, A.; and Petukhov, M.\n\n\n \n\n\n\n International Journal of Molecular Sciences, 23(14): 7733. July 2022.\n \n\n\n\n
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\n\n\n\n@Article{Khavinson2022,\n author = {Vladimir Khavinson and Natalia Linkova and Ekaterina Kozhevnikova and Anastasiia Dyatlova and Mikhael Petukhov},\n journal = {International Journal of Molecular Sciences},\n title = {Transport of Biologically Active Ultrashort Peptides Using POT and LAT Carriers},\n year = {2022},\n issn = {1422-0067},\n month = jul,\n number = {14},\n pages = {7733},\n volume = {23},\n doi = {10.3390/ijms23147733},\n keywords = {Inorganic Chemistry, Organic Chemistry, Physical and Theoretical Chemistry, Computer Science Applications, Spectroscopy, Molecular Biology, General Medicine, Catalysis},\n publisher = {MDPI AG},\n}\n\n\n\n \n\n \n \n \n \n \n Targeting sonic hedgehog pathway in combination with proton radiation or gamma irradiation decreases viability of glioma cell lines.\n \n \n \n\n\n \n Garina, A.; Volnitskiy, A.; Burdakov, V.; Tran, H. N.; Amerkanov, D.; Pack, F.; Konevega, A.; and Shtam, T.\n\n\n \n\n\n\n 2022.\n \n\n\n\n
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\n\n\n\n@Misc{Garina2022,\n author = {Alina Garina and Andrey Volnitskiy and Vladimir Burdakov and Hau Nhan Tran and Dmitry Amerkanov and Fedor Pack and Andrey Konevega and Tatiana Shtam},\n title = {Targeting sonic hedgehog pathway in combination with proton radiation or gamma irradiation decreases viability of glioma cell lines},\n year = {2022},\n booktitle = {Book of Abstracts},\n collection = {RADConf},\n doi = {10.21175/rad.spr.abstr.book.2022.29.3},\n journal = {Book of Abstracts},\n publisher = {RAD Centre},\n series = {RADConf},\n}\n\n\n\n
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\n \n \n\n \n \n \n \n \n RNA Binding by Plant Serpins in vitro.\n \n \n \n\n\n \n Tolstyko, E. A.; Chergintsev, D. A.; Tolicheva, O. A.; Vinogradova, D. S.; Konevega, A. L.; Morozov, S. Y.; and Solovyev, A. G.\n\n\n \n\n\n\n Biochemistry. Biokhimiia, 86: 1214–1224. October 2021.\n \n\n\n\n
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\n\n\n@Article{Tolstyko2021,\n author = {Tolstyko, Eugene A. and Chergintsev, Denis A. and Tolicheva, Olga A. and Vinogradova, Dariya S. and Konevega, Andrey L. and Morozov, Sergey Y. and Solovyev, Andrey G.},\n journal = {Biochemistry. Biokhimiia},\n title = {RNA Binding by Plant Serpins in vitro.},\n year = {2021},\n issn = {1608-3040},\n month = oct,\n pages = {1214--1224},\n volume = {86},\n abstract = {Serpins constitute a large family of protease inhibitors with regulatory functions found in all living organisms. Most plant serpins have not been functionally characterized, with the exception of Arabidopsis thaliana AtSerpin1, an inhibitor of pro-apoptotic proteases, which is involved in the regulation of the programmed cell death induction, and Cucurbita maxima CmPS1, a phloem protein, which presumably inhibits insect digestive proteases and binds RNA. CmPS1 interacts most efficiently with highly structured RNA; in particular, it forms a specific complex with tRNA. Here, we demonstrated that AtSerpin1 also forms a complex with tRNA. Analysis of tRNA species bound by AtSerpin1 and CmPS1 in the presence of tRNA excess revealed that both proteins have no strict selectivity for individual tRNAs, suggesting specific interaction of AtSerpin1 and CmPS1 proteins with elements of the secondary/tertiary structure universal for all tRNAs. Analysis of CmPS1 binding of the microRNA precursor pre-miR390 and its mutants demonstrated that the pre-miR390 mutant with a perfect duplex in the hairpin stem lost the ability to form a discrete complex with CmPS1, whereas another variant of pre-miR390 with the native unpaired nucleotide residues in the stem retained this ability. These data indicate that specific interactions of plant serpins with structured RNA are based on the recognition of structurally unique spatial motifs formed with the participation of unpaired nucleotide residues in the RNA duplexes.},\n chemicals = {Arabidopsis Proteins, MicroRNAs, Protease Inhibitors, Serpin1 protein, Arabidopsis, Serpins, phloem serpin 1, RNA, Transfer},\n citation-subset = {IM},\n completed = {2022-02-03},\n country = {United States},\n doi = {10.1134/S0006297921100059},\n issn-linking = {0006-2979},\n issue = {10},\n keywords = {Arabidopsis, cytology, genetics, metabolism; Arabidopsis Proteins, genetics, metabolism; Cell Death, physiology; Cucurbita, cytology, genetics, metabolism; MicroRNAs, genetics, metabolism; Protease Inhibitors, metabolism; RNA, Transfer, genetics, metabolism; Serpins, genetics, metabolism; RNA binding; RNA structure; RNA-binding protein; microRNA; phloem; serpin; tRNA},\n nlm-id = {0376536},\n owner = {NLM},\n pii = {BCM86101550},\n pmid = {34903159},\n pubmodel = {Print},\n pubstate = {ppublish},\n revised = {2022-02-03},\n}\n\n\n\n Serpins constitute a large family of protease inhibitors with regulatory functions found in all living organisms. Most plant serpins have not been functionally characterized, with the exception of Arabidopsis thaliana AtSerpin1, an inhibitor of pro-apoptotic proteases, which is involved in the regulation of the programmed cell death induction, and Cucurbita maxima CmPS1, a phloem protein, which presumably inhibits insect digestive proteases and binds RNA. CmPS1 interacts most efficiently with highly structured RNA; in particular, it forms a specific complex with tRNA. Here, we demonstrated that AtSerpin1 also forms a complex with tRNA. Analysis of tRNA species bound by AtSerpin1 and CmPS1 in the presence of tRNA excess revealed that both proteins have no strict selectivity for individual tRNAs, suggesting specific interaction of AtSerpin1 and CmPS1 proteins with elements of the secondary/tertiary structure universal for all tRNAs. Analysis of CmPS1 binding of the microRNA precursor pre-miR390 and its mutants demonstrated that the pre-miR390 mutant with a perfect duplex in the hairpin stem lost the ability to form a discrete complex with CmPS1, whereas another variant of pre-miR390 with the native unpaired nucleotide residues in the stem retained this ability. These data indicate that specific interactions of plant serpins with structured RNA are based on the recognition of structurally unique spatial motifs formed with the participation of unpaired nucleotide residues in the RNA duplexes.\n
\n\n\n\n \n\n \n \n \n \n \n Differential Contribution of Protein Factors and 70S Ribosome to Elongation.\n \n \n \n\n\n \n Paleskava, A.; Maksimova, E. M.; Vinogradova, D. S.; Kasatsky, P. S.; Kirillov, S. V.; and Konevega, A. L.\n\n\n \n\n\n\n International journal of molecular sciences, 22. September 2021.\n \n\n\n\n
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\n\n\n@Article{Paleskava2021,\n author = {Paleskava, Alena and Maksimova, Elena M. and Vinogradova, Daria S. and Kasatsky, Pavel S. and Kirillov, Stanislav V. and Konevega, Andrey L.},\n journal = {International journal of molecular sciences},\n title = {Differential Contribution of Protein Factors and 70S Ribosome to Elongation.},\n year = {2021},\n issn = {1422-0067},\n month = sep,\n volume = {22},\n abstract = {The growth of the polypeptide chain occurs due to the fast and coordinated work of the ribosome and protein elongation factors, EF-Tu and EF-G. However, the exact contribution of each of these components in the overall balance of translation kinetics remains not fully understood. We created an in vitro translation system replacing either elongation factor with heterologous thermophilic protein from . The rates of the A-site binding and decoding reactions decreased an order of magnitude in the presence of thermophilic EF-Tu, indicating that the kinetics of aminoacyl-tRNA delivery depends on the properties of the elongation factor. On the contrary, thermophilic EF-G demonstrated the same translocation kinetics as a mesophilic protein. Effects of translocation inhibitors (spectinomycin, hygromycin B, viomycin and streptomycin) were also similar for both proteins. Thus, the process of translocation largely relies on the interaction of tRNAs and the ribosome and can be efficiently catalysed by thermophilic EF-G even at suboptimal temperatures.},\n chemicals = {Bacterial Proteins, Peptide Elongation Factor G, RNA, Bacterial, RNA, Transfer, Peptide Elongation Factor Tu},\n citation-subset = {IM},\n completed = {2021-10-20},\n country = {Switzerland},\n doi = {10.3390/ijms22179614},\n issn-linking = {1422-0067},\n issue = {17},\n keywords = {Bacterial Proteins, metabolism; Escherichia coli, metabolism; Peptide Chain Elongation, Translational; Peptide Elongation Factor G, metabolism; Peptide Elongation Factor Tu, metabolism; RNA, Bacterial, metabolism; RNA, Transfer, metabolism; Ribosomes, metabolism; Thermus thermophilus; 70S ribosome; antibiotics; elongation factor; heterologous system; rapid kinetics; translation},\n nlm-id = {101092791},\n owner = {NLM},\n pii = {9614},\n pmc = {PMC8431766},\n pmid = {34502523},\n pubmodel = {Electronic},\n pubstate = {epublish},\n revised = {2021-10-20},\n}\n\n\n\n The growth of the polypeptide chain occurs due to the fast and coordinated work of the ribosome and protein elongation factors, EF-Tu and EF-G. However, the exact contribution of each of these components in the overall balance of translation kinetics remains not fully understood. We created an in vitro translation system replacing either elongation factor with heterologous thermophilic protein from . The rates of the A-site binding and decoding reactions decreased an order of magnitude in the presence of thermophilic EF-Tu, indicating that the kinetics of aminoacyl-tRNA delivery depends on the properties of the elongation factor. On the contrary, thermophilic EF-G demonstrated the same translocation kinetics as a mesophilic protein. Effects of translocation inhibitors (spectinomycin, hygromycin B, viomycin and streptomycin) were also similar for both proteins. Thus, the process of translocation largely relies on the interaction of tRNAs and the ribosome and can be efficiently catalysed by thermophilic EF-G even at suboptimal temperatures.\n
\n\n\n\n \n\n \n \n \n \n \n Multifaceted Mechanism of Amicoumacin A Inhibition of Bacterial Translation.\n \n \n \n\n\n \n Maksimova, E. M.; Vinogradova, D. S.; Osterman, I. A.; Kasatsky, P. S.; Nikonov, O. S.; Milón, P.; Dontsova, O. A.; Sergiev, P. V.; Paleskava, A.; and Konevega, A. L.\n\n\n \n\n\n\n Frontiers in microbiology, 12: 618857. 2021.\n \n\n\n\n
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\n\n\n@Article{Maksimova2021,\n author = {Maksimova, Elena M. and Vinogradova, Daria S. and Osterman, Ilya A. and Kasatsky, Pavel S. and Nikonov, Oleg S. and Milón, Pohl and Dontsova, Olga A. and Sergiev, Petr V. and Paleskava, Alena and Konevega, Andrey L.},\n journal = {Frontiers in microbiology},\n title = {Multifaceted Mechanism of Amicoumacin A Inhibition of Bacterial Translation.},\n year = {2021},\n issn = {1664-302X},\n pages = {618857},\n volume = {12},\n abstract = {Amicoumacin A (Ami) halts bacterial growth by inhibiting the ribosome during translation. The Ami binding site locates in the vicinity of the E-site codon of mRNA. However, Ami does not clash with mRNA, rather stabilizes it, which is relatively unusual and implies a unique way of translation inhibition. In this work, we performed a kinetic and thermodynamic investigation of Ami influence on the main steps of polypeptide synthesis. We show that Ami reduces the rate of the functional canonical 70S initiation complex (IC) formation by 30-fold. Additionally, our results indicate that Ami promotes the formation of erroneous 30S ICs; however, IF3 prevents them from progressing towards translation initiation. During early elongation steps, Ami does not compromise EF-Tu-dependent A-site binding or peptide bond formation. On the other hand, Ami reduces the rate of peptidyl-tRNA movement from the A to the P site and significantly decreases the amount of the ribosomes capable of polypeptide synthesis. Our data indicate that Ami progressively decreases the activity of translating ribosomes that may appear to be the main inhibitory mechanism of Ami. Indeed, the use of EF-G mutants that confer resistance to Ami (G542V, G581A, or ins544V) leads to a complete restoration of the ribosome functionality. It is possible that the changes in translocation induced by EF-G mutants compensate for the activity loss caused by Ami.},\n country = {Switzerland},\n doi = {10.3389/fmicb.2021.618857},\n issn-linking = {1664-302X},\n keywords = {amicoumacin A; antibiotic resistance; elongation factor EF-G; initiation; microscale thermophoresis; rapid kinetics; translocation},\n nlm-id = {101548977},\n owner = {NLM},\n pii = {618857},\n pmc = {PMC7907450},\n pmid = {33643246},\n pubmodel = {Electronic-eCollection},\n pubstate = {epublish},\n revised = {2021-03-03},\n}\n\n\n\n Amicoumacin A (Ami) halts bacterial growth by inhibiting the ribosome during translation. The Ami binding site locates in the vicinity of the E-site codon of mRNA. However, Ami does not clash with mRNA, rather stabilizes it, which is relatively unusual and implies a unique way of translation inhibition. In this work, we performed a kinetic and thermodynamic investigation of Ami influence on the main steps of polypeptide synthesis. We show that Ami reduces the rate of the functional canonical 70S initiation complex (IC) formation by 30-fold. Additionally, our results indicate that Ami promotes the formation of erroneous 30S ICs; however, IF3 prevents them from progressing towards translation initiation. During early elongation steps, Ami does not compromise EF-Tu-dependent A-site binding or peptide bond formation. On the other hand, Ami reduces the rate of peptidyl-tRNA movement from the A to the P site and significantly decreases the amount of the ribosomes capable of polypeptide synthesis. Our data indicate that Ami progressively decreases the activity of translating ribosomes that may appear to be the main inhibitory mechanism of Ami. Indeed, the use of EF-G mutants that confer resistance to Ami (G542V, G581A, or ins544V) leads to a complete restoration of the ribosome functionality. It is possible that the changes in translocation induced by EF-G mutants compensate for the activity loss caused by Ami.\n
\n\n\n\n \n\n \n \n \n \n \n The dynamic cycle of bacterial translation initiation factor IF3.\n \n \n \n\n\n \n Nakamoto, J. A.; Evangelista, W.; Vinogradova, D. S.; Konevega, A. L.; Spurio, R.; Fabbretti, A.; and Milón, P.\n\n\n \n\n\n\n Nucleic acids research, 49: 6958–6970. July 2021.\n \n\n\n\n
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\n\n\n@Article{Nakamoto2021,\n author = {Nakamoto, Jose A. and Evangelista, Wilfredo and Vinogradova, Daria S. and Konevega, Andrey L. and Spurio, Roberto and Fabbretti, Attilio and Milón, Pohl},\n journal = {Nucleic acids research},\n title = {The dynamic cycle of bacterial translation initiation factor IF3.},\n year = {2021},\n issn = {1362-4962},\n month = jul,\n pages = {6958--6970},\n volume = {49},\n abstract = {Initiation factor IF3 is an essential protein that enhances the fidelity and speed of bacterial mRNA translation initiation. Here, we describe the dynamic interplay between IF3 domains and their alternative binding sites using pre-steady state kinetics combined with molecular modelling of available structures of initiation complexes. Our results show that IF3 accommodates its domains at velocities ranging over two orders of magnitude, responding to the binding of each 30S ligand. IF1 and IF2 promote IF3 compaction and the movement of the C-terminal domain (IF3C) towards the P site. Concomitantly, the N-terminal domain (IF3N) creates a pocket ready to accept the initiator tRNA. Selection of the initiator tRNA is accompanied by a transient accommodation of IF3N towards the 30S platform. Decoding of the mRNA start codon displaces IF3C away from the P site and rate limits translation initiation. 70S initiation complex formation brings IF3 domains in close proximity to each other prior to dissociation and recycling of the factor for a new round of translation initiation. Altogether, our results describe the kinetic spectrum of IF3 movements and highlight functional transitions of the factor that ensure accurate mRNA translation initiation.},\n chemicals = {Bacterial Proteins, Prokaryotic Initiation Factor-1, Prokaryotic Initiation Factor-2, Prokaryotic Initiation Factor-3, RNA, Transfer, Met, fMet-tRNA(fMet)},\n citation-subset = {IM},\n completed = {2021-07-28},\n country = {England},\n doi = {10.1093/nar/gkab522},\n issn-linking = {0305-1048},\n issue = {12},\n keywords = {Bacterial Proteins, chemistry, metabolism; Binding Sites; Fluorescence Resonance Energy Transfer; Kinetics; Models, Molecular; Peptide Chain Initiation, Translational; Prokaryotic Initiation Factor-1, metabolism; Prokaryotic Initiation Factor-2, metabolism; Prokaryotic Initiation Factor-3, chemistry, metabolism; Protein Binding; Protein Conformation; Protein Domains; RNA, Transfer, Met, metabolism; Ribosome Subunits, Small, Bacterial, metabolism},\n nlm-id = {0411011},\n owner = {NLM},\n pii = {6308496},\n pmc = {PMC8266586},\n pmid = {34161576},\n pubmodel = {Print},\n pubstate = {ppublish},\n revised = {2021-07-28},\n}\n\n\n\n Initiation factor IF3 is an essential protein that enhances the fidelity and speed of bacterial mRNA translation initiation. Here, we describe the dynamic interplay between IF3 domains and their alternative binding sites using pre-steady state kinetics combined with molecular modelling of available structures of initiation complexes. Our results show that IF3 accommodates its domains at velocities ranging over two orders of magnitude, responding to the binding of each 30S ligand. IF1 and IF2 promote IF3 compaction and the movement of the C-terminal domain (IF3C) towards the P site. Concomitantly, the N-terminal domain (IF3N) creates a pocket ready to accept the initiator tRNA. Selection of the initiator tRNA is accompanied by a transient accommodation of IF3N towards the 30S platform. Decoding of the mRNA start codon displaces IF3C away from the P site and rate limits translation initiation. 70S initiation complex formation brings IF3 domains in close proximity to each other prior to dissociation and recycling of the factor for a new round of translation initiation. Altogether, our results describe the kinetic spectrum of IF3 movements and highlight functional transitions of the factor that ensure accurate mRNA translation initiation.\n
\n\n\n\n \n\n \n \n \n \n \n Binding and Action of Triphenylphosphonium Analog of Chloramphenicol upon the Bacterial Ribosome.\n \n \n \n\n\n \n Chen, C.; Pavlova, J. A.; Lukianov, D. A.; Tereshchenkov, A. G.; Makarov, G. I.; Khairullina, Z. Z.; Tashlitsky, V. N.; Paleskava, A.; Konevega, A. L.; Bogdanov, A. A.; Osterman, I. A.; Sumbatyan, N. V.; and Polikanov, Y. S.\n\n\n \n\n\n\n Antibiotics (Basel, Switzerland), 10. April 2021.\n \n\n\n\n
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\n\n\n@Article{Chen2021,\n author = {Chen, Chih-Wei and Pavlova, Julia A. and Lukianov, Dmitrii A. and Tereshchenkov, Andrey G. and Makarov, Gennady I. and Khairullina, Zimfira Z. and Tashlitsky, Vadim N. and Paleskava, Alena and Konevega, Andrey L. and Bogdanov, Alexey A. and Osterman, Ilya A. and Sumbatyan, Natalia V. and Polikanov, Yury S.},\n journal = {Antibiotics (Basel, Switzerland)},\n title = {Binding and Action of Triphenylphosphonium Analog of Chloramphenicol upon the Bacterial Ribosome.},\n year = {2021},\n issn = {2079-6382},\n month = apr,\n volume = {10},\n abstract = {Chloramphenicol (CHL) is a ribosome-targeting antibiotic that binds to the peptidyl transferase center (PTC) of the bacterial ribosome and inhibits peptide bond formation. As an approach for modifying and potentially improving the properties of this inhibitor, we explored ribosome binding and inhibitory properties of a semi-synthetic triphenylphosphonium analog of CHL-CAM-C4-TPP. Our data demonstrate that this compound exhibits a ~5-fold stronger affinity for the bacterial ribosome and higher potency as an in vitro protein synthesis inhibitor compared to CHL. The X-ray crystal structure of the 70S ribosome in complex with CAM-C4-TPP reveals that, while its amphenicol moiety binds at the PTC in a fashion identical to CHL, the C4-TPP tail adopts an extended propeller-like conformation within the ribosome exit tunnel where it establishes multiple hydrophobic Van der Waals interactions with the rRNA. The synthesized compound represents a promising chemical scaffold for further development by medicinal chemists because it simultaneously targets the two key functional centers of the bacterial ribosome-PTC and peptide exit tunnel.},\n country = {Switzerland},\n doi = {10.3390/antibiotics10040390},\n issn-linking = {2079-6382},\n issue = {4},\n keywords = {70S ribosome; X-ray structure; antibiotic; binding affinity; chloramphenicol; nascent peptide exit tunnel; peptidyl transferase center; translation inhibitor},\n nlm-id = {101637404},\n owner = {NLM},\n pii = {390},\n pmc = {PMC8066774},\n pmid = {33916420},\n pubmodel = {Electronic},\n pubstate = {epublish},\n revised = {2022-02-09},\n}\n\n\n\n Chloramphenicol (CHL) is a ribosome-targeting antibiotic that binds to the peptidyl transferase center (PTC) of the bacterial ribosome and inhibits peptide bond formation. As an approach for modifying and potentially improving the properties of this inhibitor, we explored ribosome binding and inhibitory properties of a semi-synthetic triphenylphosphonium analog of CHL-CAM-C4-TPP. Our data demonstrate that this compound exhibits a 5-fold stronger affinity for the bacterial ribosome and higher potency as an in vitro protein synthesis inhibitor compared to CHL. The X-ray crystal structure of the 70S ribosome in complex with CAM-C4-TPP reveals that, while its amphenicol moiety binds at the PTC in a fashion identical to CHL, the C4-TPP tail adopts an extended propeller-like conformation within the ribosome exit tunnel where it establishes multiple hydrophobic Van der Waals interactions with the rRNA. The synthesized compound represents a promising chemical scaffold for further development by medicinal chemists because it simultaneously targets the two key functional centers of the bacterial ribosome-PTC and peptide exit tunnel.\n
\n\n\n\n \n\n \n \n \n \n \n Triphenilphosphonium Analogs of Chloramphenicol as Dual-Acting Antimicrobial and Antiproliferating Agents.\n \n \n \n\n\n \n Pavlova, J. A.; Khairullina, Z. Z.; Tereshchenkov, A. G.; Nazarov, P. A.; Lukianov, D. A.; Volynkina, I. A.; Skvortsov, D. A.; Makarov, G. I.; Abad, E.; Murayama, S. Y.; Kajiwara, S.; Paleskava, A.; Konevega, A. L.; Antonenko, Y. N.; Lyakhovich, A.; Osterman, I. A.; Bogdanov, A. A.; and Sumbatyan, N. V.\n\n\n \n\n\n\n Antibiotics (Basel, Switzerland), 10. April 2021.\n \n\n\n\n
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\n\n\n@Article{Pavlova2021,\n author = {Pavlova, Julia A. and Khairullina, Zimfira Z. and Tereshchenkov, Andrey G. and Nazarov, Pavel A. and Lukianov, Dmitrii A. and Volynkina, Inna A. and Skvortsov, Dmitry A. and Makarov, Gennady I. and Abad, Etna and Murayama, Somay Y. and Kajiwara, Susumu and Paleskava, Alena and Konevega, Andrey L. and Antonenko, Yuri N. and Lyakhovich, Alex and Osterman, Ilya A. and Bogdanov, Alexey A. and Sumbatyan, Natalia V.},\n journal = {Antibiotics (Basel, Switzerland)},\n title = {Triphenilphosphonium Analogs of Chloramphenicol as Dual-Acting Antimicrobial and Antiproliferating Agents.},\n year = {2021},\n issn = {2079-6382},\n month = apr,\n volume = {10},\n abstract = {In the current work, in continuation of our recent research, we synthesized and studied new chimeric compounds, including the ribosome-targeting antibiotic chloramphenicol (CHL) and the membrane-penetrating cation triphenylphosphonium (TPP), which are linked by alkyl groups of different lengths. Using various biochemical assays, we showed that these CAM-Cn-TPP compounds bind to the bacterial ribosome, inhibit protein synthesis in vitro and in vivo in a way similar to that of the parent CHL, and significantly reduce membrane potential. Similar to CAM-C4-TPP, the mode of action of CAM-C10-TPP and CAM-C14-TPP in bacterial ribosomes differs from that of CHL. By simulating the dynamics of CAM-Cn-TPP complexes with bacterial ribosomes, we proposed a possible explanation for the specificity of the action of these analogs in the translation process. CAM-C10-TPP and CAM-C14-TPP more strongly inhibit the growth of the Gram-positive bacteria, as compared to CHL, and suppress some CHL-resistant bacterial strains. Thus, we have shown that TPP derivatives of CHL are dual-acting compounds targeting both the ribosomes and cellular membranes of bacteria. The TPP fragment of CAM-Cn-TPP compounds has an inhibitory effect on bacteria. Moreover, since the mitochondria of eukaryotic cells possess qualities similar to those of their prokaryotic ancestors, we demonstrate the possibility of targeting chemoresistant cancer cells with these compounds.},\n country = {Switzerland},\n doi = {10.3390/antibiotics10050489},\n issn-linking = {2079-6382},\n issue = {5},\n keywords = {alkyl(triphenyl)phosphonium; antibiotic activity; antiproliferative activity; bacterial ribosome; chloramphenicol; molecular dynamics simulations},\n nlm-id = {101637404},\n owner = {NLM},\n pii = {489},\n pmc = {PMC8145938},\n pmid = {33922611},\n pubmodel = {Electronic},\n pubstate = {epublish},\n revised = {2021-05-27},\n}\n\n\n\n In the current work, in continuation of our recent research, we synthesized and studied new chimeric compounds, including the ribosome-targeting antibiotic chloramphenicol (CHL) and the membrane-penetrating cation triphenylphosphonium (TPP), which are linked by alkyl groups of different lengths. Using various biochemical assays, we showed that these CAM-Cn-TPP compounds bind to the bacterial ribosome, inhibit protein synthesis in vitro and in vivo in a way similar to that of the parent CHL, and significantly reduce membrane potential. Similar to CAM-C4-TPP, the mode of action of CAM-C10-TPP and CAM-C14-TPP in bacterial ribosomes differs from that of CHL. By simulating the dynamics of CAM-Cn-TPP complexes with bacterial ribosomes, we proposed a possible explanation for the specificity of the action of these analogs in the translation process. CAM-C10-TPP and CAM-C14-TPP more strongly inhibit the growth of the Gram-positive bacteria, as compared to CHL, and suppress some CHL-resistant bacterial strains. Thus, we have shown that TPP derivatives of CHL are dual-acting compounds targeting both the ribosomes and cellular membranes of bacteria. The TPP fragment of CAM-Cn-TPP compounds has an inhibitory effect on bacteria. Moreover, since the mitochondria of eukaryotic cells possess qualities similar to those of their prokaryotic ancestors, we demonstrate the possibility of targeting chemoresistant cancer cells with these compounds.\n
\n\n\n\n \n\n \n \n \n \n \n RqcH and RqcP catalyze processive poly-alanine synthesis in a reconstituted ribosome-associated quality control system.\n \n \n \n\n\n \n Takada, H.; Crowe-McAuliffe, C.; Polte, C.; Sidorova, Z. Y.; Murina, V.; Atkinson, G. C.; Konevega, A. L.; Ignatova, Z.; Wilson, D. N.; and Hauryliuk, V.\n\n\n \n\n\n\n Nucleic acids research, 49: 8355–8369. August 2021.\n \n\n\n\n
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\n\n\n@Article{Takada2021,\n author = {Takada, Hiraku and Crowe-McAuliffe, Caillan and Polte, Christine and Sidorova, Zhanna Yu and Murina, Victoriia and Atkinson, Gemma C. and Konevega, Andrey L. and Ignatova, Zoya and Wilson, Daniel N. and Hauryliuk, Vasili},\n journal = {Nucleic acids research},\n title = {RqcH and RqcP catalyze processive poly-alanine synthesis in a reconstituted ribosome-associated quality control system.},\n year = {2021},\n issn = {1362-4962},\n month = aug,\n pages = {8355--8369},\n volume = {49},\n abstract = {In the cell, stalled ribosomes are rescued through ribosome-associated protein quality-control (RQC) pathways. After splitting of the stalled ribosome, a C-terminal polyalanine 'tail' is added to the unfinished polypeptide attached to the tRNA on the 50S ribosomal subunit. In Bacillus subtilis, polyalanine tailing is catalyzed by the NEMF family protein RqcH, in cooperation with RqcP. However, the mechanistic details of this process remain unclear. Here we demonstrate that RqcH is responsible for tRNAAla selection during RQC elongation, whereas RqcP lacks any tRNA specificity. The ribosomal protein uL11 is crucial for RqcH, but not RqcP, recruitment to the 50S subunit, and B. subtilis lacking uL11 are RQC-deficient. Through mutational mapping, we identify critical residues within RqcH and RqcP that are important for interaction with the P-site tRNA and/or the 50S subunit. Additionally, we have reconstituted polyalanine-tailing in vitro and can demonstrate that RqcH and RqcP are necessary and sufficient for processivity in a minimal system. Moreover, the in vitro reconstituted system recapitulates our in vivo findings by reproducing the importance of conserved residues of RqcH and RqcP for functionality. Collectively, our findings provide mechanistic insight into the role of RqcH and RqcP in the bacterial RQC pathway.},\n chemicals = {Peptides, Ribosomal Proteins, polyalanine, RNA, Transfer, DNA Helicases},\n citation-subset = {IM},\n completed = {2021-10-07},\n country = {England},\n doi = {10.1093/nar/gkab589},\n issn-linking = {0305-1048},\n issue = {14},\n keywords = {Bacillus subtilis, genetics; DNA Helicases, genetics; Peptides, genetics, metabolism; RNA, Transfer; Ribosomal Proteins, genetics; Ribosome Subunits, Large, Bacterial, genetics; Ribosomes, genetics},\n nlm-id = {0411011},\n owner = {NLM},\n pii = {6320412},\n pmc = {PMC8373112},\n pmid = {34255840},\n pubmodel = {Print},\n pubstate = {ppublish},\n revised = {2021-10-07},\n}\n\n\n\n In the cell, stalled ribosomes are rescued through ribosome-associated protein quality-control (RQC) pathways. After splitting of the stalled ribosome, a C-terminal polyalanine 'tail' is added to the unfinished polypeptide attached to the tRNA on the 50S ribosomal subunit. In Bacillus subtilis, polyalanine tailing is catalyzed by the NEMF family protein RqcH, in cooperation with RqcP. However, the mechanistic details of this process remain unclear. Here we demonstrate that RqcH is responsible for tRNAAla selection during RQC elongation, whereas RqcP lacks any tRNA specificity. The ribosomal protein uL11 is crucial for RqcH, but not RqcP, recruitment to the 50S subunit, and B. subtilis lacking uL11 are RQC-deficient. Through mutational mapping, we identify critical residues within RqcH and RqcP that are important for interaction with the P-site tRNA and/or the 50S subunit. Additionally, we have reconstituted polyalanine-tailing in vitro and can demonstrate that RqcH and RqcP are necessary and sufficient for processivity in a minimal system. Moreover, the in vitro reconstituted system recapitulates our in vivo findings by reproducing the importance of conserved residues of RqcH and RqcP for functionality. Collectively, our findings provide mechanistic insight into the role of RqcH and RqcP in the bacterial RQC pathway.\n
\n\n\n\n \n\n \n \n \n \n \n Delivery of functional exogenous proteins by plant-derived vesicles to human cells in vitro.\n \n \n \n\n\n \n Garaeva, L.; Kamyshinsky, R.; Kil, Y.; Varfolomeeva, E.; Verlov, N.; Komarova, E.; Garmay, Y.; Landa, S.; Burdakov, V.; Myasnikov, A.; Vinnikov, I. A.; Margulis, B.; Guzhova, I.; Kagansky, A.; Konevega, A. L.; and Shtam, T.\n\n\n \n\n\n\n Scientific reports, 11: 6489. March 2021.\n \n\n\n\n
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\n\n\n@Article{Garaeva2021,\n author = {Garaeva, Luiza and Kamyshinsky, Roman and Kil, Yury and Varfolomeeva, Elena and Verlov, Nikolai and Komarova, Elena and Garmay, Yuri and Landa, Sergey and Burdakov, Vladimir and Myasnikov, Alexander and Vinnikov, Ilya A. and Margulis, Boris and Guzhova, Irina and Kagansky, Alexander and Konevega, Andrey L. and Shtam, Tatiana},\n journal = {Scientific reports},\n title = {Delivery of functional exogenous proteins by plant-derived vesicles to human cells in vitro.},\n year = {2021},\n issn = {2045-2322},\n month = mar,\n pages = {6489},\n volume = {11},\n abstract = {Plant-derived extracellular vesicles (EVs) gain more and more attention as promising carriers of exogenous bioactive molecules to the human cells. Derived from various edible sources, these EVs are remarkably biocompatible, biodegradable and highly abundant from plants. In this work, EVs from grapefruit juice were isolated by differential centrifugation followed by characterization of their size, quantity and morphology by nanoparticle tracking analysis, dynamic light scattering, atomic force microscopy and cryo-electron microscopy (Cryo-EM). In Cryo-EM experiments, we visualized grapefruit EVs with the average size of 41 ± 13 nm, confirmed their round-shaped morphology and estimated the thickness of their lipid bilayer as 5.3 ± 0.8 nm. Further, using cell culture models, we have successfully demonstrated that native grapefruit-derived extracellular vesicles (GF-EVs) are highly efficient carriers for the delivery of the exogenous Alexa Fluor 647 labeled bovine serum albumin (BSA) and heat shock protein 70 (HSP70) into both human peripheral blood mononuclear cells and colon cancer cells. Interestingly, loading to plant EVs significantly ameliorated the uptake of exogenous proteins by human cells compared to the same proteins without EVs. Most importantly, we have confirmed the functional activity of human recombinant HSP70 in the colon cancer cell culture upon delivery by GF-EVs. Analysis of the biodistribution of GF-EVs loaded with I-labeled BSA in mice demonstrated a significant uptake of the grapefruit-derived extracellular vesicles by the majority of organs. The results of our study indicate that native plant EVs might be safe and effective carriers of exogenous proteins into human cells.},\n chemicals = {HSP70 Heat-Shock Proteins, Nanocapsules, Serum Albumin, Bovine},\n citation-subset = {IM},\n completed = {2021-10-15},\n country = {England},\n doi = {10.1038/s41598-021-85833-y},\n issn-linking = {2045-2322},\n issue = {1},\n keywords = {Cells, Cultured; Citrus paradisi, chemistry; Extracellular Vesicles, chemistry, ultrastructure; HCT116 Cells; HSP70 Heat-Shock Proteins, administration & dosage; Humans; Leukocytes, Mononuclear, metabolism; Nanocapsules, chemistry, ultrastructure; Serum Albumin, Bovine, administration & dosage},\n nlm-id = {101563288},\n owner = {NLM},\n pii = {6489},\n pmc = {PMC7985202},\n pmid = {33753795},\n pubmodel = {Electronic},\n pubstate = {epublish},\n revised = {2021-10-15},\n}\n\n\n\n Plant-derived extracellular vesicles (EVs) gain more and more attention as promising carriers of exogenous bioactive molecules to the human cells. Derived from various edible sources, these EVs are remarkably biocompatible, biodegradable and highly abundant from plants. In this work, EVs from grapefruit juice were isolated by differential centrifugation followed by characterization of their size, quantity and morphology by nanoparticle tracking analysis, dynamic light scattering, atomic force microscopy and cryo-electron microscopy (Cryo-EM). In Cryo-EM experiments, we visualized grapefruit EVs with the average size of 41 ± 13 nm, confirmed their round-shaped morphology and estimated the thickness of their lipid bilayer as 5.3 ± 0.8 nm. Further, using cell culture models, we have successfully demonstrated that native grapefruit-derived extracellular vesicles (GF-EVs) are highly efficient carriers for the delivery of the exogenous Alexa Fluor 647 labeled bovine serum albumin (BSA) and heat shock protein 70 (HSP70) into both human peripheral blood mononuclear cells and colon cancer cells. Interestingly, loading to plant EVs significantly ameliorated the uptake of exogenous proteins by human cells compared to the same proteins without EVs. Most importantly, we have confirmed the functional activity of human recombinant HSP70 in the colon cancer cell culture upon delivery by GF-EVs. Analysis of the biodistribution of GF-EVs loaded with I-labeled BSA in mice demonstrated a significant uptake of the grapefruit-derived extracellular vesicles by the majority of organs. The results of our study indicate that native plant EVs might be safe and effective carriers of exogenous proteins into human cells.\n
\n\n\n\n \n\n \n \n \n \n \n [Plasma Exosomes in Inherited Forms of Parkinson's Disease].\n \n \n \n\n\n \n Kulabukhova, D. G.; Garaeva, L. A.; Emelyanov, A. K.; Senkevich, K. A.; Gracheva, E. V.; Miliukhina, I. V.; Varfolomeeva, E. Y.; Timofeeva, A. A.; Schwartsman, A. L.; Shtam, T. A.; and Pchelina, S. N.\n\n\n \n\n\n\n Molekuliarnaia biologiia, 55: 338–345. 2021.\n \n\n\n\n
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\n\n\n@Article{Kulabukhova2021,\n author = {Kulabukhova, D. G. and Garaeva, L. A. and Emelyanov, A. K. and Senkevich, K. A. and Gracheva, E. V. and Miliukhina, I. V. and Varfolomeeva, E. Y. and Timofeeva, A. A. and Schwartsman, A. L. and Shtam, T. A. and Pchelina, S. N.},\n journal = {Molekuliarnaia biologiia},\n title = {[Plasma Exosomes in Inherited Forms of Parkinson's Disease].},\n year = {2021},\n issn = {0026-8984},\n pages = {338--345},\n volume = {55},\n abstract = {Parkinson's disease (PD) is the second most common neurodegenerative disorder. Alpha-synuclein misfolding and aggregation resulting in neurototoxicity is a hallmark of PD. The prion properties of alpha-synuclein are still under discussion. Exosomes (extrcellular vesicles 40-100 nm in size) can play a key role in the transport of pathogenic forms of alpha-synuclein. The most frequent inherited forms of the disease are PD associated with mutation in the leucine-rich repeat kinase 2 (LRRK2-PD) and glucocerebrosidase (GBA-PD) genes. The aim of our work is to evaluate the concentration and size of exosomes derived from blood plasma of patients with GBA-PD, asymptomatic GBA mutation carriers, and the effect of GBA and LRRK2 mutations on alpha-synuclein level in exosomes derived from peripheral blood plasma. Plasma extracellular vesicles were isolated via chemical precipitation and sequential ultracentrifugation and characterized by transmission electron microscopy, nanoparticle tracking analysis (NTA), and flow cytometry. Total alpha-synuclein level in plasma exosomes was estimated by enzyme-linked immunosorbent assay. Patients with sporadic PD, PD with dementia, patients with inherited PD (GBA-PD, LRRK2-PD), and GBA mutation carriers were included in the study. The concentration on plasma exosomes was higher in GBA-PD patients that in sporadic PD patients, asymptomatic carriers of mutations on GBA gene, and control (p = 0.004, 0.019 and 0.0001 respectively). The size of plasma exosomes was higher in GBA-PD patients compared to asymptomatic carriers of GBA mutations and control (p = 0.009 and 0.0001, respectively). No significant difference was found for exosomal alpha-synuclein levels in the studied groups. Our results allowed us to suggest that a decrease in GBA activity may affect the pool of plasma exosomes, and mutations in the LRRK2 and GBA genes do not influence the level of plasma exosomal alpha-synuclein.},\n chemicals = {Leucine-Rich Repeat Serine-Threonine Protein Kinase-2, Glucosylceramidase},\n citation-subset = {IM},\n completed = {2021-04-21},\n country = {Russia (Federation)},\n doi = {10.31857/S0026898421010092},\n issn-linking = {0026-8984},\n issue = {2},\n keywords = {Exosomes, genetics; Glucosylceramidase, genetics; Humans; Leucine-Rich Repeat Serine-Threonine Protein Kinase-2, genetics; Mutation; Parkinson Disease, genetics; Plasma; GBA; LRRK2; Parkinson's disease; alpha-synuclein; exosomes},\n nlm-id = {0105454},\n owner = {NLM},\n pmid = {33871446},\n pubmodel = {Print},\n pubstate = {ppublish},\n revised = {2021-04-21},\n season = {Mar-Apr},\n}\n\n\n\n Parkinson's disease (PD) is the second most common neurodegenerative disorder. Alpha-synuclein misfolding and aggregation resulting in neurototoxicity is a hallmark of PD. The prion properties of alpha-synuclein are still under discussion. Exosomes (extrcellular vesicles 40-100 nm in size) can play a key role in the transport of pathogenic forms of alpha-synuclein. The most frequent inherited forms of the disease are PD associated with mutation in the leucine-rich repeat kinase 2 (LRRK2-PD) and glucocerebrosidase (GBA-PD) genes. The aim of our work is to evaluate the concentration and size of exosomes derived from blood plasma of patients with GBA-PD, asymptomatic GBA mutation carriers, and the effect of GBA and LRRK2 mutations on alpha-synuclein level in exosomes derived from peripheral blood plasma. Plasma extracellular vesicles were isolated via chemical precipitation and sequential ultracentrifugation and characterized by transmission electron microscopy, nanoparticle tracking analysis (NTA), and flow cytometry. Total alpha-synuclein level in plasma exosomes was estimated by enzyme-linked immunosorbent assay. Patients with sporadic PD, PD with dementia, patients with inherited PD (GBA-PD, LRRK2-PD), and GBA mutation carriers were included in the study. The concentration on plasma exosomes was higher in GBA-PD patients that in sporadic PD patients, asymptomatic carriers of mutations on GBA gene, and control (p = 0.004, 0.019 and 0.0001 respectively). The size of plasma exosomes was higher in GBA-PD patients compared to asymptomatic carriers of GBA mutations and control (p = 0.009 and 0.0001, respectively). No significant difference was found for exosomal alpha-synuclein levels in the studied groups. Our results allowed us to suggest that a decrease in GBA activity may affect the pool of plasma exosomes, and mutations in the LRRK2 and GBA genes do not influence the level of plasma exosomal alpha-synuclein.\n
\n\n\n\n \n\n \n \n \n \n \n Hsp70-containing extracellular vesicles are capable of activating of adaptive immunity in models of mouse melanoma and colon carcinoma.\n \n \n \n\n\n \n Komarova, E. Y.; Suezov, R. V.; Nikotina, A. D.; Aksenov, N. D.; Garaeva, L. A.; Shtam, T. A.; Zhakhov, A. V.; Martynova, M. G.; Bystrova, O. A.; Istomina, M. S.; Ischenko, A. M.; Margulis, B. A.; and Guzhova, I. V.\n\n\n \n\n\n\n Scientific reports, 11: 21314. October 2021.\n \n\n\n\n
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\n\n\n@Article{Komarova2021,\n author = {Komarova, Elena Y. and Suezov, Roman V. and Nikotina, Alina D. and Aksenov, Nikolay D. and Garaeva, Luiza A. and Shtam, Tatiana A. and Zhakhov, Alexander V. and Martynova, Marina G. and Bystrova, Olga A. and Istomina, Maria S. and Ischenko, Alexander M. and Margulis, Boris A. and Guzhova, Irina V.},\n journal = {Scientific reports},\n title = {Hsp70-containing extracellular vesicles are capable of activating of adaptive immunity in models of mouse melanoma and colon carcinoma.},\n year = {2021},\n issn = {2045-2322},\n month = oct,\n pages = {21314},\n volume = {11},\n abstract = {The release of Hsp70 chaperone from tumor cells is found to trigger the full-scale anti-cancer immune response. Such release and the proper immune reaction can be induced by the delivery of recombinant Hsp70 to a tumor and we sought to explore how the endogenous Hsp70 can be transported to extracellular space leading to the burst of anti-cancer activity. Hsp70 transport mechanisms were studied by analyzing its intracellular tracks with Rab proteins as well as by using specific inhibitors of membrane domains. To study Hsp70 forms released from cells we employed the assay consisting of two affinity chromatography methods. Hsp70 content in culture medium and extracellular vesicles (EVs) was measured with the aid of ELISA. The properties and composition of EVs were assessed using nanoparticle tracking analysis and immunoblotting. The activity of immune cells was studied using an assay of cytotoxic lymphocytes, and for in vivo studies we employed methods of affinity separation of lymphocyte fractions. Analyzing B16 melanoma cells treated with recombinant Hsp70 we found that the chaperone triggered extracellular transport of its endogenous analog in soluble and enclosed in EVs forms; both species efficiently penetrated adjacent cells and this secondary transport was corroborated with the strong increase of Natural Killer (NK) cell toxicity towards melanoma. When B16 and CT-26 colon cancer cells before their injection in animals were treated with Hsp70-enriched EVs, a powerful anti-cancer effect was observed as shown by a two-fold reduction in tumor growth rate and elevation of life span. We found that the immunomodulatory effect was due to the enhancement of the CD8-positive response and anti-tumor cytokine accumulation; supporting this there was no delay in CT-26 tumor growth when Hsp70-enriched EVs were grafted in nude mice. Importantly, pre-treatment of B16 cells with Hsp70-bearing EVs resulted in a decline of arginase-1-positive macrophages, showing no generation of tumor-associated macrophages. In conclusion, Hsp70-containing EVs generated by specifically treated cancer cells give a full-scale and effective pattern of anti-tumor immune responses.},\n chemicals = {HSP70 Heat-Shock Proteins},\n citation-subset = {IM},\n completed = {2022-01-21},\n country = {England},\n doi = {10.1038/s41598-021-00734-4},\n issn-linking = {2045-2322},\n issue = {1},\n keywords = {Adaptive Immunity; Animals; Carcinoma, immunology; Cell Line, Tumor; Colonic Neoplasms, immunology; Extracellular Vesicles; HEK293 Cells; HSP70 Heat-Shock Proteins, pharmacology; Humans; Killer Cells, Natural, immunology; Melanoma, Experimental, immunology; Mice},\n nlm-id = {101563288},\n owner = {NLM},\n pii = {21314},\n pmc = {PMC8556270},\n pmid = {34716378},\n pubmodel = {Electronic},\n pubstate = {epublish},\n revised = {2022-01-21},\n}\n\n\n\n The release of Hsp70 chaperone from tumor cells is found to trigger the full-scale anti-cancer immune response. Such release and the proper immune reaction can be induced by the delivery of recombinant Hsp70 to a tumor and we sought to explore how the endogenous Hsp70 can be transported to extracellular space leading to the burst of anti-cancer activity. Hsp70 transport mechanisms were studied by analyzing its intracellular tracks with Rab proteins as well as by using specific inhibitors of membrane domains. To study Hsp70 forms released from cells we employed the assay consisting of two affinity chromatography methods. Hsp70 content in culture medium and extracellular vesicles (EVs) was measured with the aid of ELISA. The properties and composition of EVs were assessed using nanoparticle tracking analysis and immunoblotting. The activity of immune cells was studied using an assay of cytotoxic lymphocytes, and for in vivo studies we employed methods of affinity separation of lymphocyte fractions. Analyzing B16 melanoma cells treated with recombinant Hsp70 we found that the chaperone triggered extracellular transport of its endogenous analog in soluble and enclosed in EVs forms; both species efficiently penetrated adjacent cells and this secondary transport was corroborated with the strong increase of Natural Killer (NK) cell toxicity towards melanoma. When B16 and CT-26 colon cancer cells before their injection in animals were treated with Hsp70-enriched EVs, a powerful anti-cancer effect was observed as shown by a two-fold reduction in tumor growth rate and elevation of life span. We found that the immunomodulatory effect was due to the enhancement of the CD8-positive response and anti-tumor cytokine accumulation; supporting this there was no delay in CT-26 tumor growth when Hsp70-enriched EVs were grafted in nude mice. Importantly, pre-treatment of B16 cells with Hsp70-bearing EVs resulted in a decline of arginase-1-positive macrophages, showing no generation of tumor-associated macrophages. In conclusion, Hsp70-containing EVs generated by specifically treated cancer cells give a full-scale and effective pattern of anti-tumor immune responses.\n
\n\n\n\n \n\n \n \n \n \n \n Potential of Magnetic Hyperthermia to Stimulate Localized Immune Activation.\n \n \n \n\n\n \n Carter, T. J.; Agliardi, G.; Lin, F.; Ellis, M.; Jones, C.; Robson, M.; Richard-Londt, A.; Southern, P.; Lythgoe, M.; Zaw Thin, M.; Ryzhov, V.; de Rosales, R. T. M.; Gruettner, C.; Abdollah, M. R. A.; Pedley, R. B.; Pankhurst, Q. A.; Kalber, T. L.; Brandner, S.; Quezada, S.; Mulholland, P.; Shevtsov, M.; and Chester, K.\n\n\n \n\n\n\n Small (Weinheim an der Bergstrasse, Germany), 17: e2005241. April 2021.\n \n\n\n\n
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\n\n\n@Article{Carter2021,\n author = {Carter, Thomas J. and Agliardi, Giulia and Lin, Fang-Yu and Ellis, Matthew and Jones, Clare and Robson, Mathew and Richard-Londt, Angela and Southern, Paul and Lythgoe, Mark and Zaw Thin, May and Ryzhov, Vyacheslav and de Rosales, Rafael T. M. and Gruettner, Cordula and Abdollah, Maha R. A. and Pedley, R. Barbara and Pankhurst, Quentin A. and Kalber, Tammy L. and Brandner, Sebastian and Quezada, Sergio and Mulholland, Paul and Shevtsov, Maxim and Chester, Kerry},\n journal = {Small (Weinheim an der Bergstrasse, Germany)},\n title = {Potential of Magnetic Hyperthermia to Stimulate Localized Immune Activation.},\n year = {2021},\n issn = {1613-6829},\n month = apr,\n pages = {e2005241},\n volume = {17},\n abstract = {Magnetic hyperthermia (MH) harnesses the heat-releasing properties of superparamagnetic iron oxide nanoparticles (SPIONs) and has potential to stimulate immune activation in the tumor microenvironment whilst sparing surrounding normal tissues. To assess feasibility of localized MH in vivo, SPIONs are injected intratumorally and their fate tracked by Zirconium-89-positron emission tomography, histological analysis, and electron microscopy. Experiments show that an average of 49% (21-87%, n = 9) of SPIONs are retained within the tumor or immediately surrounding tissue. In situ heating is subsequently generated by exposure to an externally applied alternating magnetic field and monitored by thermal imaging. Tissue response to hyperthermia, measured by immunohistochemical image analysis, reveals specific and localized heat-shock protein expression following treatment. Tumor growth inhibition is also observed. To evaluate the potential effects of MH on the immune landscape, flow cytometry is used to characterize immune cells from excised tumors and draining lymph nodes. Results show an influx of activated cytotoxic T cells, alongside an increase in proliferating regulatory T cells, following treatment. Complementary changes are found in draining lymph nodes. In conclusion, results indicate that biologically reactive MH is achievable in vivo and can generate localized changes consistent with an anti-tumor immune response.},\n chemicals = {Ferric Compounds, Magnetite Nanoparticles},\n citation-subset = {IM},\n completed = {2021-07-14},\n country = {Germany},\n doi = {10.1002/smll.202005241},\n issn-linking = {1613-6810},\n issue = {14},\n keywords = {Ferric Compounds; Humans; Hyperthermia; Hyperthermia, Induced; Magnetic Fields; Magnetics; Magnetite Nanoparticles; biological response; heat-shock protein 70; immune stimulation; magnetic hyperthermia; superparamagnetic iron oxide nanoparticles},\n nlm-id = {101235338},\n owner = {NLM},\n pmid = {33734595},\n pubmodel = {Print-Electronic},\n pubstate = {ppublish},\n revised = {2021-07-14},\n}\n\n\n\n Magnetic hyperthermia (MH) harnesses the heat-releasing properties of superparamagnetic iron oxide nanoparticles (SPIONs) and has potential to stimulate immune activation in the tumor microenvironment whilst sparing surrounding normal tissues. To assess feasibility of localized MH in vivo, SPIONs are injected intratumorally and their fate tracked by Zirconium-89-positron emission tomography, histological analysis, and electron microscopy. Experiments show that an average of 49% (21-87%, n = 9) of SPIONs are retained within the tumor or immediately surrounding tissue. In situ heating is subsequently generated by exposure to an externally applied alternating magnetic field and monitored by thermal imaging. Tissue response to hyperthermia, measured by immunohistochemical image analysis, reveals specific and localized heat-shock protein expression following treatment. Tumor growth inhibition is also observed. To evaluate the potential effects of MH on the immune landscape, flow cytometry is used to characterize immune cells from excised tumors and draining lymph nodes. Results show an influx of activated cytotoxic T cells, alongside an increase in proliferating regulatory T cells, following treatment. Complementary changes are found in draining lymph nodes. In conclusion, results indicate that biologically reactive MH is achievable in vivo and can generate localized changes consistent with an anti-tumor immune response.\n
\n\n\n\n \n\n \n \n \n \n \n \n Signs and Symptoms of Central Nervous System Involvement and Their Pathogenesis in COVID-19 According to The Clinical Data (Review).\n \n \n \n \n\n\n \n Tsygan, N. V.; Trashkov, A. P.; Ryabtsev, A. V.; Yakovleva, V. A.; Konevega, A. L.; Vasiliev, A. G.; Tsygan, V. N.; Odinak, M. M.; and Litvinenko, I. V.\n\n\n \n\n\n\n Общая реаниматология, 17(3): 65–77. 7 2021.\n \n\n\n\n
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\n\n\n@Article{Tsygan2021,\n author = {N. V. Tsygan and A. P. Trashkov and A. V. Ryabtsev and V. A. Yakovleva and A. L. Konevega and A. G. Vasiliev and V. N. Tsygan and M. M. Odinak and I. V. Litvinenko},\n journal = {Общая реаниматология},\n title = {Signs and Symptoms of Central Nervous System Involvement and Their Pathogenesis in COVID-19 According to The Clinical Data (Review)},\n year = {2021},\n issn = {2411-7110},\n month = {7},\n number = {3},\n pages = {65--77},\n volume = {17},\n abstract = {Detailed clinical assessment of the central nervous system involvement in SARS-CoV-2 infection is relevant due to the low specificity of neurological manifestations, the complexity of evaluation of patient complaints, reduced awareness of the existing spectrum of neurological manifestations of COVID-19, as well as low yield of the neurological imaging.The aim. To reveal the patterns of central nervous system involvement in COVID-19 and its pathogenesis based on clinical data.Among more than 200 primary literature sources from various databases (Scopus, Web of Science, RSCI, etc.), 80 sources were selected for evaluation, of them 72 were published in the recent years (2016-2020). The criteria for exclusion of sources were low relevance and outdated information.The clinical manifestations of central nervous system involvement in COVID-19 include smell (5-98% of cases) and taste disorders (6-89%), dysphonia (28%), dysphagia (19%), consciousness disorders (3-53%), headache (0-70%), dizziness (0-20%), and, in less than 3% of cases, visual impairment, hearing impairment, ataxia, seizures, stroke. Analysis of the literature data revealed the following significant mechanisms of the effects of highly contagious coronaviruses (including SARS-CoV-2) on the central nervous system: neurodegeneration (including cytokine- induced); cerebral thrombosis and thromboembolism; damage to the neurovascular unit; immune-mediated damage of nervous tissue, resulting in infection and allergy-induced demyelination.The neurological signs and symptoms seen in COVID-19 such as headache, dizziness, impaired smell and taste, altered level of consciousness, bulbar disorders (dysphagia, dysphonia) have been examined. Accordingly, we discussed the possible routes of SARS-CoV-2 entry into the central nervous system and the mechanisms of nervous tissue damage.Based on the literature analysis, a high frequency and variability of central nervous system manifestations of COVID-19 were revealed, and an important role of vascular brain damage and neurodegeneration in the pathogenesis of COVID-19 was highlighted.},\n doi = {10.15360/1813-9779-2021-3-65-77},\n keywords = {covid-19, sars-cov-2, центральная нервная система, центральная гипертермия, гипоксия, нейродегенерация},\n publisher = {Federal Research and Clinical Center of Intensive Care Medicine and Rehabilitology, Moscow, Russia},\n url = {https://www.reanimatology.com/rmt/article/view/2083},\n}\n\n\n\n Detailed clinical assessment of the central nervous system involvement in SARS-CoV-2 infection is relevant due to the low specificity of neurological manifestations, the complexity of evaluation of patient complaints, reduced awareness of the existing spectrum of neurological manifestations of COVID-19, as well as low yield of the neurological imaging.The aim. To reveal the patterns of central nervous system involvement in COVID-19 and its pathogenesis based on clinical data.Among more than 200 primary literature sources from various databases (Scopus, Web of Science, RSCI, etc.), 80 sources were selected for evaluation, of them 72 were published in the recent years (2016-2020). The criteria for exclusion of sources were low relevance and outdated information.The clinical manifestations of central nervous system involvement in COVID-19 include smell (5-98% of cases) and taste disorders (6-89%), dysphonia (28%), dysphagia (19%), consciousness disorders (3-53%), headache (0-70%), dizziness (0-20%), and, in less than 3% of cases, visual impairment, hearing impairment, ataxia, seizures, stroke. Analysis of the literature data revealed the following significant mechanisms of the effects of highly contagious coronaviruses (including SARS-CoV-2) on the central nervous system: neurodegeneration (including cytokine- induced); cerebral thrombosis and thromboembolism; damage to the neurovascular unit; immune-mediated damage of nervous tissue, resulting in infection and allergy-induced demyelination.The neurological signs and symptoms seen in COVID-19 such as headache, dizziness, impaired smell and taste, altered level of consciousness, bulbar disorders (dysphagia, dysphonia) have been examined. Accordingly, we discussed the possible routes of SARS-CoV-2 entry into the central nervous system and the mechanisms of nervous tissue damage.Based on the literature analysis, a high frequency and variability of central nervous system manifestations of COVID-19 were revealed, and an important role of vascular brain damage and neurodegeneration in the pathogenesis of COVID-19 was highlighted.\n
\n\n\n\n \n\n \n \n \n \n \n \n Neutron Scattering Techniques and Complementary Methods for Structural and Functional Studies of Biological Macromolecules and Large Macromolecular Complexes.\n \n \n \n \n\n\n \n Lebedev, D.; Egorov, V.; Shvetsov, A.; Zabrodskaya, Y.; Isaev-Ivanov, V.; and Konevega, A.\n\n\n \n\n\n\n Crystallography Reports, 66(2): 242-253. March 2021.\n \n\n\n\n
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\n\n\n@Article{Lebedev2021,\n author = {Lebedev, D.~V. and Egorov, V.~V. and Shvetsov, A.~V. and Zabrodskaya, Y.~A. and Isaev-Ivanov, V.~V. and Konevega, A.~L.},\n journal = {Crystallography Reports},\n title = {Neutron Scattering Techniques and Complementary Methods for Structural and Functional Studies of Biological Macromolecules and Large Macromolecular Complexes},\n year = {2021},\n month = mar,\n number = {2},\n pages = {242-253},\n volume = {66},\n abstract = {The review describes the application of small-angle scattering (SAS) of neutrons and complementary methods to study the structures of biomacromolecules. Here we cover SAS techniques, such as the contrast variation, the neutron spin-echo, and the solution of direct and inverse problems of three-dimensional reconstruction of the structures of macromolecules from SAS spectra by means of molecular modeling. A special section is devoted to specific objects of research, such as supramolecular complexes, influenza virus nucleoprotein, and chromatin.},\n doi = {10.1134/S1063774521020103},\n url = {https://ui.adsabs.harvard.edu/abs/2021CryRp..66..242L},\n}\n\n\n\n The review describes the application of small-angle scattering (SAS) of neutrons and complementary methods to study the structures of biomacromolecules. Here we cover SAS techniques, such as the contrast variation, the neutron spin-echo, and the solution of direct and inverse problems of three-dimensional reconstruction of the structures of macromolecules from SAS spectra by means of molecular modeling. A special section is devoted to specific objects of research, such as supramolecular complexes, influenza virus nucleoprotein, and chromatin.\n
\n\n\n\n \n\n \n \n \n \n \n \n Abstract P-29: Cryoem Study of the Inhibition of Bacterial Ribosomes by Madumycin II.\n \n \n \n \n\n\n \n Yakusheva, A.; Shulenina, O.; Pichkur, E.; Paleskava, A.; Myasnikov, A.; and Konevega, A.\n\n\n \n\n\n\n International Journal of Biomedicine, 11(Suppl_1): 24–25. 6 2021.\n \n\n\n\n
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\n\n\n@Article{Yakusheva2021,\n author = {Alena Yakusheva and Olga Shulenina and Evgeny Pichkur and Alena Paleskava and Alexander Myasnikov and Andrey Konevega},\n journal = {International Journal of Biomedicine},\n title = {Abstract P-29: Cryoem Study of the Inhibition of Bacterial Ribosomes by Madumycin II},\n year = {2021},\n issn = {2158-0529},\n month = {6},\n number = {Suppl_1},\n pages = {24--25},\n volume = {11},\n abstract = {Background: The efficiency of widely used antibiotics is limited by continuous improvement of resistance mechanisms. Thus, the research of poorly studied drugs that have not received practical use until now becomes relevant again. Protein translation is one of the major targets for antibiotics. Madumycin II (MADU) is an antibiotic of the streptogramin A class that binds to the peptidyl transferase center of the initiated bacterial 70S ribosome inhibiting the first cycle of peptide bond formation (I.A. Osterman et al. Nucleic Acids Res., 2017). The ability of MADU to interfere with translating ribosome is an open question that we address by investigation of high-resolution cryo-EM structures of MADU bound 70S ribosome complexes from Escherichia coli.\nMethods: Purified initiated and translating ribosome complexes preincubated with MADU were applied onto freshly glow discharged carbon-coated grids (Quantifoil R 1.2/1.3) and flash-frozen in the liquid ethane pre-cooled by liquid nitrogen in the Vitrobot Mark IV. Frozen grids were transferred into an in-house Titan Krios microscope. Data were collected using EPU software. Movie stacks were preprocessed in Warp software. For image processing, we have used several software packages: Relion 3.1, CryoSPARC, and CisTEM. The model was built in Coot.\nResults: We have obtained high-resolution cryo-EM structures of two ribosomal complexes with MADU before and after the first cycle of peptide bond formation with an average resolution of 2.3 Å. Preliminary analysis of the structures shows no major differences in the MADU binding mode to the ribosomal complexes under study suggesting that the quantity of amino acid residues attached to the P-site tRNA does not impact MADU bonding. Moreover, in both cases, we observed similar destabilization of the CCA-ends of A- and P-site tRNAs underlining the comparable influence of MADU on the ribosomal complexes.\nConclusion: Our results suggest that although MADU binding site is located in the peptidyl transferase center, the presence of the second amino acid residue on the P-site tRNA does not preclude antibiotic binding. We assume that further elongation of the polypeptide chain would not have any impact either. High conformational lability of the CCA-ends of tRNA at the A and P sites upon binding of MADU obviously plays an important role in the inhibition mechanism of the bacterial ribosome. The further structural and biochemical analysis will be necessary to shed more light on the detailed mechanism of MADU action.},\n doi = {10.21103/IJBM.11.Suppl_1.P29},\n keywords = {ribosome, antibiotics, structure, cryo-em},\n publisher = {International Medical Research and Development Corporation},\n url = {http://ijbm.org/articles/v11s1/ijbm_2021_11_s1_p29.pdf},\n}\n\n\n\n Background: The efficiency of widely used antibiotics is limited by continuous improvement of resistance mechanisms. Thus, the research of poorly studied drugs that have not received practical use until now becomes relevant again. Protein translation is one of the major targets for antibiotics. Madumycin II (MADU) is an antibiotic of the streptogramin A class that binds to the peptidyl transferase center of the initiated bacterial 70S ribosome inhibiting the first cycle of peptide bond formation (I.A. Osterman et al. Nucleic Acids Res., 2017). The ability of MADU to interfere with translating ribosome is an open question that we address by investigation of high-resolution cryo-EM structures of MADU bound 70S ribosome complexes from Escherichia coli. Methods: Purified initiated and translating ribosome complexes preincubated with MADU were applied onto freshly glow discharged carbon-coated grids (Quantifoil R 1.2/1.3) and flash-frozen in the liquid ethane pre-cooled by liquid nitrogen in the Vitrobot Mark IV. Frozen grids were transferred into an in-house Titan Krios microscope. Data were collected using EPU software. Movie stacks were preprocessed in Warp software. For image processing, we have used several software packages: Relion 3.1, CryoSPARC, and CisTEM. The model was built in Coot. Results: We have obtained high-resolution cryo-EM structures of two ribosomal complexes with MADU before and after the first cycle of peptide bond formation with an average resolution of 2.3 Å. Preliminary analysis of the structures shows no major differences in the MADU binding mode to the ribosomal complexes under study suggesting that the quantity of amino acid residues attached to the P-site tRNA does not impact MADU bonding. Moreover, in both cases, we observed similar destabilization of the CCA-ends of A- and P-site tRNAs underlining the comparable influence of MADU on the ribosomal complexes. Conclusion: Our results suggest that although MADU binding site is located in the peptidyl transferase center, the presence of the second amino acid residue on the P-site tRNA does not preclude antibiotic binding. We assume that further elongation of the polypeptide chain would not have any impact either. High conformational lability of the CCA-ends of tRNA at the A and P sites upon binding of MADU obviously plays an important role in the inhibition mechanism of the bacterial ribosome. The further structural and biochemical analysis will be necessary to shed more light on the detailed mechanism of MADU action.\n
\n\n\n\n \n\n \n \n \n \n \n Neuroprotective Effects of Tripeptides—Epigenetic Regulators in Mouse Model of Alzheimer’s Disease.\n \n \n \n\n\n \n Khavinson, V.; Ilina, A.; Kraskovskaya, N.; Linkova, N.; Kolchina, N.; Mironova, E.; Erofeev, A.; and Petukhov, M.\n\n\n \n\n\n\n Pharmaceuticals, 14(6): 515. May 2021.\n \n\n\n\n
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\n\n\n\n@Article{Khavinson2021,\n author = {Vladimir Khavinson and Anastasiia Ilina and Nina Kraskovskaya and Natalia Linkova and Nina Kolchina and Ekaterina Mironova and Alexander Erofeev and Michael Petukhov},\n journal = {Pharmaceuticals},\n title = {Neuroprotective Effects of Tripeptides—Epigenetic Regulators in Mouse Model of Alzheimer’s Disease},\n year = {2021},\n issn = {1424-8247},\n month = may,\n number = {6},\n pages = {515},\n volume = {14},\n doi = {10.3390/ph14060515},\n keywords = {Drug Discovery, Pharmaceutical Science, Molecular Medicine},\n publisher = {MDPI AG},\n}\n\n\n\n \n\n \n \n \n \n \n Boron compound as a sensitizer to proton radiation for cancer cells in vitro.\n \n \n \n\n\n \n Garaeva, L.; Burdakov, V.; Kuus, E.; Volnitskiy, A.; Garina, A.; Tran, H. N.; Andreev, G.; Lubinskiy, A.; Shabalin, K.; Ezhov, V.; Lebedev, D.; Verlov, N.; Konevega, A.; and Shtam, T.\n\n\n \n\n\n\n 2021.\n \n\n\n\n
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\n\n\n\n@Misc{Garaeva2021a,\n author = {Luiza Garaeva and Vladimir Burdakov and Eva Kuus and Andrey Volnitskiy and Alina Garina and Hau Nhan Tran and Georgy Andreev and Andrey Lubinskiy and Konstantin Shabalin and Victor Ezhov and Dmitry Lebedev and Nicolay Verlov and Andrey Konevega and Tatiana Shtam},\n title = {Boron compound as a sensitizer to proton radiation for cancer cells in vitro},\n year = {2021},\n booktitle = {Book of Abstracts},\n collection = {RADConf},\n doi = {10.21175/rad.abstr.book.2021.36.10},\n journal = {Book of Abstracts},\n publisher = {RAD Centre},\n series = {RADConf},\n}\n\n\n\n \n\n \n \n \n \n \n Abstract P-16: Cryo-Electron Microscopy Study of Vesicles from Various Species.\n \n \n \n\n\n \n Yastremsky, E.; Garaeva, L.; Putevich, E.; Sazonov, D.; Vasiliev, A.; Kamyshinsky, R.; and Shtam, T.\n\n\n \n\n\n\n International Journal of Biomedicine, 11(Suppl_1): S18-S18. 2021.\n \n\n\n\n
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\n\n\n\n@Article{Yastremsky2021,\n author = {Evgeny Yastremsky and Luiza Garaeva and Elena Putevich and Dmitry Sazonov and Alexander Vasiliev and Roman Kamyshinsky and Tatiana Shtam},\n journal = {International Journal of Biomedicine},\n title = {Abstract P-16: Cryo-Electron Microscopy Study of Vesicles from Various Species},\n year = {2021},\n issn = {2158-0510},\n number = {Suppl_1},\n pages = {S18-S18},\n volume = {11},\n doi = {10.21103/ijbm.11.suppl_1.p16},\n keywords = {General Immunology and Microbiology, General Biochemistry, Genetics and Molecular Biology, General Neuroscience},\n publisher = {International Medical Research and Development Corporation},\n}\n\n\n\n
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\n \n \n\n \n \n \n \n \n Peculiarities in Activation of Hydrolytic Activity of Elongation Factors.\n \n \n \n\n\n \n Paleskava, A.; Kaiumov, M. Y.; Kirillov, S. V.; and Konevega, A. L.\n\n\n \n\n\n\n Biochemistry. Biokhimiia, 85: 1422–1433. November 2020.\n \n\n\n\n
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\n\n\n@Article{Paleskava2020,\n author = {Paleskava, A. and Kaiumov, M. Yu and Kirillov, S. V. and Konevega, A. L.},\n journal = {Biochemistry. Biokhimiia},\n title = {Peculiarities in Activation of Hydrolytic Activity of Elongation Factors.},\n year = {2020},\n issn = {1608-3040},\n month = nov,\n pages = {1422--1433},\n volume = {85},\n abstract = {Translational GTPases (trGTPases) belong to the family of G proteins and play key roles at all stages of protein biosynthesis on the ribosome. Unidirectional and cyclic functioning of G proteins is ensured by their ability to switch between the active and inactive states due to GTP hydrolysis accelerated by the auxiliary GTPase-activating proteins. Although trGTPases interact with the ribosomes in different conformational states, they bind to the same conserved region, which, unlike in classical GTPase-activating proteins, is represented by ribosomal RNA. The resulting catalytic sites have almost identical structure in all elongation factors suggesting a common mechanism of GTP hydrolysis. However, fine details of the activated state formation and significantly different rates of GTP hydrolysis indicate the existence of distinctive features upon GTP hydrolysis catalyzed by the different factors. Here, we present a contemporary view on the mechanism of GTPase activation and GTP hydrolysis by the elongation factors EF-Tu, EF-G, and SelB based on the analysis of structural, biochemical, and bioinformatics data.},\n chemicals = {Peptide Elongation Factors, Guanosine Triphosphate},\n citation-subset = {IM},\n completed = {2021-07-06},\n country = {United States},\n doi = {10.1134/S0006297920110103},\n issn-linking = {0006-2979},\n issue = {11},\n keywords = {Guanosine Triphosphate, genetics, metabolism; Hydrolysis; Peptide Elongation Factors, genetics, metabolism; Protein Biosynthesis; Ribosomes, genetics, metabolism},\n nlm-id = {0376536},\n owner = {NLM},\n pii = {BCM85111676},\n pmid = {33280582},\n pubmodel = {Print},\n pubstate = {ppublish},\n revised = {2021-07-06},\n}\n\n\n\n Translational GTPases (trGTPases) belong to the family of G proteins and play key roles at all stages of protein biosynthesis on the ribosome. Unidirectional and cyclic functioning of G proteins is ensured by their ability to switch between the active and inactive states due to GTP hydrolysis accelerated by the auxiliary GTPase-activating proteins. Although trGTPases interact with the ribosomes in different conformational states, they bind to the same conserved region, which, unlike in classical GTPase-activating proteins, is represented by ribosomal RNA. The resulting catalytic sites have almost identical structure in all elongation factors suggesting a common mechanism of GTP hydrolysis. However, fine details of the activated state formation and significantly different rates of GTP hydrolysis indicate the existence of distinctive features upon GTP hydrolysis catalyzed by the different factors. Here, we present a contemporary view on the mechanism of GTPase activation and GTP hydrolysis by the elongation factors EF-Tu, EF-G, and SelB based on the analysis of structural, biochemical, and bioinformatics data.\n
\n\n\n\n \n\n \n \n \n \n \n Cryo-electron microscopy of extracellular vesicles from cerebrospinal fluid.\n \n \n \n\n\n \n Emelyanov, A.; Shtam, T.; Kamyshinsky, R.; Garaeva, L.; Verlov, N.; Miliukhina, I.; Kudrevatykh, A.; Gavrilov, G.; Zabrodskaya, Y.; Pchelina, S.; and Konevega, A.\n\n\n \n\n\n\n PloS one, 15: e0227949. 2020.\n \n\n\n\n
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\n\n\n@Article{Emelyanov2020,\n author = {Emelyanov, Anton and Shtam, Tatiana and Kamyshinsky, Roman and Garaeva, Luiza and Verlov, Nikolai and Miliukhina, Irina and Kudrevatykh, Anastasia and Gavrilov, Gaspar and Zabrodskaya, Yulia and Pchelina, Sofya and Konevega, Andrey},\n journal = {PloS one},\n title = {Cryo-electron microscopy of extracellular vesicles from cerebrospinal fluid.},\n year = {2020},\n issn = {1932-6203},\n pages = {e0227949},\n volume = {15},\n abstract = {Extracellular vesicles (EVs) are membrane-enclosed vesicles which play important role for cell communication and physiology. EVs are found in many human biological fluids, including blood, breast milk, urine, cerebrospinal fluid (CSF), ejaculate, saliva etc. These nano-sized vesicles contain proteins, mRNAs, microRNAs, non-coding RNAs and lipids that are derived from producing cells. EVs deliver complex sets of biological information to recipient cells thereby modulating their behaviors by their molecular cargo. In this way EVs are involved in the pathological development and progression of many human disorders, including neurodegenerative diseases. In this study EVs purified by ultracentrifugation from CSF of patients with Parkinson's disease (PD) and individuals of the comparison group were characterized using nanoparticle tracking analysis, flow cytometry and cryo-electron microscopy. Vesicular size and the presence of exosomal marker CD9 on the surface provided evidence that most of the EVs were exosome-like vesicles. Cryo-electron microscopy allowed us to visualize a large spectrum of extracellular vesicles of various size and morphology with lipid bilayers and vesicular internal structures. Thus, we described the diversity and new characteristics of the vesicles from CSF suggesting that subpopulations of EVs with different and specific functions may exist.},\n chemicals = {Biomarkers, Lipid Bilayers, MicroRNAs, Tetraspanin 29},\n citation-subset = {IM},\n completed = {2020-04-14},\n country = {United States},\n doi = {10.1371/journal.pone.0227949},\n issn-linking = {1932-6203},\n issue = {1},\n keywords = {Aged; Animals; Biomarkers, cerebrospinal fluid; Cerebrospinal Fluid, diagnostic imaging; Cryoelectron Microscopy; Exosomes, chemistry, ultrastructure; Extracellular Vesicles, chemistry, ultrastructure; Female; Flow Cytometry; Humans; Lipid Bilayers, cerebrospinal fluid; Male; MicroRNAs, chemistry, isolation & purification; Middle Aged; Nanoparticles, chemistry; Parkinson Disease, cerebrospinal fluid, pathology; Tetraspanin 29, cerebrospinal fluid},\n nlm-id = {101285081},\n owner = {NLM},\n pii = {e0227949},\n pmc = {PMC6991974},\n pmid = {31999742},\n pubmodel = {Electronic-eCollection},\n pubstate = {epublish},\n revised = {2020-04-14},\n}\n\n\n\n Extracellular vesicles (EVs) are membrane-enclosed vesicles which play important role for cell communication and physiology. EVs are found in many human biological fluids, including blood, breast milk, urine, cerebrospinal fluid (CSF), ejaculate, saliva etc. These nano-sized vesicles contain proteins, mRNAs, microRNAs, non-coding RNAs and lipids that are derived from producing cells. EVs deliver complex sets of biological information to recipient cells thereby modulating their behaviors by their molecular cargo. In this way EVs are involved in the pathological development and progression of many human disorders, including neurodegenerative diseases. In this study EVs purified by ultracentrifugation from CSF of patients with Parkinson's disease (PD) and individuals of the comparison group were characterized using nanoparticle tracking analysis, flow cytometry and cryo-electron microscopy. Vesicular size and the presence of exosomal marker CD9 on the surface provided evidence that most of the EVs were exosome-like vesicles. Cryo-electron microscopy allowed us to visualize a large spectrum of extracellular vesicles of various size and morphology with lipid bilayers and vesicular internal structures. Thus, we described the diversity and new characteristics of the vesicles from CSF suggesting that subpopulations of EVs with different and specific functions may exist.\n
\n\n\n\n \n\n \n \n \n \n \n How the initiating ribosome copes with ppGpp to translate mRNAs.\n \n \n \n\n\n \n Vinogradova, D. S.; Zegarra, V.; Maksimova, E.; Nakamoto, J. A.; Kasatsky, P.; Paleskava, A.; Konevega, A. L.; and Milón, P.\n\n\n \n\n\n\n PLoS biology, 18: e3000593. January 2020.\n \n\n\n\n
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\n\n\n@Article{Vinogradova2020,\n author = {Vinogradova, Daria S. and Zegarra, Victor and Maksimova, Elena and Nakamoto, Jose Alberto and Kasatsky, Pavel and Paleskava, Alena and Konevega, Andrey L. and Milón, Pohl},\n journal = {PLoS biology},\n title = {How the initiating ribosome copes with ppGpp to translate mRNAs.},\n year = {2020},\n issn = {1545-7885},\n month = jan,\n pages = {e3000593},\n volume = {18},\n abstract = {During host colonization, bacteria use the alarmones (p)ppGpp to reshape their proteome by acting pleiotropically on DNA, RNA, and protein synthesis. Here, we elucidate how the initiating ribosome senses the cellular pool of guanosine nucleotides and regulates the progression towards protein synthesis. Our results show that the affinity of guanosine triphosphate (GTP) and the inhibitory concentration of ppGpp for the 30S-bound initiation factor IF2 vary depending on the programmed mRNA. The TufA mRNA enhanced GTP affinity for 30S complexes, resulting in improved ppGpp tolerance and allowing efficient protein synthesis. Conversely, the InfA mRNA allowed ppGpp to compete with GTP for IF2, thus stalling 30S complexes. Structural modeling and biochemical analysis of the TufA mRNA unveiled a structured enhancer of translation initiation (SETI) composed of two consecutive hairpins proximal to the translation initiation region (TIR) that largely account for ppGpp tolerance under physiological concentrations of guanosine nucleotides. Furthermore, our results show that the mechanism enhancing ppGpp tolerance is not restricted to the TufA mRNA, as similar ppGpp tolerance was found for the SETI-containing Rnr mRNA. Finally, we show that IF2 can use pppGpp to promote the formation of 30S initiation complexes (ICs), albeit requiring higher factor concentration and resulting in slower transitions to translation elongation. Altogether, our data unveil a novel regulatory mechanism at the onset of protein synthesis that tolerates physiological concentrations of ppGpp and that bacteria can exploit to modulate their proteome as a function of the nutritional shift happening during stringent response and infection.},\n chemicals = {Escherichia coli Proteins, RNA, Messenger, Guanosine Tetraphosphate, Guanosine Triphosphate, Peptide Elongation Factor Tu, tufB protein, E coli},\n citation-subset = {IM},\n completed = {2020-04-24},\n country = {United States},\n doi = {10.1371/journal.pbio.3000593},\n issn-linking = {1544-9173},\n issue = {1},\n keywords = {Binding, Competitive; Escherichia coli, genetics, metabolism; Escherichia coli Proteins, metabolism; Guanosine Tetraphosphate, metabolism, pharmacology; Guanosine Triphosphate, metabolism, pharmacology; Host-Pathogen Interactions, physiology; Kinetics; Nucleic Acid Conformation; Peptide Chain Initiation, Translational, drug effects, physiology; Peptide Elongation Factor Tu, metabolism; Protein Biosynthesis, drug effects; RNA, Messenger, chemistry, drug effects, genetics, metabolism; Ribosomes, drug effects, metabolism},\n nlm-id = {101183755},\n owner = {NLM},\n pii = {e3000593},\n pmc = {PMC7010297},\n pmid = {31995552},\n pubmodel = {Electronic-eCollection},\n pubstate = {epublish},\n revised = {2020-04-24},\n}\n\n\n\n During host colonization, bacteria use the alarmones (p)ppGpp to reshape their proteome by acting pleiotropically on DNA, RNA, and protein synthesis. Here, we elucidate how the initiating ribosome senses the cellular pool of guanosine nucleotides and regulates the progression towards protein synthesis. Our results show that the affinity of guanosine triphosphate (GTP) and the inhibitory concentration of ppGpp for the 30S-bound initiation factor IF2 vary depending on the programmed mRNA. The TufA mRNA enhanced GTP affinity for 30S complexes, resulting in improved ppGpp tolerance and allowing efficient protein synthesis. Conversely, the InfA mRNA allowed ppGpp to compete with GTP for IF2, thus stalling 30S complexes. Structural modeling and biochemical analysis of the TufA mRNA unveiled a structured enhancer of translation initiation (SETI) composed of two consecutive hairpins proximal to the translation initiation region (TIR) that largely account for ppGpp tolerance under physiological concentrations of guanosine nucleotides. Furthermore, our results show that the mechanism enhancing ppGpp tolerance is not restricted to the TufA mRNA, as similar ppGpp tolerance was found for the SETI-containing Rnr mRNA. Finally, we show that IF2 can use pppGpp to promote the formation of 30S initiation complexes (ICs), albeit requiring higher factor concentration and resulting in slower transitions to translation elongation. Altogether, our data unveil a novel regulatory mechanism at the onset of protein synthesis that tolerates physiological concentrations of ppGpp and that bacteria can exploit to modulate their proteome as a function of the nutritional shift happening during stringent response and infection.\n
\n\n\n\n \n\n \n \n \n \n \n Dual Targeting of Cancer Cells with DARPin-Based Toxins for Overcoming Tumor Escape.\n \n \n \n\n\n \n Shramova, E.; Proshkina, G.; Shipunova, V.; Ryabova, A.; Kamyshinsky, R.; Konevega, A.; Schulga, A.; Konovalova, E.; Telegin, G.; and Deyev, S.\n\n\n \n\n\n\n Cancers, 12. October 2020.\n \n\n\n\n
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\n\n\n@Article{Shramova2020,\n author = {Shramova, Elena and Proshkina, Galina and Shipunova, Victoria and Ryabova, Anastasia and Kamyshinsky, Roman and Konevega, Andrey and Schulga, Aleksey and Konovalova, Elena and Telegin, Georgij and Deyev, Sergey},\n journal = {Cancers},\n title = {Dual Targeting of Cancer Cells with DARPin-Based Toxins for Overcoming Tumor Escape.},\n year = {2020},\n issn = {2072-6694},\n month = oct,\n volume = {12},\n abstract = {We report here a combined anti-cancer therapy directed toward HER2 and EpCAM, common tumor-associated antigens of breast cancer cells. The combined therapeutic effect is achieved owing to two highly toxic proteins-a low immunogenic variant of exotoxin A and ribonuclease Barnase from . The delivery of toxins to cancer cells was carried out by targeting designed ankyrin repeat proteins (DARPins). We have shown that both target agents efficiently accumulate in the tumor. Simultaneous treatment of breast carcinoma-bearing mice with anti-EpCAM fusion toxin based on LoPE and HER2-specific liposomes loaded with Barnase leads to concurrent elimination of primary tumor and metastases. Monotherapy with anti-HER2- or anti-EpCAM-toxins did not produce a comparable effect on metastases. The proposed approach can be considered as a promising strategy for significant improvement of cancer therapy.},\n country = {Switzerland},\n doi = {10.3390/cancers12103014},\n issn-linking = {2072-6694},\n issue = {10},\n keywords = {Barnase; EpCAM; HER2; cancer therapy; liposomes},\n nlm-id = {101526829},\n owner = {NLM},\n pii = {3014},\n pmc = {PMC7602955},\n pmid = {33081407},\n pubmodel = {Electronic},\n pubstate = {epublish},\n revised = {2020-11-03},\n}\n\n\n\n We report here a combined anti-cancer therapy directed toward HER2 and EpCAM, common tumor-associated antigens of breast cancer cells. The combined therapeutic effect is achieved owing to two highly toxic proteins-a low immunogenic variant of exotoxin A and ribonuclease Barnase from . The delivery of toxins to cancer cells was carried out by targeting designed ankyrin repeat proteins (DARPins). We have shown that both target agents efficiently accumulate in the tumor. Simultaneous treatment of breast carcinoma-bearing mice with anti-EpCAM fusion toxin based on LoPE and HER2-specific liposomes loaded with Barnase leads to concurrent elimination of primary tumor and metastases. Monotherapy with anti-HER2- or anti-EpCAM-toxins did not produce a comparable effect on metastases. The proposed approach can be considered as a promising strategy for significant improvement of cancer therapy.\n
\n\n\n\n \n\n \n \n \n \n \n Evaluation of immune and chemical precipitation methods for plasma exosome isolation.\n \n \n \n\n\n \n Shtam, T.; Evtushenko, V.; Samsonov, R.; Zabrodskaya, Y.; Kamyshinsky, R.; Zabegina, L.; Verlov, N.; Burdakov, V.; Garaeva, L.; Slyusarenko, M.; Nikiforova, N.; Konevega, A.; and Malek, A.\n\n\n \n\n\n\n PloS one, 15: e0242732. 2020.\n \n\n\n\n
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\n\n\n@Article{Shtam2020,\n author = {Shtam, Tatiana and Evtushenko, Vladimir and Samsonov, Roman and Zabrodskaya, Yana and Kamyshinsky, Roman and Zabegina, Lidia and Verlov, Nikolay and Burdakov, Vladimir and Garaeva, Luiza and Slyusarenko, Maria and Nikiforova, Nadezhda and Konevega, Andrey and Malek, Anastasia},\n journal = {PloS one},\n title = {Evaluation of immune and chemical precipitation methods for plasma exosome isolation.},\n year = {2020},\n issn = {1932-6203},\n pages = {e0242732},\n volume = {15},\n abstract = {Exosomes are a type of extracellular vesicles (EVs) secreted by multiple mammalian cell types and involved in intercellular communication. Numerous studies have explored the diagnostic and therapeutic potential of exosomes. The key challenge is the lack of efficient and standard techniques for isolation and downstream analysis of nanovesicles. Conventional isolation methods, such as ultracentrifugation, precipitation, filtration, chromatography, and immune-affinity-based approaches, rely on specific physical properties or on surface biomarkers. However, any of the existing methods has its limitations. Various parameters, such as efficacy, specificity, labor input, cost and scalability, and standardization options, must be considered for the correct choice of appropriate approach. The isolation of exosomes from biological fluids is especially challenged by the complex nature and variability of these liquids. Here, we present a comparison of five protocols for exosome isolation from human plasma: two chemical affinity precipitation methods (lectin-based purification and SubX™ technology), immunoaffinity precipitation, and reference ultracentrifugation-based exosome isolation method in two modifications. An approach for the isolation of exosomes based on the phenomenon of binding and aggregation of these particles via clusters of outer membrane phosphate groups in the presence of SubX™ molecules has been put forward in the present study. The isolated EVs were characterized based upon size, quantity, and protein content.},\n chemicals = {Lectins},\n citation-subset = {IM},\n completed = {2021-01-04},\n country = {United States},\n doi = {10.1371/journal.pone.0242732},\n issn-linking = {1932-6203},\n issue = {11},\n keywords = {Cell-Derived Microparticles, chemistry; Exosomes, chemistry; Humans; Immunoprecipitation; Lectins, chemistry; Plasma, chemistry; Ultracentrifugation},\n nlm-id = {101285081},\n owner = {NLM},\n pii = {e0242732},\n pmc = {PMC7685508},\n pmid = {33232386},\n pubmodel = {Electronic-eCollection},\n pubstate = {epublish},\n revised = {2021-01-04},\n}\n\n\n\n Exosomes are a type of extracellular vesicles (EVs) secreted by multiple mammalian cell types and involved in intercellular communication. Numerous studies have explored the diagnostic and therapeutic potential of exosomes. The key challenge is the lack of efficient and standard techniques for isolation and downstream analysis of nanovesicles. Conventional isolation methods, such as ultracentrifugation, precipitation, filtration, chromatography, and immune-affinity-based approaches, rely on specific physical properties or on surface biomarkers. However, any of the existing methods has its limitations. Various parameters, such as efficacy, specificity, labor input, cost and scalability, and standardization options, must be considered for the correct choice of appropriate approach. The isolation of exosomes from biological fluids is especially challenged by the complex nature and variability of these liquids. Here, we present a comparison of five protocols for exosome isolation from human plasma: two chemical affinity precipitation methods (lectin-based purification and SubX™ technology), immunoaffinity precipitation, and reference ultracentrifugation-based exosome isolation method in two modifications. An approach for the isolation of exosomes based on the phenomenon of binding and aggregation of these particles via clusters of outer membrane phosphate groups in the presence of SubX™ molecules has been put forward in the present study. The isolated EVs were characterized based upon size, quantity, and protein content.\n
\n\n\n\n \n\n \n \n \n \n \n Erratum for Khabibullina et al., \"Structure of Dirithromycin Bound to the Bacterial Ribosome Suggests New Ways for Rational Improvement of Macrolides\".\n \n \n \n\n\n \n Khabibullina, N. F.; Tereshchenkov, A. G.; Komarova, E. S.; Syroegin, E. A.; Shiriaev, D. I.; Paleskava, A.; Kartsev, V. G.; Bogdanov, A. A.; Konevega, A. L.; Dontsova, O. A.; Sergiev, P. V.; Osterman, I. A.; and Polikanov, Y. S.\n\n\n \n\n\n\n Antimicrobial agents and chemotherapy, 64. January 2020.\n \n\n\n\n
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\n\n\n\n@Article{Khabibullina2020,\n author = {Khabibullina, Nelli F. and Tereshchenkov, Andrey G. and Komarova, Ekaterina S. and Syroegin, Egor A. and Shiriaev, Dmitrii I. and Paleskava, Alena and Kartsev, Victor G. and Bogdanov, Alexey A. and Konevega, Andrey L. and Dontsova, Olga A. and Sergiev, Petr V. and Osterman, Ilya A. and Polikanov, Yury S.},\n journal = {Antimicrobial agents and chemotherapy},\n title = {Erratum for Khabibullina et al., "Structure of Dirithromycin Bound to the Bacterial Ribosome Suggests New Ways for Rational Improvement of Macrolides".},\n year = {2020},\n issn = {1098-6596},\n month = jan,\n volume = {64},\n citation-subset = {IM},\n country = {United States},\n doi = {10.1128/AAC.02360-19},\n issn-linking = {0066-4804},\n issue = {2},\n nlm-id = {0315061},\n owner = {NLM},\n pii = {e02360-19},\n pmc = {PMC6985756},\n pmid = {31988110},\n pubmodel = {Electronic-Print},\n pubstate = {epublish},\n revised = {2020-02-12},\n}\n\n\n\n \n\n \n \n \n \n \n Insights into the improved macrolide inhibitory activity from the high-resolution cryo-EM structure of dirithromycin bound to the , jakarta.xml.bind.JAXBElement@7eb1c84c, 70S ribosome.\n \n \n \n\n\n \n Pichkur, E. B.; Paleskava, A.; Tereshchenkov, A. G.; Kasatsky, P.; Komarova, E. S.; Shiriaev, D. I.; Bogdanov, A. A.; Dontsova, O. A.; Osterman, I. A.; Sergiev, P. V.; Polikanov, Y. S.; Myasnikov, A. G.; and Konevega, A. L.\n\n\n \n\n\n\n RNA (New York, N.Y.), 26: 715–723. June 2020.\n \n\n\n\n
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\n\n\n@Article{Pichkur2020,\n author = {Pichkur, Evgeny B. and Paleskava, Alena and Tereshchenkov, Andrey G. and Kasatsky, Pavel and Komarova, Ekaterina S. and Shiriaev, Dmitrii I. and Bogdanov, Alexey A. and Dontsova, Olga A. and Osterman, Ilya A. and Sergiev, Petr V. and Polikanov, Yury S. and Myasnikov, Alexander G. and Konevega, Andrey L.},\n journal = {RNA (New York, N.Y.)},\n title = {Insights into the improved macrolide inhibitory activity from the high-resolution cryo-EM structure of dirithromycin bound to the , jakarta.xml.bind.JAXBElement@7eb1c84c, 70S ribosome.},\n year = {2020},\n issn = {1469-9001},\n month = jun,\n pages = {715--723},\n volume = {26},\n abstract = {Macrolides are one of the most successful and widely used classes of antibacterials, which kill or stop the growth of pathogenic bacteria by binding near the active site of the ribosome and interfering with protein synthesis. Dirithromycin is a derivative of the prototype macrolide erythromycin with additional hydrophobic side chain. In our recent study, we have discovered that the side chain of dirithromycin forms lone pair-π stacking interaction with the aromatic imidazole ring of the His69 residue in ribosomal protein uL4 of the 70S ribosome. In the current work, we found that neither the presence of the side chain, nor the additional contact with the ribosome, improve the binding affinity of dirithromycin to the ribosome. Nevertheless, we found that dirithromycin is a more potent inhibitor of in vitro protein synthesis in comparison with its parent compound, erythromycin. Using high-resolution cryo-electron microscopy, we determined the structure of the dirithromycin bound to the translating 70S ribosome, which suggests that the better inhibitory properties of the drug could be rationalized by the side chain of dirithromycin pointing into the lumen of the nascent peptide exit tunnel, where it can interfere with the normal passage of the growing polypeptide chain.},\n chemicals = {Anti-Bacterial Agents, Protein Synthesis Inhibitors, RNA, Ribosomal, 23S, dirithromycin, Erythromycin},\n citation-subset = {IM},\n completed = {2020-06-15},\n country = {United States},\n doi = {10.1261/rna.073817.119},\n issn-linking = {1355-8382},\n issue = {6},\n keywords = {Anti-Bacterial Agents, chemistry, pharmacology; Cryoelectron Microscopy; Erythromycin, analogs & derivatives, chemistry, pharmacology; Escherichia coli, genetics; Models, Molecular; Protein Biosynthesis, drug effects; Protein Synthesis Inhibitors, chemistry, pharmacology; RNA, Ribosomal, 23S, chemistry; Ribosomes, chemistry; 70S ribosome; antibiotic; cryo-EM; dirithromycin; inhibitor; macrolide; nascent peptide exit tunnel},\n medline = {9509184},\n nlm-id = {9509184},\n owner = {NLM},\n pii = {rna.073817.119},\n pmc = {PMC7266154},\n pmid = {32144191},\n pubmodel = {Print-Electronic},\n pubstate = {ppublish},\n revised = {2021-06-02},\n}\n\n\n\n Macrolides are one of the most successful and widely used classes of antibacterials, which kill or stop the growth of pathogenic bacteria by binding near the active site of the ribosome and interfering with protein synthesis. Dirithromycin is a derivative of the prototype macrolide erythromycin with additional hydrophobic side chain. In our recent study, we have discovered that the side chain of dirithromycin forms lone pair-π stacking interaction with the aromatic imidazole ring of the His69 residue in ribosomal protein uL4 of the 70S ribosome. In the current work, we found that neither the presence of the side chain, nor the additional contact with the ribosome, improve the binding affinity of dirithromycin to the ribosome. Nevertheless, we found that dirithromycin is a more potent inhibitor of in vitro protein synthesis in comparison with its parent compound, erythromycin. Using high-resolution cryo-electron microscopy, we determined the structure of the dirithromycin bound to the translating 70S ribosome, which suggests that the better inhibitory properties of the drug could be rationalized by the side chain of dirithromycin pointing into the lumen of the nascent peptide exit tunnel, where it can interfere with the normal passage of the growing polypeptide chain.\n
\n\n\n\n \n\n \n \n \n \n \n Proteome of Glioblastoma-Derived Exosomes as a Source of Biomarkers.\n \n \n \n\n\n \n Naryzhny, S.; Volnitskiy, A.; Kopylov, A.; Zorina, E.; Kamyshinsky, R.; Bairamukov, V.; Garaeva, L.; Shlikht, A.; and Shtam, T.\n\n\n \n\n\n\n Biomedicines, 8. July 2020.\n \n\n\n\n
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\n\n\n@Article{Naryzhny2020,\n author = {Naryzhny, Stanislav and Volnitskiy, Andrey and Kopylov, Arthur and Zorina, Elena and Kamyshinsky, Roman and Bairamukov, Viktor and Garaeva, Luiza and Shlikht, Anatoly and Shtam, Tatiana},\n journal = {Biomedicines},\n title = {Proteome of Glioblastoma-Derived Exosomes as a Source of Biomarkers.},\n year = {2020},\n issn = {2227-9059},\n month = jul,\n volume = {8},\n abstract = {Extracellular vesicles (EV) are involved in important processes of glioblastoma multiforme (GBM), including malignancy and invasion. EV secreted by glioblastoma cells may cross the hematoencephalic barrier and carry molecular cargo derived from the tumor into the peripheral circulation. Therefore, the determination of the molecular composition of exosomes released by glioblastoma cells seems to be a promising approach for the development of non-invasive methods of the detection of the specific exosomal protein markers in the peripheral blood. The present study aimed to determine the common exosomal proteins presented in preparations from different cell lines and search potential glioblastoma biomarkers in exosomes. We have performed proteomics analysis of exosomes obtained from the conditioned culture medium of five glioblastoma cell lines. A list of 133 proteins common for all these samples was generated. Based on the data obtained, virtual two-dimensional electrophoresis (2DE) maps of proteins presented in exosomes of glioblastoma cells were constructed and the gene ontology (GO) analysis of exosome proteins was performed. A correlation between overexpressed in glial cell proteins and their presence in exosomes have been found. Thus, the existence of many potential glioblastoma biomarkers in exosomes was confirmed.},\n country = {Switzerland},\n doi = {10.3390/biomedicines8070216},\n issn-linking = {2227-9059},\n issue = {7},\n keywords = {biomarkers; exosomes; glioblastoma; protein expression; proteomics},\n nlm-id = {101691304},\n owner = {NLM},\n pii = {216},\n pmc = {PMC7399833},\n pmid = {32708613},\n pubmodel = {Electronic},\n pubstate = {epublish},\n revised = {2020-09-28},\n}\n\n\n\n Extracellular vesicles (EV) are involved in important processes of glioblastoma multiforme (GBM), including malignancy and invasion. EV secreted by glioblastoma cells may cross the hematoencephalic barrier and carry molecular cargo derived from the tumor into the peripheral circulation. Therefore, the determination of the molecular composition of exosomes released by glioblastoma cells seems to be a promising approach for the development of non-invasive methods of the detection of the specific exosomal protein markers in the peripheral blood. The present study aimed to determine the common exosomal proteins presented in preparations from different cell lines and search potential glioblastoma biomarkers in exosomes. We have performed proteomics analysis of exosomes obtained from the conditioned culture medium of five glioblastoma cell lines. A list of 133 proteins common for all these samples was generated. Based on the data obtained, virtual two-dimensional electrophoresis (2DE) maps of proteins presented in exosomes of glioblastoma cells were constructed and the gene ontology (GO) analysis of exosome proteins was performed. A correlation between overexpressed in glial cell proteins and their presence in exosomes have been found. Thus, the existence of many potential glioblastoma biomarkers in exosomes was confirmed.\n
\n\n\n\n \n\n \n \n \n \n \n Biomechanical Properties of Blood Plasma Extracellular Vesicles Revealed by Atomic Force Microscopy.\n \n \n \n\n\n \n Bairamukov, V.; Bukatin, A.; Landa, S.; Burdakov, V.; Shtam, T.; Chelnokova, I.; Fedorova, N.; Filatov, M.; and Starodubtseva, M.\n\n\n \n\n\n\n Biology, 10. December 2020.\n \n\n\n\n
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\n\n\n@Article{Bairamukov2020,\n author = {Bairamukov, Viktor and Bukatin, Anton and Landa, Sergey and Burdakov, Vladimir and Shtam, Tatiana and Chelnokova, Irina and Fedorova, Natalia and Filatov, Michael and Starodubtseva, Maria},\n journal = {Biology},\n title = {Biomechanical Properties of Blood Plasma Extracellular Vesicles Revealed by Atomic Force Microscopy.},\n year = {2020},\n issn = {2079-7737},\n month = dec,\n volume = {10},\n abstract = {While extracellular vesicles (EVs) are extensively studied by various practical applications in biomedicine, there is still little information on their biomechanical properties due to their nanoscale size. We identified isolated blood plasma vesicles that carried on biomarkers associated with exosomes and exomeres and applied atomic force microscopy (AFM) to study them at single particle level in air and in liquid. Air measurements of exosomes revealed a mechanically indented internal cavity in which highly adhesive sites were located. In contrast, the highly adhesive sites of exomeres were located at the periphery and the observed diameter of the particles was ~35 nm. In liquid, the reversible deformation of the internal cavity of exosomes was observed and a slightly deformed lipid bi-layer was identified. In contrast, exomeres were not deformed and their observed diameter was ~16 nm. The difference in diameters might be associated with a higher sorption of water film in air. The parameters we revealed correlated with the well-known structure and function for exosomes and were observed for exomeres for the first time. Our data provide a new insight into the biomechanical properties of nanoparticles and positioned AFM as an exclusive source of in situ information about their biophysical characteristics.},\n country = {Switzerland},\n doi = {10.3390/biology10010004},\n issn-linking = {2079-7737},\n issue = {1},\n keywords = {atomic-force microscopy; exomeres; exosomes; extracellular vesicles; quantitative nanomechanical mapping},\n nlm-id = {101587988},\n owner = {NLM},\n pii = {4},\n pmc = {PMC7822188},\n pmid = {33374530},\n pubmodel = {Electronic},\n pubstate = {epublish},\n revised = {2021-02-18},\n}\n\n\n\n While extracellular vesicles (EVs) are extensively studied by various practical applications in biomedicine, there is still little information on their biomechanical properties due to their nanoscale size. We identified isolated blood plasma vesicles that carried on biomarkers associated with exosomes and exomeres and applied atomic force microscopy (AFM) to study them at single particle level in air and in liquid. Air measurements of exosomes revealed a mechanically indented internal cavity in which highly adhesive sites were located. In contrast, the highly adhesive sites of exomeres were located at the periphery and the observed diameter of the particles was 35 nm. In liquid, the reversible deformation of the internal cavity of exosomes was observed and a slightly deformed lipid bi-layer was identified. In contrast, exomeres were not deformed and their observed diameter was 16 nm. The difference in diameters might be associated with a higher sorption of water film in air. The parameters we revealed correlated with the well-known structure and function for exosomes and were observed for exomeres for the first time. Our data provide a new insight into the biomechanical properties of nanoparticles and positioned AFM as an exclusive source of in situ information about their biophysical characteristics.\n
\n\n\n\n \n\n \n \n \n \n \n Total Blood Exosomes in Breast Cancer: Potential Role in Crucial Steps of Tumorigenesis.\n \n \n \n\n\n \n Konoshenko, M.; Sagaradze, G.; Orlova, E.; Shtam, T.; Proskura, K.; Kamyshinsky, R.; Yunusova, N.; Alexandrova, A.; Efimenko, A.; and Tamkovich, S.\n\n\n \n\n\n\n International journal of molecular sciences, 21. October 2020.\n \n\n\n\n
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\n\n\n@Article{Konoshenko2020,\n author = {Konoshenko, Maria and Sagaradze, Georgy and Orlova, Evgeniya and Shtam, Tatiana and Proskura, Ksenia and Kamyshinsky, Roman and Yunusova, Natalia and Alexandrova, Antonina and Efimenko, Anastasia and Tamkovich, Svetlana},\n journal = {International journal of molecular sciences},\n title = {Total Blood Exosomes in Breast Cancer: Potential Role in Crucial Steps of Tumorigenesis.},\n year = {2020},\n issn = {1422-0067},\n month = oct,\n volume = {21},\n abstract = {Exosomes are crucial players in cell-to-cell communication and are involved in tumorigenesis. There are two fractions of blood circulating exosomes: free and cell-surface-associated. Here, we compared the effect of total blood exosomes (contain plasma exosomes and blood cell-surface-associated exosomes) and plasma exosomes from breast cancer patients (BCPs, = 43) and healthy females (HFs, = 35) on crucial steps of tumor progression. Exosomes were isolated by ultrafiltration, followed by ultracentrifugation, and characterized by cryo-electron microscopy (cryo-EM), nanoparticle tracking analysis, and flow cytometry. Cryo-EM revealed a wider spectrum of exosome morphology with lipid bilayers and vesicular internal structures in the HF total blood in comparison with plasma. No differences in the morphology of both exosomes fractions were detected in BCP blood. The plasma exosomes and total blood exosomes of BCPs had different expression levels of tumor-associated miR-92a and miR-25-3p, induced angiogenesis and epithelial-to-mesenchymal transition (EMT), and increased the number of migrating pseudo-normal breast cells and the total migration path length of cancer cells. The multidirectional effects of HF total blood exosomes on tumor dissemination were revealed; they suppress the angiogenesis and total migration path length of MCF10A, but stimulate EMT and increase the number of migrating MCF10A and the total path length of SKBR3 cells. In addition, HF plasma exosomes enhance the metastasis-promoting properties of SKBR3 cells and stimulate angiogenesis. Both cell-free and blood cell-surface-associated exosomes are involved in the crucial stages of carcinogenesis: the initiation of EMT and the stimulation of proliferation, cell migration, and angiogenesis. Thus, for the estimation of the diagnostic/prognostic significance of circulating exosomes in the blood of cancer patients more correctly, the total blood exosomes, which consist of plasma exosomes and blood cell-surface-associated exosomes should be used.},\n chemicals = {Biomarkers, Tumor, MicroRNAs},\n citation-subset = {IM},\n completed = {2021-02-24},\n country = {Switzerland},\n doi = {10.3390/ijms21197341},\n issn-linking = {1422-0067},\n issue = {19},\n keywords = {Adult; Aged; Biomarkers, Tumor, blood, genetics; Breast, metabolism, pathology; Breast Neoplasms, blood, genetics, pathology; Carcinogenesis, genetics; Cell Movement, genetics; Cell Proliferation, genetics; Cryoelectron Microscopy; Epithelial-Mesenchymal Transition, genetics; Exosomes, genetics, pathology; Female; Gene Expression Regulation, Neoplastic, genetics; Humans; MicroRNAs, genetics; Middle Aged; Prognosis; angiogenesis; breast cancer; cryo-electron microscopy; exosomes; microRNAs; migration},\n nlm-id = {101092791},\n owner = {NLM},\n pii = {7341},\n pmc = {PMC7582945},\n pmid = {33027894},\n pubmodel = {Electronic},\n pubstate = {epublish},\n revised = {2021-02-24},\n}\n\n\n\n Exosomes are crucial players in cell-to-cell communication and are involved in tumorigenesis. There are two fractions of blood circulating exosomes: free and cell-surface-associated. Here, we compared the effect of total blood exosomes (contain plasma exosomes and blood cell-surface-associated exosomes) and plasma exosomes from breast cancer patients (BCPs, = 43) and healthy females (HFs, = 35) on crucial steps of tumor progression. Exosomes were isolated by ultrafiltration, followed by ultracentrifugation, and characterized by cryo-electron microscopy (cryo-EM), nanoparticle tracking analysis, and flow cytometry. Cryo-EM revealed a wider spectrum of exosome morphology with lipid bilayers and vesicular internal structures in the HF total blood in comparison with plasma. No differences in the morphology of both exosomes fractions were detected in BCP blood. The plasma exosomes and total blood exosomes of BCPs had different expression levels of tumor-associated miR-92a and miR-25-3p, induced angiogenesis and epithelial-to-mesenchymal transition (EMT), and increased the number of migrating pseudo-normal breast cells and the total migration path length of cancer cells. The multidirectional effects of HF total blood exosomes on tumor dissemination were revealed; they suppress the angiogenesis and total migration path length of MCF10A, but stimulate EMT and increase the number of migrating MCF10A and the total path length of SKBR3 cells. In addition, HF plasma exosomes enhance the metastasis-promoting properties of SKBR3 cells and stimulate angiogenesis. Both cell-free and blood cell-surface-associated exosomes are involved in the crucial stages of carcinogenesis: the initiation of EMT and the stimulation of proliferation, cell migration, and angiogenesis. Thus, for the estimation of the diagnostic/prognostic significance of circulating exosomes in the blood of cancer patients more correctly, the total blood exosomes, which consist of plasma exosomes and blood cell-surface-associated exosomes should be used.\n
\n\n\n\n \n\n \n \n \n \n \n Particularities of dirithromycin interaction with the ribosome.\n \n \n \n\n\n \n Konevega, A.\n\n\n \n\n\n\n May 2020.\n \n\n\n\n
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\n\n\n\n@Misc{Konevega2020,\n author = {Andrey Konevega},\n month = may,\n title = {Particularities of dirithromycin interaction with the ribosome.},\n year = {2020},\n doi = {10.26226/morressier.5ebd45acffea6f735881b109},\n publisher = {Morressier},\n}\n\n\n\n \n\n \n \n \n \n \n The new mechanism of the dynamic regulation of the initiating ribosome during stringent response.\n \n \n \n\n\n \n Konevega, A.\n\n\n \n\n\n\n May 2020.\n \n\n\n\n
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\n\n\n\n@Misc{Konevega2020a,\n author = {Andrey Konevega},\n month = may,\n title = {The new mechanism of the dynamic regulation of the initiating ribosome during stringent response.},\n year = {2020},\n doi = {10.26226/morressier.5ebd45acffea6f735881b140},\n publisher = {Morressier},\n}\n\n\n\n \n\n \n \n \n \n \n E. coli 70S ribosome in complex with dirithromycin, and deacylated tRNA(iMet) (focused classification).\n \n \n \n\n\n \n Pichkur, E. B.; Polikanov, Y. S.; Myasnikov, A. G.; and Konevega, A. L.\n\n\n \n\n\n\n November 2020.\n \n\n\n\n
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\n\n\n\n@Misc{Pichkur2020a,\n author = {E. B. Pichkur and Y. S. Polikanov and A. G. Myasnikov and A. L. Konevega},\n month = nov,\n title = {E. coli 70S ribosome in complex with dirithromycin, and deacylated tRNA(iMet) (focused classification).},\n year = {2020},\n doi = {10.2210/pdb6xza/pdb},\n publisher = {Worldwide Protein Data Bank},\n}\n\n\n\n \n\n \n \n \n \n \n E. coli 50S ribosomal subunit in complex with dirithromycin, fMet-Phe-tRNA(Phe) and deacylated tRNA(iMet).\n \n \n \n\n\n \n Pichkur, E. B.; Polikanov, Y. S.; Myasnikov, A. G.; and Konevega, A. L.\n\n\n \n\n\n\n July 2020.\n \n\n\n\n
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\n\n\n\n@Misc{Pichkur2020b,\n author = {E. B. Pichkur and Y. S. Polikanov and A. G. Myasnikov and A. L. Konevega},\n month = jul,\n title = {E. coli 50S ribosomal subunit in complex with dirithromycin, fMet-Phe-tRNA(Phe) and deacylated tRNA(iMet).},\n year = {2020},\n doi = {10.2210/pdb6xz7/pdb},\n publisher = {Worldwide Protein Data Bank},\n}\n\n\n\n \n\n \n \n \n \n \n E. coli 70S ribosome in complex with dirithromycin, fMet-Phe-tRNA(Phe) and deacylated tRNA(iMet) (focused classification).\n \n \n \n\n\n \n Pichkur, E. B.; Polikanov, Y. S.; Myasnikov, A. G.; and Konevega, A. L.\n\n\n \n\n\n\n November 2020.\n \n\n\n\n
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\n\n\n\n@Misc{Pichkur2020c,\n author = {E. B. Pichkur and Y. S. Polikanov and A. G. Myasnikov and A. L. Konevega},\n month = nov,\n title = {E. coli 70S ribosome in complex with dirithromycin, fMet-Phe-tRNA(Phe) and deacylated tRNA(iMet) (focused classification).},\n year = {2020},\n doi = {10.2210/pdb6xzb/pdb},\n publisher = {Worldwide Protein Data Bank},\n}\n\n\n\n \n\n \n \n \n \n \n Proteomic Profiling of Plasma and Total Blood Exosomes in Breast Cancer: A Potential Role in Tumor Progression, Diagnosis, and Prognosis.\n \n \n \n\n\n \n Tutanov, O.; Proskura, K.; Kamyshinsky, R.; Shtam, T.; Tsentalovich, Y.; and Tamkovich, S.\n\n\n \n\n\n\n Frontiers in Oncology, 10. October 2020.\n \n\n\n\n
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\n\n\n\n@Article{Tutanov2020,\n author = {Oleg Tutanov and Ksenia Proskura and Roman Kamyshinsky and Tatiana Shtam and Yuri Tsentalovich and Svetlana Tamkovich},\n journal = {Frontiers in Oncology},\n title = {Proteomic Profiling of Plasma and Total Blood Exosomes in Breast Cancer: A Potential Role in Tumor Progression, Diagnosis, and Prognosis},\n year = {2020},\n issn = {2234-943X},\n month = oct,\n volume = {10},\n doi = {10.3389/fonc.2020.580891},\n keywords = {Cancer Research, Oncology},\n publisher = {Frontiers Media SA},\n}\n\n\n\n \n\n \n \n \n \n \n RADIOSENSITIZING EFFECT OF BORON ENHANCES THE EFFECTIVENESS OF PROTON THERAPY IN VITRO.\n \n \n \n\n\n \n Lebedev, D.; Garaeva, L.; Burdakov, V.; Volnitskiy, A.; Razgildina, N.; Garina, A.; Amerkanov, D.; Pack, F.; Shabalin, K.; Ivanov, E.; Ezhov, V.; Konevega, A.; and Shtam, T.\n\n\n \n\n\n\n 2020.\n \n\n\n\n
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\n\n\n\n@Misc{Lebedev2020,\n author = {Dmitry Lebedev and Luiza Garaeva and Vladimir Burdakov and Andrey Volnitskiy and Natalya Razgildina and Alina Garina and Dmitry Amerkanov and Fedor Pack and Konstantin Shabalin and Evgeniy Ivanov and Victor Ezhov and Andrey Konevega and Tatiana Shtam},\n title = {RADIOSENSITIZING EFFECT OF BORON ENHANCES THE EFFECTIVENESS OF PROTON THERAPY IN VITRO},\n year = {2020},\n booktitle = {RAD Conference Proceedings},\n collection = {RADConf},\n doi = {10.21175/radproc.2020.12},\n journal = {RAD Conference Proceedings},\n publisher = {RAD Centre},\n series = {RADConf},\n}\n\n\n\n
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\n \n \n\n \n \n \n \n \n Structure of Dirithromycin Bound to the Bacterial Ribosome Suggests New Ways for Rational Improvement of Macrolides.\n \n \n \n\n\n \n Khabibullina, N. F.; Tereshchenkov, A. G.; Komarova, E. S.; Syroegin, E. A.; Shiriaev, D. I.; Paleskava, A.; Kartsev, V. G.; Bogdanov, A. A.; Konevega, A. L.; Dontsova, O. A.; Sergiev, P. V.; Osterman, I. A.; and Polikanov, Y. S.\n\n\n \n\n\n\n Antimicrobial agents and chemotherapy, 63. June 2019.\n \n\n\n\n
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\n\n\n@Article{Khabibullina2019,\n author = {Khabibullina, Nelli F. and Tereshchenkov, Andrey G. and Komarova, Ekaterina S. and Syroegin, Egor A. and Shiriaev, Dmitrii I. and Paleskava, Alena and Kartsev, Victor G. and Bogdanov, Alexey A. and Konevega, Andrey L. and Dontsova, Olga A. and Sergiev, Petr V. and Osterman, Ilya A. and Polikanov, Yury S.},\n journal = {Antimicrobial agents and chemotherapy},\n title = {Structure of Dirithromycin Bound to the Bacterial Ribosome Suggests New Ways for Rational Improvement of Macrolides.},\n year = {2019},\n issn = {1098-6596},\n month = jun,\n volume = {63},\n abstract = {Although macrolides are known as excellent antibacterials, their medical use has been significantly limited due to the spread of bacterial drug resistance. Therefore, it is necessary to develop new potent macrolides to combat the emergence of drug-resistant pathogens. One of the key steps in rational drug design is the identification of chemical groups that mediate binding of the drug to its target and their subsequent derivatization to strengthen drug-target interactions. In the case of macrolides, a few groups are known to be important for drug binding to the ribosome, such as desosamine. Search for new chemical moieties that improve the interactions of a macrolide with the 70S ribosome might be of crucial importance for the invention of new macrolides. For this purpose, here we studied a classic macrolide, dirithromycin, which has an extended (2-methoxyethoxy)-methyl side chain attached to the C-9/C-11 atoms of the macrolactone ring that can account for strong binding of dirithromycin to the 70S ribosome. By solving the crystal structure of the 70S ribosome in complex with dirithromycin, we found that its side chain interacts with the wall of the nascent peptide exit tunnel in an idiosyncratic fashion: its side chain forms a lone pair-π stacking interaction with the aromatic imidazole ring of the His69 residue in ribosomal protein uL4. To our knowledge, the ability of this side chain to form a contact in the macrolide binding pocket has not been reported previously and potentially can open new avenues for further exploration by medicinal chemists developing next-generation macrolide antibiotics active against resistant pathogens.},\n chemicals = {Amino Sugars, Anti-Bacterial Agents, Macrolides, Peptides, Protein Synthesis Inhibitors, Ribosomal Proteins, ribosomal protein L4, dirithromycin, desosamine, Erythromycin},\n citation-subset = {IM},\n completed = {2020-04-20},\n country = {United States},\n doi = {10.1128/AAC.02266-18},\n issn-linking = {0066-4804},\n issue = {6},\n keywords = {Amino Sugars, pharmacology; Anti-Bacterial Agents, pharmacology; Drug Resistance, Bacterial; Erythromycin, analogs & derivatives, pharmacology; Macrolides, pharmacology; Peptides, pharmacology; Protein Structure, Secondary; Protein Synthesis Inhibitors, pharmacology; Ribosomal Proteins, metabolism; Ribosomes, metabolism; X-ray structure; antibiotic; dirithromycin; inhibitor; macrolides; nascent peptide exit tunnel; ribosomal protein uL4},\n nlm-id = {0315061},\n owner = {NLM},\n pii = {e02266-18},\n pmc = {PMC6535518},\n pmid = {30936109},\n pubmodel = {Electronic-Print},\n pubstate = {epublish},\n revised = {2020-04-20},\n}\n\n\n\n Although macrolides are known as excellent antibacterials, their medical use has been significantly limited due to the spread of bacterial drug resistance. Therefore, it is necessary to develop new potent macrolides to combat the emergence of drug-resistant pathogens. One of the key steps in rational drug design is the identification of chemical groups that mediate binding of the drug to its target and their subsequent derivatization to strengthen drug-target interactions. In the case of macrolides, a few groups are known to be important for drug binding to the ribosome, such as desosamine. Search for new chemical moieties that improve the interactions of a macrolide with the 70S ribosome might be of crucial importance for the invention of new macrolides. For this purpose, here we studied a classic macrolide, dirithromycin, which has an extended (2-methoxyethoxy)-methyl side chain attached to the C-9/C-11 atoms of the macrolactone ring that can account for strong binding of dirithromycin to the 70S ribosome. By solving the crystal structure of the 70S ribosome in complex with dirithromycin, we found that its side chain interacts with the wall of the nascent peptide exit tunnel in an idiosyncratic fashion: its side chain forms a lone pair-π stacking interaction with the aromatic imidazole ring of the His69 residue in ribosomal protein uL4. To our knowledge, the ability of this side chain to form a contact in the macrolide binding pocket has not been reported previously and potentially can open new avenues for further exploration by medicinal chemists developing next-generation macrolide antibiotics active against resistant pathogens.\n
\n\n\n\n \n\n \n \n \n \n \n Abnormal activity of transcription factors gli in high-grade gliomas.\n \n \n \n\n\n \n Volnitskiy, A.; Shtam, T.; Burdakov, V.; Kovalev, R.; Konev, A.; and Filatov, M.\n\n\n \n\n\n\n PloS one, 14: e0211980. 2019.\n \n\n\n\n
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\n\n\n@Article{Volnitskiy2019,\n author = {Volnitskiy, Andrey and Shtam, Tatiana and Burdakov, Vladimir and Kovalev, Roman and Konev, Alexander and Filatov, Michael},\n journal = {PloS one},\n title = {Abnormal activity of transcription factors gli in high-grade gliomas.},\n year = {2019},\n issn = {1932-6203},\n pages = {e0211980},\n volume = {14},\n abstract = {Malignant transformation is associated with loss of cell differentiation, anaplasia. Transcription factors gli, required for embryonic development, may be involved in this process. We studied the activity of transcription factors gli in high-grade gliomas and their role in maintenance of stem cell state and glioma cell survival. 20 glioma cell lines and a sample of a normal adult brain tissue were used in the present study. We found the expression of gli target genes, including GLI1 and FOXM1, in all tested glioma cell lines, but not in the normal tissue. Interestingly, the expression of gli target genes in some glioma cell lines was observed together with a high level of their transcriptional repressor, Gli3R. Knockdown of GLI3 in one of these lines resulted in decrease of gli target gene expression. These data suggest that Gli3R does not prevent the gli target genes transcription, and gli3 acts in glioma cells more as an activator, than a repressor of transcription. We observed that gli regulated the expression of such genes, as SOX2 or OCT4 that maintain stem cell state, and TET1, involving in DNA demethylation. Treatment with GANT61 or siRNA against GLI1, GLI2, or GLI3 could result in complete glioma cell death, while cyclopamine had a weaker and line-specific effect on glioma cell survival. Thus, the gli transcription factors are abnormally active in high-grade gliomas, regulate expression of genes, maintaining the stem cell state, and contribute to glioma cell survival.},\n chemicals = {FOXM1 protein, human, Forkhead Box Protein M1, GANT 61, GLI1 protein, human, GLI2 protein, human, GLI3 protein, human, Nerve Tissue Proteins, Nuclear Proteins, Pyridines, Pyrimidines, Repressor Proteins, Zinc Finger Protein GLI1, Zinc Finger Protein Gli2, Zinc Finger Protein Gli3},\n citation-subset = {IM},\n completed = {2019-11-11},\n country = {United States},\n doi = {10.1371/journal.pone.0211980},\n issn-linking = {1932-6203},\n issue = {2},\n keywords = {Brain Neoplasms, genetics, metabolism; Cell Line, Tumor; Cell Survival, drug effects; Forkhead Box Protein M1, genetics; Gene Expression Regulation, Neoplastic, drug effects; Gene Knockdown Techniques; Glioma, genetics, metabolism; HeLa Cells; Humans; Neoplastic Stem Cells, drug effects, metabolism; Nerve Tissue Proteins, antagonists & inhibitors, genetics; Nuclear Proteins, antagonists & inhibitors, genetics; Pyridines, pharmacology; Pyrimidines, pharmacology; Repressor Proteins, antagonists & inhibitors, genetics; Zinc Finger Protein GLI1, antagonists & inhibitors, genetics; Zinc Finger Protein Gli2, antagonists & inhibitors, genetics; Zinc Finger Protein Gli3, antagonists & inhibitors, genetics},\n nlm-id = {101285081},\n owner = {NLM},\n pii = {e0211980},\n pmc = {PMC6366868},\n pmid = {30730955},\n pubmodel = {Electronic-eCollection},\n pubstate = {epublish},\n revised = {2020-03-09},\n}\n\n\n\n Malignant transformation is associated with loss of cell differentiation, anaplasia. Transcription factors gli, required for embryonic development, may be involved in this process. We studied the activity of transcription factors gli in high-grade gliomas and their role in maintenance of stem cell state and glioma cell survival. 20 glioma cell lines and a sample of a normal adult brain tissue were used in the present study. We found the expression of gli target genes, including GLI1 and FOXM1, in all tested glioma cell lines, but not in the normal tissue. Interestingly, the expression of gli target genes in some glioma cell lines was observed together with a high level of their transcriptional repressor, Gli3R. Knockdown of GLI3 in one of these lines resulted in decrease of gli target gene expression. These data suggest that Gli3R does not prevent the gli target genes transcription, and gli3 acts in glioma cells more as an activator, than a repressor of transcription. We observed that gli regulated the expression of such genes, as SOX2 or OCT4 that maintain stem cell state, and TET1, involving in DNA demethylation. Treatment with GANT61 or siRNA against GLI1, GLI2, or GLI3 could result in complete glioma cell death, while cyclopamine had a weaker and line-specific effect on glioma cell survival. Thus, the gli transcription factors are abnormally active in high-grade gliomas, regulate expression of genes, maintaining the stem cell state, and contribute to glioma cell survival.\n
\n\n\n\n \n\n \n \n \n \n \n Plasma exosomes stimulate breast cancer metastasis through surface interactions and activation of FAK signaling.\n \n \n \n\n\n \n Shtam, T.; Naryzhny, S.; Samsonov, R.; Karasik, D.; Mizgirev, I.; Kopylov, A.; Petrenko, E.; Zabrodskaya, Y.; Kamyshinsky, R.; Nikitin, D.; Sorokin, M.; Buzdin, A.; Gil-Henn, H.; and Malek, A.\n\n\n \n\n\n\n Breast cancer research and treatment, 174: 129–141. February 2019.\n \n\n\n\n
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\n\n\n@Article{Shtam2019,\n author = {Shtam, Tatiana and Naryzhny, Stanislav and Samsonov, Roman and Karasik, David and Mizgirev, Igor and Kopylov, Artur and Petrenko, Elena and Zabrodskaya, Yana and Kamyshinsky, Roman and Nikitin, Daniil and Sorokin, Maxim and Buzdin, Anton and Gil-Henn, Hava and Malek, Anastasia},\n journal = {Breast cancer research and treatment},\n title = {Plasma exosomes stimulate breast cancer metastasis through surface interactions and activation of FAK signaling.},\n year = {2019},\n issn = {1573-7217},\n month = feb,\n pages = {129--141},\n volume = {174},\n abstract = {The interaction between malignant cells and surrounding healthy tissues is a critical factor in the metastatic progression of breast cancer (BC). Extracellular vesicles, especially exosomes, are known to be involved in inter-cellular communication during cancer progression. In the study presented herein, we aimed to evaluate the role of circulating plasma exosomes in the metastatic dissemination of BC and to investigate the underlying molecular mechanisms of this phenomenon. Exosomes isolated from plasma of healthy female donors were applied in various concentrations into the medium of MDA-MB-231 and MCF-7 cell lines. Motility and invasive properties of BC cells were examined by random migration and Transwell invasion assays, and the effect of plasma exosomes on the metastatic dissemination of BC cells was demonstrated in an in vivo zebrafish model. To reveal the molecular mechanism of interaction between plasma exosomes and BC cells, a comparison between un-treated and enzymatically modified exosomes was performed, followed by mass spectrometry, gene ontology, and pathway analysis. Plasma exosomes stimulated the adhesive properties, two-dimensional random migration, and transwell invasion of BC cells in vitro as well as their in vivo metastatic dissemination in a dose-dependent manner. This stimulatory effect was mediated by interactions of surface exosome proteins with BC cells and consequent activation of focal adhesion kinase (FAK) signaling in the tumor cells. Plasma exosomes have a potency to stimulate the metastasis-promoting properties of BC cells. This pro-metastatic property of normal plasma exosomes may have impact on the course of the disease and on its prognosis.},\n chemicals = {Focal Adhesion Kinase 1, PTK2 protein, human},\n citation-subset = {IM},\n completed = {2019-07-08},\n country = {Netherlands},\n doi = {10.1007/s10549-018-5043-0},\n issn-linking = {0167-6806},\n issue = {1},\n keywords = {Animals; Breast Neoplasms, enzymology, pathology; Cell Movement, physiology; Exosomes, metabolism, pathology; Female; Focal Adhesion Kinase 1, metabolism; Heterografts; Humans; MCF-7 Cells; Neoplasm Invasiveness, pathology; Signal Transduction, physiology; Zebrafish; Breast cancer; Exosomes; FAK signaling; Mass spectrometry; Metastasis; Surface interaction},\n nlm-id = {8111104},\n owner = {NLM},\n pii = {10.1007/s10549-018-5043-0},\n pmid = {30484103},\n pubmodel = {Print-Electronic},\n pubstate = {ppublish},\n revised = {2019-07-08},\n}\n\n\n\n The interaction between malignant cells and surrounding healthy tissues is a critical factor in the metastatic progression of breast cancer (BC). Extracellular vesicles, especially exosomes, are known to be involved in inter-cellular communication during cancer progression. In the study presented herein, we aimed to evaluate the role of circulating plasma exosomes in the metastatic dissemination of BC and to investigate the underlying molecular mechanisms of this phenomenon. Exosomes isolated from plasma of healthy female donors were applied in various concentrations into the medium of MDA-MB-231 and MCF-7 cell lines. Motility and invasive properties of BC cells were examined by random migration and Transwell invasion assays, and the effect of plasma exosomes on the metastatic dissemination of BC cells was demonstrated in an in vivo zebrafish model. To reveal the molecular mechanism of interaction between plasma exosomes and BC cells, a comparison between un-treated and enzymatically modified exosomes was performed, followed by mass spectrometry, gene ontology, and pathway analysis. Plasma exosomes stimulated the adhesive properties, two-dimensional random migration, and transwell invasion of BC cells in vitro as well as their in vivo metastatic dissemination in a dose-dependent manner. This stimulatory effect was mediated by interactions of surface exosome proteins with BC cells and consequent activation of focal adhesion kinase (FAK) signaling in the tumor cells. Plasma exosomes have a potency to stimulate the metastasis-promoting properties of BC cells. This pro-metastatic property of normal plasma exosomes may have impact on the course of the disease and on its prognosis.\n
\n\n\n\n \n\n \n \n \n \n \n Effect of alpha-lactalbumin and lactoferrin oleic acid complexes on chromatin structural organization.\n \n \n \n\n\n \n Lebedev, D. V.; Zabrodskaya, Y. A.; Pipich, V.; Kuklin, A. I.; Ramsay, E.; Sokolov, A. V.; Elizarova, A. Y.; Shaldzhyan, A. A.; Grudinina, N. A.; Pantina, R. A.; Wu, B.; Shtam, T. A.; Volnitskiy, A. V.; Schmidt, A. E.; Shvetsov, A. V.; Vasilyev, V. B.; Isaev-Ivanov, V. V.; and Egorov, V. V.\n\n\n \n\n\n\n Biochemical and biophysical research communications, 520: 136–139. November 2019.\n \n\n\n\n
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\n\n\n@Article{Lebedev2019,\n author = {Lebedev, Dmitry V. and Zabrodskaya, Yana A. and Pipich, Vitaly and Kuklin, Alexander I. and Ramsay, Edward and Sokolov, Alexey V. and Elizarova, Anna Yu and Shaldzhyan, Aram A. and Grudinina, Natalia A. and Pantina, Rimma A. and Wu, Baohu and Shtam, Tatiana A. and Volnitskiy, Andrey V. and Schmidt, Alexander E. and Shvetsov, Alexey V. and Vasilyev, Vadim B. and Isaev-Ivanov, Vladimir V. and Egorov, Vladimir V.},\n journal = {Biochemical and biophysical research communications},\n title = {Effect of alpha-lactalbumin and lactoferrin oleic acid complexes on chromatin structural organization.},\n year = {2019},\n issn = {1090-2104},\n month = nov,\n pages = {136--139},\n volume = {520},\n abstract = {This work focuses on the study of multimeric alpha-lactalbumin oleic acid and lactoferrin oleic acid complexes. The purpose of the research is to study possible mechanisms involved in their pro-apoptotic activities, as seen in some tumor cell cultures. Complexes featuring oleic acid (OA) with human alpha-lactalbumin (hAl) or with bovine alpha-lactalbumin (bAl), and human lactoferrin (hLf) were investigated using small-angle neutron scattering (SANS). It was shown that while alpha-lactalbumin protein complexes were formed on the surface of polydisperse OA micelles, the lactoferrin complexes comprised a monodisperse system of nanoscale particles. Both hAl and hLf complexes appeared to interact with the chromatin of isolated nuclei affecting chromatin structural organization. The possible roles of these processes in the specific anti-tumor activity of these complexes are discussed.},\n chemicals = {Antineoplastic Agents, Chromatin, LTF protein, human, Micelles, Oleic Acids, Oleic Acid, Lactalbumin, Lactoferrin},\n citation-subset = {IM},\n completed = {2020-06-23},\n country = {United States},\n doi = {10.1016/j.bbrc.2019.09.116},\n issn-linking = {0006-291X},\n issue = {1},\n keywords = {Animals; Antineoplastic Agents, pharmacology; Apoptosis, drug effects; Cattle; Cell Nucleus, chemistry; Chromatin, chemistry; HeLa Cells; Humans; Lactalbumin, chemistry; Lactoferrin, chemistry; Micelles; Oleic Acid, chemistry; Oleic Acids, chemistry; Scattering, Small Angle; Antitumor agents; Chromatin structural organization; Lactalbumin; Lactoferrin; Oleic acid},\n nlm-id = {0372516},\n owner = {NLM},\n pii = {S0006-291X(19)31854-6},\n pmid = {31582209},\n pubmodel = {Print-Electronic},\n pubstate = {ppublish},\n revised = {2020-06-23},\n}\n\n\n\n This work focuses on the study of multimeric alpha-lactalbumin oleic acid and lactoferrin oleic acid complexes. The purpose of the research is to study possible mechanisms involved in their pro-apoptotic activities, as seen in some tumor cell cultures. Complexes featuring oleic acid (OA) with human alpha-lactalbumin (hAl) or with bovine alpha-lactalbumin (bAl), and human lactoferrin (hLf) were investigated using small-angle neutron scattering (SANS). It was shown that while alpha-lactalbumin protein complexes were formed on the surface of polydisperse OA micelles, the lactoferrin complexes comprised a monodisperse system of nanoscale particles. Both hAl and hLf complexes appeared to interact with the chromatin of isolated nuclei affecting chromatin structural organization. The possible roles of these processes in the specific anti-tumor activity of these complexes are discussed.\n
\n\n\n\n \n\n \n \n \n \n \n Granzyme B Functionalized Nanoparticles Targeting Membrane Hsp70-Positive Tumors for Multimodal Cancer Theranostics.\n \n \n \n\n\n \n Shevtsov, M.; Stangl, S.; Nikolaev, B.; Yakovleva, L.; Marchenko, Y.; Tagaeva, R.; Sievert, W.; Pitkin, E.; Mazur, A.; Tolstoy, P.; Galibin, O.; Ryzhov, V.; Steiger, K.; Smirnov, O.; Khachatryan, W.; Chester, K.; and Multhoff, G.\n\n\n \n\n\n\n Small (Weinheim an der Bergstrasse, Germany), 15: e1900205. March 2019.\n \n\n\n\n
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\n\n\n@Article{Shevtsov2019,\n author = {Shevtsov, Maxim and Stangl, Stefan and Nikolaev, Boris and Yakovleva, Ludmila and Marchenko, Yaroslav and Tagaeva, Ruslana and Sievert, Wolfgang and Pitkin, Emil and Mazur, Anton and Tolstoy, Peter and Galibin, Oleg and Ryzhov, Vyacheslav and Steiger, Katja and Smirnov, Oleg and Khachatryan, William and Chester, Kerry and Multhoff, Gabriele},\n journal = {Small (Weinheim an der Bergstrasse, Germany)},\n title = {Granzyme B Functionalized Nanoparticles Targeting Membrane Hsp70-Positive Tumors for Multimodal Cancer Theranostics.},\n year = {2019},\n issn = {1613-6829},\n month = mar,\n pages = {e1900205},\n volume = {15},\n abstract = {Functionalized superparamagnetic iron oxide nanoparticles (SPIONs) have emerged as potential clinical tools for cancer theranostics. Membrane-bound 70 kDa heat shock protein (mHsp70) is ubiquitously expressed on the cell membrane of various tumor types but not normal cells and therefore provides a tumor-specific target. The serine protease granzyme B (GrB) that is produced as an effector molecule by activated T and NK cells has been shown to specifically target mHsp70 on tumor cells. Following binding to Hsp70, GrB is rapidly internalized into tumor cells. Herein, it is demonstrated that GrB functionalized SPIONs act as a contrast enhancement agent for magnetic resonance imaging and induce specific tumor cell apoptosis. Combinatorial regimens employing stereotactic radiotherapy and/or magnetic targeting are found to further enhance the therapeutic efficacy of GrB-SPIONs in different tumor mouse models.},\n chemicals = {Antineoplastic Agents, Dextrans, HSP70 Heat-Shock Proteins, Magnetite Nanoparticles, Granzymes, ferumoxides},\n citation-subset = {IM},\n completed = {2020-08-21},\n country = {Germany},\n doi = {10.1002/smll.201900205},\n issn-linking = {1613-6810},\n issue = {13},\n keywords = {Animals; Antineoplastic Agents, pharmacology, therapeutic use; Apoptosis; Cell Line, Tumor; Cell Membrane, metabolism; Combined Modality Therapy; Dextrans, chemistry; Female; Granzymes, metabolism; HSP70 Heat-Shock Proteins, metabolism; Humans; Magnetic Resonance Imaging; Magnetite Nanoparticles, chemistry; Male; Mice, Inbred C57BL; Mice, SCID; Nanoparticles, chemistry; Neoplasms, diagnosis, diagnostic imaging, therapy; Rats, Wistar; Theranostic Nanomedicine; glioblastoma; granzyme B; magnetic targeting; radiotherapy; superparamagnetic nanoparticles},\n nlm-id = {101235338},\n owner = {NLM},\n pmid = {30828968},\n pubmodel = {Print-Electronic},\n pubstate = {ppublish},\n revised = {2020-08-21},\n}\n\n\n\n Functionalized superparamagnetic iron oxide nanoparticles (SPIONs) have emerged as potential clinical tools for cancer theranostics. Membrane-bound 70 kDa heat shock protein (mHsp70) is ubiquitously expressed on the cell membrane of various tumor types but not normal cells and therefore provides a tumor-specific target. The serine protease granzyme B (GrB) that is produced as an effector molecule by activated T and NK cells has been shown to specifically target mHsp70 on tumor cells. Following binding to Hsp70, GrB is rapidly internalized into tumor cells. Herein, it is demonstrated that GrB functionalized SPIONs act as a contrast enhancement agent for magnetic resonance imaging and induce specific tumor cell apoptosis. Combinatorial regimens employing stereotactic radiotherapy and/or magnetic targeting are found to further enhance the therapeutic efficacy of GrB-SPIONs in different tumor mouse models.\n
\n\n\n\n \n\n \n \n \n \n \n The complete, functional and dynamic cycle of the bacterial Initiation Factor 3.\n \n \n \n\n\n \n Nakamoto, J. A.; Spurio, R.; Konevega, A. L.; Fabbretti, A.; and Milón, P.\n\n\n \n\n\n\n March 2019.\n \n\n\n\n
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\n\n\n\n@Misc{Nakamoto2019,\n author = {Jose A. Nakamoto and Roberto Spurio and Andrey L. Konevega and Attilio Fabbretti and Pohl Milón},\n month = mar,\n title = {The complete, functional and dynamic cycle of the bacterial Initiation Factor 3},\n year = {2019},\n doi = {10.1101/579326},\n publisher = {Cold Spring Harbor Laboratory},\n}\n\n\n\n \n\n \n \n \n \n \n How the initiating ribosome copes with (p)ppGpp to translate mRNAs.\n \n \n \n\n\n \n Vinogradova, D. S.; Kasatsky, P.; Maksimova, E.; Zegarra, V.; Paleskava, A.; Konevega, A. L.; and Milón, P.\n\n\n \n\n\n\n February 2019.\n \n\n\n\n
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\n\n\n\n@Misc{Vinogradova2019,\n author = {Daria S. Vinogradova and Pavel Kasatsky and Elena Maksimova and Victor Zegarra and Alena Paleskava and Andrey L. Konevega and Pohl Milón},\n month = feb,\n title = {How the initiating ribosome copes with (p)ppGpp to translate mRNAs},\n year = {2019},\n doi = {10.1101/545970},\n publisher = {Cold Spring Harbor Laboratory},\n}\n\n\n\n \n\n \n \n \n \n \n \n Abstract OR-4: Molecular Mechanism of Antibiotics Inhibiting Prokaryotic Translation.\n \n \n \n \n\n\n \n Konevega, A.; Pichkur, E.; Paleskava, A.; Kasatsky, P.; Maksimova, E.; Vinogradova, D.; Polikanov, Y.; and Myasnikov, A.\n\n\n \n\n\n\n International Journal of Biomedicine, 9(Suppl_1): S7–S7. 6 2019.\n \n\n\n\n
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\n\n\n@Article{Konevega2019,\n author = {Andrey Konevega and Evgeny Pichkur and Alena Paleskava and Pavel Kasatsky and Elena Maksimova and Daria Vinogradova and Yury Polikanov and Alexander Myasnikov},\n journal = {International Journal of Biomedicine},\n title = {Abstract OR-4: Molecular Mechanism of Antibiotics Inhibiting Prokaryotic Translation},\n year = {2019},\n issn = {2158-0529},\n month = {6},\n number = {Suppl_1},\n pages = {S7--S7},\n volume = {9},\n abstract = {Background: About 50% of antibiotics used in the therapy of infectious diseases target bacterial 70S ribosomes. High resolution X-ray crystallographic studies allow us for determination of position of drug on the ribosome, but to elucidate the detailed molecular mechanism of inhibition it is necessary to study the dynamics of partial reactions of protein biosynthesis. Majority of high resolution structures were obtained on ribosomes from thermophilic bacteria T. thermophilus, whereas most of the functional studies were performed on reconstituted in vitro translation system from mesophilic organism E. coli. Despite of high homology among bacterial ribosomes, in many cases particular contacts observed are specific to thermophilic organism and is not allowing us to generalize the molecular mechanism of inhibition.\nMethods: Functional ribosomal pre-translocation complexes containing deacylated tRNAfMet in the P site and fMetPhe-tRNAPhe or fMetVal-tRNAVal in the A site were incubated with specific inhibitors: spectinomycin, amicoumacin, dirithromycin. Functional and structural studies were performed by using pre-steady state stopped-flow fluorescent spectroscopy and time-resolved cryo-electron microscopy. Kinetic studies of partial reactions of elongation were performed with thermophilic elongation factors and mesophilic reconstituted translation system.\nResults: Combination of structural data and pre-steady state kinetics reveals the details of molecular mechanism of inhibition of EF-G catalysed translocation and shows the intermediate conformations of ribosome-tRNA complexes during forward translocation. Heterologous translation system with substituted thermophilic elongation factors allows for differential studies of elongation cycle.\nConclusion: Time-resolved high resolution cryo-electron microscopy is a method of choice for structural characterization of active complexes in physiological conditions in the process of functioning. Reconstituted in vitro translation system from E. coli can be used both for structural and functional studies, allowing merging of two types of data for extensive characterization of bacterial protein synthesis apparatus.},\n doi = {10.21103/IJBM.9.Suppl_1.OR4},\n keywords = {ribosome, antibiotics, structure, cryo-EM},\n publisher = {International Medical Research and Development Corporation},\n url = {http://ijbm.org/articles/ijbm_2019_9_s1_or4.pdf},\n}\n\n\n\n Background: About 50% of antibiotics used in the therapy of infectious diseases target bacterial 70S ribosomes. High resolution X-ray crystallographic studies allow us for determination of position of drug on the ribosome, but to elucidate the detailed molecular mechanism of inhibition it is necessary to study the dynamics of partial reactions of protein biosynthesis. Majority of high resolution structures were obtained on ribosomes from thermophilic bacteria T. thermophilus, whereas most of the functional studies were performed on reconstituted in vitro translation system from mesophilic organism E. coli. Despite of high homology among bacterial ribosomes, in many cases particular contacts observed are specific to thermophilic organism and is not allowing us to generalize the molecular mechanism of inhibition. Methods: Functional ribosomal pre-translocation complexes containing deacylated tRNAfMet in the P site and fMetPhe-tRNAPhe or fMetVal-tRNAVal in the A site were incubated with specific inhibitors: spectinomycin, amicoumacin, dirithromycin. Functional and structural studies were performed by using pre-steady state stopped-flow fluorescent spectroscopy and time-resolved cryo-electron microscopy. Kinetic studies of partial reactions of elongation were performed with thermophilic elongation factors and mesophilic reconstituted translation system. Results: Combination of structural data and pre-steady state kinetics reveals the details of molecular mechanism of inhibition of EF-G catalysed translocation and shows the intermediate conformations of ribosome-tRNA complexes during forward translocation. Heterologous translation system with substituted thermophilic elongation factors allows for differential studies of elongation cycle. Conclusion: Time-resolved high resolution cryo-electron microscopy is a method of choice for structural characterization of active complexes in physiological conditions in the process of functioning. Reconstituted in vitro translation system from E. coli can be used both for structural and functional studies, allowing merging of two types of data for extensive characterization of bacterial protein synthesis apparatus.\n
\n\n\n\n \n\n \n \n \n \n \n \n Abstract P-15: Structural Insights of Dirithromycin Binding to the Bacterial Ribosome.\n \n \n \n \n\n\n \n Pichkur, E.; Kasatsky, P.; Paleskava, A.; Myasnikov, A.; Polikanov, Y.; Osterman, I. A.; and Konevega, A.\n\n\n \n\n\n\n International Journal of Biomedicine, 9(Suppl_1): S23–S23. 6 2019.\n \n\n\n\n
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\n\n\n@Article{Pichkur2019,\n author = {Evgeny Pichkur and Pavel Kasatsky and Alena Paleskava and Alexander Myasnikov and Yury Polikanov and Ilya A. Osterman and Andrey Konevega},\n journal = {International Journal of Biomedicine},\n title = {Abstract P-15: Structural Insights of Dirithromycin Binding to the Bacterial Ribosome},\n year = {2019},\n issn = {2158-0529},\n month = {6},\n number = {Suppl_1},\n pages = {S23--S23},\n volume = {9},\n abstract = {Background: Macrolide antibiotics bind in the nascent peptide exit tunnel (NPET) of the bacterial ribosome near the peptidyl transferase center. One of the second-generation macrolides, dirithromycin (DIR), differs from the parent erythromycin (ERY) by the presence of a hydrophobic (2-methoxyethoxy)-methyl side chain that has significantly increased the delivery of this antibiotic to tissues due to better lipophilicity. In this work, we present a cryo-EM structure of DIR bound to the functional complex of 70S ribosome from E. coli. \nMethods: Ribosomal complexes containing deacylated tRNAfMet in the P site and fMet-Phe-tRNAPhe in the A site were incubated with 30 mkM DIR for 10 min before application onto carbon coated grids (Quantifoil R 2/2) and freezing. Cryo-EM data was collected using cryo-TEM Titan Krios and processed using Warp, Relion 3.0 and CisTEM. Model building was performed in Phenix.real_space_refine and Coot.\nResults: Preliminary analysis failed to reveal any significant differences in location of macrolactone ring of DIR (current work) and ERY (pdb: 4v7u). In both structures only one hydrogen bond is formed between antibiotic and residue A2058. However, in comparison to the crystal structure of the ribosomal complex with ERY, our cryo-EM map demonstrates additional rotation of A2062 of 23S rRNA towards desosamine of DIR. \nConclusion: Structural peculiarities of DIR binding to the E. coli ribosome determined by high-resolution cryo-EM overall coincide with the mode of ERY interaction with the E. coli ribosome revealed by X-ray crystallography. Our results suggest a conformational lability of the (2-methoxyethoxy)-methyl side-chain of DIR, which is directed towards tunnel cavity and doesn’t form any additional contacts with its walls.},\n doi = {10.21103/IJBM.9.Suppl_1.P15},\n keywords = {ribosome, antibiotics, structure, cryo-EM},\n publisher = {International Medical Research and Development Corporation},\n url = {http://ijbm.org/articles/IJBM_2019_9_S1_P15.pdf},\n}\n\n\n\n Background: Macrolide antibiotics bind in the nascent peptide exit tunnel (NPET) of the bacterial ribosome near the peptidyl transferase center. One of the second-generation macrolides, dirithromycin (DIR), differs from the parent erythromycin (ERY) by the presence of a hydrophobic (2-methoxyethoxy)-methyl side chain that has significantly increased the delivery of this antibiotic to tissues due to better lipophilicity. In this work, we present a cryo-EM structure of DIR bound to the functional complex of 70S ribosome from E. coli. Methods: Ribosomal complexes containing deacylated tRNAfMet in the P site and fMet-Phe-tRNAPhe in the A site were incubated with 30 mkM DIR for 10 min before application onto carbon coated grids (Quantifoil R 2/2) and freezing. Cryo-EM data was collected using cryo-TEM Titan Krios and processed using Warp, Relion 3.0 and CisTEM. Model building was performed in Phenix.real_space_refine and Coot. Results: Preliminary analysis failed to reveal any significant differences in location of macrolactone ring of DIR (current work) and ERY (pdb: 4v7u). In both structures only one hydrogen bond is formed between antibiotic and residue A2058. However, in comparison to the crystal structure of the ribosomal complex with ERY, our cryo-EM map demonstrates additional rotation of A2062 of 23S rRNA towards desosamine of DIR. Conclusion: Structural peculiarities of DIR binding to the E. coli ribosome determined by high-resolution cryo-EM overall coincide with the mode of ERY interaction with the E. coli ribosome revealed by X-ray crystallography. Our results suggest a conformational lability of the (2-methoxyethoxy)-methyl side-chain of DIR, which is directed towards tunnel cavity and doesn’t form any additional contacts with its walls.\n
\n\n\n\n \n\n \n \n \n \n \n P11.42 Magnetic targeting of the granzyme B functionalized nanoparticles for therapy of glioblastoma.\n \n \n \n\n\n \n Shevtsov, M.; Stangl, S.; Marchenko, Y.; Yakovleva, L.; Ryzhov, V.; Nikolaev, B.; Galibin, O.; Pitkin, E.; and Multhoff, G.\n\n\n \n\n\n\n Neuro-Oncology, 21(Supplement_3): iii52-iii52. 2019.\n \n\n\n\n
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\n\n\n\n@Article{Shevtsov2019a,\n author = {M. Shevtsov and S. Stangl and Y. Marchenko and L. Yakovleva and V. Ryzhov and B. Nikolaev and O. Galibin and E. Pitkin and G. Multhoff},\n journal = {Neuro-Oncology},\n title = {P11.42 Magnetic targeting of the granzyme B functionalized nanoparticles for therapy of glioblastoma},\n year = {2019},\n issn = {1522-8517},\n number = {Supplement_3},\n pages = {iii52-iii52},\n volume = {21},\n doi = {10.1093/neuonc/noz126.188},\n keywords = {Cancer Research, Neurology (clinical), Oncology},\n publisher = {Oxford University Press (OUP)},\n}\n\n\n\n \n\n \n \n \n \n \n Comprehensive characterization of magnetite-based colloid for biomedical applications.\n \n \n \n\n\n \n Ryzhov, V. A.; Kiselev, I. A.; Smirnov, O. P.; Chernenkov, Y. P.; Deriglazov, V. V.; Marchenko, Y. Y.; Yakovleva, L. Y.; Nikolaev, B. P.; and Bogachev, Y. V.\n\n\n \n\n\n\n Applied Physics A, 125(5). 2019.\n \n\n\n\n
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\n\n\n\n@Article{Ryzhov2019,\n author = {V. A. Ryzhov and I. A. Kiselev and O. P. Smirnov and Yu. P. Chernenkov and V. V. Deriglazov and Ya. Yu. Marchenko and L. Y. Yakovleva and B. P. Nikolaev and Yu. V. Bogachev},\n journal = {Applied Physics A},\n title = {Comprehensive characterization of magnetite-based colloid for biomedical applications},\n year = {2019},\n issn = {0947-8396},\n number = {5},\n volume = {125},\n doi = {10.1007/s00339-019-2596-7},\n keywords = {General Materials Science, General Chemistry},\n publisher = {Springer Science and Business Media LLC},\n}\n\n\n\n \n\n \n \n \n \n \n Systematic search for structural motifs of peptide binding to double-stranded DNA.\n \n \n \n\n\n \n Kolchina, N.; Khavinson, V.; Linkova, N.; Yakimov, A.; Baitin, D.; Afanasyeva, A.; and Petukhov, M.\n\n\n \n\n\n\n Nucleic Acids Research, 47(20): 10553-10563. 2019.\n \n\n\n\n
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\n\n\n\n@Article{Kolchina2019,\n author = {Nina Kolchina and Vladimir Khavinson and Natalia Linkova and Alexander Yakimov and Dmitry Baitin and Arina Afanasyeva and Michael Petukhov},\n journal = {Nucleic Acids Research},\n title = {Systematic search for structural motifs of peptide binding to double-stranded DNA},\n year = {2019},\n issn = {0305-1048},\n number = {20},\n pages = {10553-10563},\n volume = {47},\n doi = {10.1093/nar/gkz850},\n keywords = {Genetics},\n publisher = {Oxford University Press (OUP)},\n}\n\n\n\n \n\n \n \n \n \n \n Abstract P-25: Cryo-Electron Microscopy of Extracellular Vesicles from Cerebrospinal Fluid.\n \n \n \n\n\n \n Shtam, T.; Emelyanov, A.; Kamyshinsky, R.; Garaeva, L.; Verlov, N.; Kudrevatykh, A.; Gavrilov, G.; and Pchelina, S.\n\n\n \n\n\n\n International Journal of Biomedicine, 9(Suppl_1): S27-S28. 2019.\n \n\n\n\n
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\n\n\n\n@Article{Shtam2019a,\n author = {Tatiana Shtam and Anton Emelyanov and Roman Kamyshinsky and Luiza Garaeva and Nikolay Verlov and Anastasia Kudrevatykh and Gaspar Gavrilov and Sofia Pchelina},\n journal = {International Journal of Biomedicine},\n title = {Abstract P-25: Cryo-Electron Microscopy of Extracellular Vesicles from Cerebrospinal Fluid},\n year = {2019},\n issn = {2158-0510},\n number = {Suppl_1},\n pages = {S27-S28},\n volume = {9},\n doi = {10.21103/ijbm.9.suppl_1.p25},\n keywords = {General Immunology and Microbiology, General Biochemistry, Genetics and Molecular Biology, General Neuroscience},\n publisher = {International Medical Research and Development Corporation},\n}\n\n\n\n \n\n \n \n \n \n \n Abstract P-36: HBc4M2e Virus-Like Particles for Influenza A Vaccine Development: a Cryo-EM Study.\n \n \n \n\n\n \n Shvetsov, A.; Pichkur, E.; Shtam, T.; Egorov, V.; Tsybalova, L.; Stepanova, L.; Shaldzhyan, A.; and Zabrodskaya, Y.\n\n\n \n\n\n\n International Journal of Biomedicine, 9(Suppl_1): S32-S33. 2019.\n \n\n\n\n
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\n\n\n\n@Article{Shvetsov2019,\n author = {Alexey Shvetsov and Evgeny Pichkur and Tatiana Shtam and Vladimir Egorov and Liudmila Tsybalova and Liudmila Stepanova and Aram Shaldzhyan and Yana Zabrodskaya},\n journal = {International Journal of Biomedicine},\n title = {Abstract P-36: HBc4M2e Virus-Like Particles for Influenza A Vaccine Development: a Cryo-EM Study},\n year = {2019},\n issn = {2158-0510},\n number = {Suppl_1},\n pages = {S32-S33},\n volume = {9},\n doi = {10.21103/ijbm.9.suppl_1.p36},\n keywords = {General Immunology and Microbiology, General Biochemistry, Genetics and Molecular Biology, General Neuroscience},\n publisher = {International Medical Research and Development Corporation},\n}\n\n\n\n
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\n \n \n\n \n \n \n \n \n Binding and Action of Amino Acid Analogs of Chloramphenicol upon the Bacterial Ribosome.\n \n \n \n\n\n \n Tereshchenkov, A. G.; Dobosz-Bartoszek, M.; Osterman, I. A.; Marks, J.; Sergeeva, V. A.; Kasatsky, P.; Komarova, E. S.; Stavrianidi, A. N.; Rodin, I. A.; Konevega, A. L.; Sergiev, P. V.; Sumbatyan, N. V.; Mankin, A. S.; Bogdanov, A. A.; and Polikanov, Y. S.\n\n\n \n\n\n\n Journal of molecular biology, 430: 842–852. March 2018.\n \n\n\n\n
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\n\n\n@Article{Tereshchenkov2018,\n author = {Tereshchenkov, Andrey G. and Dobosz-Bartoszek, Malgorzata and Osterman, Ilya A. and Marks, James and Sergeeva, Vasilina A. and Kasatsky, Pavel and Komarova, Ekaterina S. and Stavrianidi, Andrey N. and Rodin, Igor A. and Konevega, Andrey L. and Sergiev, Petr V. and Sumbatyan, Natalia V. and Mankin, Alexander S. and Bogdanov, Alexey A. and Polikanov, Yury S.},\n journal = {Journal of molecular biology},\n title = {Binding and Action of Amino Acid Analogs of Chloramphenicol upon the Bacterial Ribosome.},\n year = {2018},\n issn = {1089-8638},\n month = mar,\n pages = {842--852},\n volume = {430},\n abstract = {Antibiotic chloramphenicol (CHL) binds with a moderate affinity at the peptidyl transferase center of the bacterial ribosome and inhibits peptide bond formation. As an approach for modifying and potentially improving properties of this inhibitor, we explored ribosome binding and inhibitory activity of a number of amino acid analogs of CHL. The L-histidyl analog binds to the ribosome with the affinity exceeding that of CHL by 10 fold. Several of the newly synthesized analogs were able to inhibit protein synthesis and exhibited the mode of action that was distinct from the action of CHL. However, the inhibitory properties of the semi-synthetic CHL analogs did not correlate with their affinity and in general, the amino acid analogs of CHL were less active inhibitors of translation in comparison with the original antibiotic. The X-ray crystal structures of the Thermus thermophilus 70S ribosome in complex with three semi-synthetic analogs showed that CHL derivatives bind at the peptidyl transferase center, where the aminoacyl moiety of the tested compounds established idiosyncratic interactions with rRNA. Although still fairly inefficient inhibitors of translation, the synthesized compounds represent promising chemical scaffolds that target the peptidyl transferase center of the ribosome and potentially are suitable for further exploration.},\n chemicals = {Amino Acids, Anti-Bacterial Agents, Chloramphenicol, Peptidyl Transferases},\n citation-subset = {IM},\n completed = {2019-03-06},\n country = {Netherlands},\n doi = {10.1016/j.jmb.2018.01.016},\n issn-linking = {0022-2836},\n issue = {6},\n keywords = {Amino Acids, pharmacology; Anti-Bacterial Agents, pharmacology; Binding Sites; Chloramphenicol, metabolism, pharmacology; Crystallography, X-Ray; Escherichia coli, metabolism; Models, Molecular; Peptidyl Transferases, metabolism; Protein Binding, drug effects; Protein Biosynthesis, drug effects; Protein Conformation; Ribosome Subunits, Large, Bacterial, drug effects, metabolism; Thermus thermophilus, metabolism; X-ray structure; antibiotic; peptidyl transferase center; protein synthesis; ribosome},\n mid = {NIHMS973732},\n nlm-id = {2985088R},\n owner = {NLM},\n pii = {S0022-2836(18)30042-1},\n pmc = {PMC6023675},\n pmid = {29410130},\n pubmodel = {Print-Electronic},\n pubstate = {ppublish},\n revised = {2021-01-09},\n}\n\n\n\n Antibiotic chloramphenicol (CHL) binds with a moderate affinity at the peptidyl transferase center of the bacterial ribosome and inhibits peptide bond formation. As an approach for modifying and potentially improving properties of this inhibitor, we explored ribosome binding and inhibitory activity of a number of amino acid analogs of CHL. The L-histidyl analog binds to the ribosome with the affinity exceeding that of CHL by 10 fold. Several of the newly synthesized analogs were able to inhibit protein synthesis and exhibited the mode of action that was distinct from the action of CHL. However, the inhibitory properties of the semi-synthetic CHL analogs did not correlate with their affinity and in general, the amino acid analogs of CHL were less active inhibitors of translation in comparison with the original antibiotic. The X-ray crystal structures of the Thermus thermophilus 70S ribosome in complex with three semi-synthetic analogs showed that CHL derivatives bind at the peptidyl transferase center, where the aminoacyl moiety of the tested compounds established idiosyncratic interactions with rRNA. Although still fairly inefficient inhibitors of translation, the synthesized compounds represent promising chemical scaffolds that target the peptidyl transferase center of the ribosome and potentially are suitable for further exploration.\n
\n\n\n\n \n\n \n \n \n \n \n The ribosomal A-site finger is crucial for binding and activation of the stringent factor RelA.\n \n \n \n\n\n \n Kudrin, P.; Dzhygyr, I.; Ishiguro, K.; Beljantseva, J.; Maksimova, E.; Oliveira, S. R. A.; Varik, V.; Payoe, R.; Konevega, A. L.; Tenson, T.; Suzuki, T.; and Hauryliuk, V.\n\n\n \n\n\n\n Nucleic acids research, 46: 1973–1983. February 2018.\n \n\n\n\n
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\n\n\n@Article{Kudrin2018,\n author = {Kudrin, Pavel and Dzhygyr, Ievgen and Ishiguro, Kensuke and Beljantseva, Jelena and Maksimova, Elena and Oliveira, Sofia Raquel Alves and Varik, Vallo and Payoe, Roshani and Konevega, Andrey L. and Tenson, Tanel and Suzuki, Tsutomu and Hauryliuk, Vasili},\n journal = {Nucleic acids research},\n title = {The ribosomal A-site finger is crucial for binding and activation of the stringent factor RelA.},\n year = {2018},\n issn = {1362-4962},\n month = feb,\n pages = {1973--1983},\n volume = {46},\n abstract = {During amino acid starvation the Escherichia coli stringent response factor RelA recognizes deacylated tRNA in the ribosomal A-site. This interaction activates RelA-mediated synthesis of alarmone nucleotides pppGpp and ppGpp, collectively referred to as (p)ppGpp. These two alarmones are synthesized by addition of a pyrophosphate moiety to the 3' position of the abundant cellular nucleotide GTP and less abundant nucleotide GDP, respectively. Using untagged native RelA we show that allosteric activation of RelA by pppGpp increases the efficiency of GDP conversion to achieve the maximum rate of (p)ppGpp production. Using a panel of ribosomal RNA mutants, we show that the A-site finger structural element of 23S rRNA helix 38 is crucial for RelA binding to the ribosome and consequent activation, and deletion of the element severely compromises (p)ppGpp accumulation in E. coli upon amino acid starvation. Through binding assays and enzymology, we show that E. coli RelA does not form a stable complex with, and is not activated by, deacylated tRNA off the ribosome. This indicates that in the cell, RelA first binds the empty A-site and then recruits tRNA rather than first binding tRNA and then binding the ribosome.},\n chemicals = {Escherichia coli Proteins, Peptide Elongation Factor G, RNA, Ribosomal, 23S, RNA, Transfer, GTP Pyrophosphokinase, relA protein, E coli, Ligases, guanosine 3',5'-polyphosphate synthetases},\n citation-subset = {IM},\n completed = {2019-07-15},\n country = {England},\n doi = {10.1093/nar/gky023},\n issn-linking = {0305-1048},\n issue = {4},\n keywords = {Enzyme Activation; Escherichia coli, enzymology; Escherichia coli Proteins, chemistry, metabolism; GTP Pyrophosphokinase, chemistry, metabolism; Ligases, chemistry, metabolism; Mutation; Peptide Elongation Factor G; Protein Binding; RNA, Ribosomal, 23S, chemistry, metabolism; RNA, Transfer, chemistry, metabolism; Ribosomes, metabolism},\n nlm-id = {0411011},\n owner = {NLM},\n pii = {4829690},\n pmc = {PMC5829649},\n pmid = {29390134},\n pubmodel = {Print},\n pubstate = {ppublish},\n revised = {2019-08-29},\n}\n\n\n\n During amino acid starvation the Escherichia coli stringent response factor RelA recognizes deacylated tRNA in the ribosomal A-site. This interaction activates RelA-mediated synthesis of alarmone nucleotides pppGpp and ppGpp, collectively referred to as (p)ppGpp. These two alarmones are synthesized by addition of a pyrophosphate moiety to the 3' position of the abundant cellular nucleotide GTP and less abundant nucleotide GDP, respectively. Using untagged native RelA we show that allosteric activation of RelA by pppGpp increases the efficiency of GDP conversion to achieve the maximum rate of (p)ppGpp production. Using a panel of ribosomal RNA mutants, we show that the A-site finger structural element of 23S rRNA helix 38 is crucial for RelA binding to the ribosome and consequent activation, and deletion of the element severely compromises (p)ppGpp accumulation in E. coli upon amino acid starvation. Through binding assays and enzymology, we show that E. coli RelA does not form a stable complex with, and is not activated by, deacylated tRNA off the ribosome. This indicates that in the cell, RelA first binds the empty A-site and then recruits tRNA rather than first binding tRNA and then binding the ribosome.\n
\n\n\n\n \n\n \n \n \n \n \n [Isolation of extracellular micro-vesicles from cell culture medium: comparative evaluation of methods].\n \n \n \n\n\n \n Shtam, T. A.; Samsonov, R. A.; Volnitskiy, A. V.; Kamyshinsky, R. A.; Verlov, N. A.; Kniazeva, M. S.; Korobkina, E. A.; Orehov, A. S.; Vasiliev, A. L.; Konevega, A. L.; and Malek, A. V.\n\n\n \n\n\n\n Biomeditsinskaia khimiia, 64: 23–30. January 2018.\n \n\n\n\n
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\n\n\n@Article{Shtam2018,\n author = {Shtam, T. A. and Samsonov, R. A. and Volnitskiy, A. V. and Kamyshinsky, R. A. and Verlov, N. A. and Kniazeva, M. S. and Korobkina, E. A. and Orehov, A. S. and Vasiliev, A. L. and Konevega, A. L. and Malek, A. V.},\n journal = {Biomeditsinskaia khimiia},\n title = {[Isolation of extracellular micro-vesicles from cell culture medium: comparative evaluation of methods].},\n year = {2018},\n issn = {2310-6972},\n month = jan,\n pages = {23--30},\n volume = {64},\n abstract = {Extracellular vesicles (EV) are secreted by cells of multicellular organisms. EV mediate specific mode of intercellular communication by "horizontal" exchange of substances and information. This phenomenon seems to have an essential biological significance and became a subject of intensive research. Biogenesis, structural and functional features of the EV is being commonly studies in in vitro condition. Several methods of EV isolation from cell culture medium are established, however selection of method might influence on obtained results. The choice of the optimal method depends usually from the amount of medium and the aims of the research while is still challenging issue. We performed a comparative analysis of four different methods of EV isolation from cell culture medium: differential ultracentrifugation, ultracentrifugation with a 30% sucrose/D2O "cushion", precipitation with plant proteins and immune-affinity capturing. EV isolated by different approaches were compared in terms of following parameters: size, concentration, morphology of EV, contamination by non-vesicular particles, content of exosomal tetraspanins on the EV surface, content of total proteins, RNA, and several glioma-associated miRNAs. Applied methods included nano-patricle tracking analysis (NTA), dynamic light scattering (DLS), cryo-electron microscopy, flow cytometry and RT-qPCR. On the base of obtained results, we developed practical recommendations that may help researchers to make a best choice of EV isolation method.},\n chemicals = {Culture Media},\n citation-subset = {IM},\n completed = {2019-05-03},\n country = {Russia (Federation)},\n doi = {10.18097/PBMC20186401023},\n issn-linking = {2310-6905},\n issue = {1},\n keywords = {Cell Culture Techniques; Cryoelectron Microscopy; Culture Media; Extracellular Vesicles; Ultracentrifugation; exsosomes; extracellular vesicles; immunoprecipitation; lectines; methods of isolation; ultracentrifugation},\n nlm-id = {101196966},\n owner = {NLM},\n pmid = {29460831},\n pubmodel = {Print},\n pubstate = {ppublish},\n revised = {2019-05-03},\n}\n\n\n\n Extracellular vesicles (EV) are secreted by cells of multicellular organisms. EV mediate specific mode of intercellular communication by \"horizontal\" exchange of substances and information. This phenomenon seems to have an essential biological significance and became a subject of intensive research. Biogenesis, structural and functional features of the EV is being commonly studies in in vitro condition. Several methods of EV isolation from cell culture medium are established, however selection of method might influence on obtained results. The choice of the optimal method depends usually from the amount of medium and the aims of the research while is still challenging issue. We performed a comparative analysis of four different methods of EV isolation from cell culture medium: differential ultracentrifugation, ultracentrifugation with a 30% sucrose/D2O \"cushion\", precipitation with plant proteins and immune-affinity capturing. EV isolated by different approaches were compared in terms of following parameters: size, concentration, morphology of EV, contamination by non-vesicular particles, content of exosomal tetraspanins on the EV surface, content of total proteins, RNA, and several glioma-associated miRNAs. Applied methods included nano-patricle tracking analysis (NTA), dynamic light scattering (DLS), cryo-electron microscopy, flow cytometry and RT-qPCR. On the base of obtained results, we developed practical recommendations that may help researchers to make a best choice of EV isolation method.\n
\n\n\n\n \n\n \n \n \n \n \n Functional Properties of Circulating Exosomes Mediated by Surface-Attached Plasma Proteins.\n \n \n \n\n\n \n Shtam, T.; Naryzhny, S.; Kopylov, A.; Petrenko, E.; Samsonov, R.; Kamyshinsky, R.; Zabrodskaya, Y.; Nikitin, D.; Sorokin, M.; Buzdin, A.; and Malek, A.\n\n\n \n\n\n\n Journal of hematology, 7: 149–153. December 2018.\n \n\n\n\n
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\n\n\n@Article{Shtam2018a,\n author = {Shtam, Tatiana and Naryzhny, Stanislav and Kopylov, Arthur and Petrenko, Elena and Samsonov, Roman and Kamyshinsky, Roman and Zabrodskaya, Yana and Nikitin, Daniil and Sorokin, Maxim and Buzdin, Anton and Malek, Anastasia},\n journal = {Journal of hematology},\n title = {Functional Properties of Circulating Exosomes Mediated by Surface-Attached Plasma Proteins.},\n year = {2018},\n issn = {1927-1212},\n month = dec,\n pages = {149--153},\n volume = {7},\n abstract = {Exosomes and other types of extracellular vesicles present an important component of circulating plasma. Exosomes released by endothelial and blood cells account for majority of plasma exosomal population; exosomes secreted by other cells might cross tissue-plasma barrier and reach circulating plasma as well. Definitely, exosomes of different cellular origins are different by content and function. However, exosomal surface membrane interacts with plasma components. This interaction may alter composition of exosomal surface and hence, provide these vesicles with new functional properties. This study was aimed to estimate composition and possible functional role of proteins attached on the surface of plasma exosomes. Here, extracellular vesicles from human plasma were isolated by ultracentrifugation and treated by trypsin. Trypsinized and native exosomes were analyzed by nanoparticle tracking analysis, Western blotting and quantitative high-resolution mass spectrometry. Surface-attached proteins were removed from exosomes isolated from plasma of healthy donors by incubation with serine protease (trypsin). Treatment did not impact exosomes integrity while slightly reduced hydrodynamic radius. Mass spectrometry revealed 259 exosomal proteins; among them 79 proteins were completely removed and more than half of the proteins were partially removed by trypsinization. Gene ontology functional annotation revealed mostly extracellular locations of proteins cleaved from a surface of the plasma exosomes. Moreover, proteins cleaved from the exosome surface are supposed to be implicated into integrin-linked kinase (ILK), focal adhesion kinase (FAK) and other pathways connecting cell surface with intracellular signaling cascades. Taken together, our results demonstrate that a surface of circulating exosomes is decorated by plasma proteins, and these proteins can mask tissue-specific characteristic of the exosomal surface membrane and provide exosomes with new and uniform properties.},\n country = {Canada},\n doi = {10.14740/jh412w},\n issn-linking = {1927-1212},\n issue = {4},\n keywords = {Exosomes; FAK signaling; ILK signaling; Mass spectrometry; Plasma proteins},\n nlm-id = {101635099},\n owner = {NLM},\n pmc = {PMC7155850},\n pmid = {32300430},\n pubmodel = {Print-Electronic},\n pubstate = {ppublish},\n revised = {2022-04-14},\n}\n\n\n\n Exosomes and other types of extracellular vesicles present an important component of circulating plasma. Exosomes released by endothelial and blood cells account for majority of plasma exosomal population; exosomes secreted by other cells might cross tissue-plasma barrier and reach circulating plasma as well. Definitely, exosomes of different cellular origins are different by content and function. However, exosomal surface membrane interacts with plasma components. This interaction may alter composition of exosomal surface and hence, provide these vesicles with new functional properties. This study was aimed to estimate composition and possible functional role of proteins attached on the surface of plasma exosomes. Here, extracellular vesicles from human plasma were isolated by ultracentrifugation and treated by trypsin. Trypsinized and native exosomes were analyzed by nanoparticle tracking analysis, Western blotting and quantitative high-resolution mass spectrometry. Surface-attached proteins were removed from exosomes isolated from plasma of healthy donors by incubation with serine protease (trypsin). Treatment did not impact exosomes integrity while slightly reduced hydrodynamic radius. Mass spectrometry revealed 259 exosomal proteins; among them 79 proteins were completely removed and more than half of the proteins were partially removed by trypsinization. Gene ontology functional annotation revealed mostly extracellular locations of proteins cleaved from a surface of the plasma exosomes. Moreover, proteins cleaved from the exosome surface are supposed to be implicated into integrin-linked kinase (ILK), focal adhesion kinase (FAK) and other pathways connecting cell surface with intracellular signaling cascades. Taken together, our results demonstrate that a surface of circulating exosomes is decorated by plasma proteins, and these proteins can mask tissue-specific characteristic of the exosomal surface membrane and provide exosomes with new and uniform properties.\n
\n\n\n\n \n\n \n \n \n \n \n Targeting experimental orthotopic glioblastoma with chitosan-based superparamagnetic iron oxide nanoparticles (CS-DX-SPIONs).\n \n \n \n\n\n \n Shevtsov, M.; Nikolaev, B.; Marchenko, Y.; Yakovleva, L.; Skvortsov, N.; Mazur, A.; Tolstoy, P.; Ryzhov, V.; and Multhoff, G.\n\n\n \n\n\n\n International journal of nanomedicine, 13: 1471–1482. 2018.\n \n\n\n\n
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\n\n\n@Article{Shevtsov2018,\n author = {Shevtsov, Maxim and Nikolaev, Boris and Marchenko, Yaroslav and Yakovleva, Ludmila and Skvortsov, Nikita and Mazur, Anton and Tolstoy, Peter and Ryzhov, Vyacheslav and Multhoff, Gabriele},\n journal = {International journal of nanomedicine},\n title = {Targeting experimental orthotopic glioblastoma with chitosan-based superparamagnetic iron oxide nanoparticles (CS-DX-SPIONs).},\n year = {2018},\n issn = {1178-2013},\n pages = {1471--1482},\n volume = {13},\n abstract = {Glioblastoma is the most devastating primary brain tumor of the central nervous system in adults. Magnetic nanocarriers may help not only for a targeted delivery of chemotherapeutic agents into the tumor site but also provide contrast enhancing properties for diagnostics using magnetic resonance imaging (MRI). Synthesized hybrid chitosan-dextran superparamagnetic nanoparticles (CS-DX-SPIONs) were characterized using transmission electron microscopy (TEM) and relaxometry studies. Nonlinear magnetic response measurements were employed for confirming the superparamagnetic state of particles. Following in vitro analysis of nanoparticles cellular uptake tumor targeting was assessed in the model of the orthotopic glioma in rodents. CS-DX-SPIONs nanoparticles showed a uniform diameter of 55 nm under TEM and superparamagentic characteristics as determined by T (1)(spin-lattice relaxation time) and T (2)(spin-spin relaxation time) proton relaxation times. Application of the chitosan increased the charge from +8.9 to +19.3 mV of the dextran-based SPIONs. The nonlinear magnetic response at second harmonic of CS-DX-SPIONs following the slow change of stationary magnetic fields with very low hysteresis evidenced superparamagnetic state of particles at ambient temperatures. Confocal microscopy and flow cytometry studies showed an enhanced internalization of the chitosan-based nanoparticles in U87, C6 glioma and HeLa cells as compared to dextran-coated particles. Cytotoxicity assay demonstrated acceptable toxicity profile of the synthesized nanoparticles up to a concentration of 10 μg/ml. Intravenously administered CS-DX-SPIONs in orthotopic C6 gliomas in rats accumulated in the tumor site as shown by high-resolution MRI (11.0 T). Retention of nanoparticles resulted in a significant contrast enhancement of the tumor image that was accompanied with a dramatic drop in T (2)values ( P <0.001). Subsequent histological studies proved the accumulation of the nanoparticles inside glioblastoma cells. Hybrid chitosan-dextran magnetic particles demonstrated high MR contrast enhancing properties for the delineation of the brain tumor. Due to a significant retention of the particles in the tumor an application of the CS-DX-SPIONs could not only improve the tumor imaging but also could allow a targeted delivery of chemotherapeutic agents.},\n chemicals = {Antineoplastic Agents, Ferric Compounds, Magnetite Nanoparticles, ferric oxide, Chitosan},\n citation-subset = {IM},\n completed = {2018-05-14},\n country = {New Zealand},\n doi = {10.2147/IJN.S152461},\n issn-linking = {1176-9114},\n keywords = {Animals; Antineoplastic Agents, pharmacology, therapeutic use; Brain Neoplasms, drug therapy, pathology; Cell Communication; Chitosan, chemistry; Ferric Compounds, chemistry; Glioblastoma, drug therapy, pathology; HeLa Cells; Humans; Magnetic Resonance Imaging, methods; Magnetite Nanoparticles, administration & dosage, chemistry, ultrastructure; Male; Rats, Wistar; brain tumor; chitosan; glioblastoma; magnetic resonance imaging; superparamagnetic iron oxide nanoparticles; tumor targeting},\n nlm-id = {101263847},\n owner = {NLM},\n pii = {ijn-13-1471},\n pmc = {PMC5856030},\n pmid = {29559776},\n pubmodel = {Electronic-eCollection},\n pubstate = {epublish},\n revised = {2022-03-30},\n}\n\n\n\n Glioblastoma is the most devastating primary brain tumor of the central nervous system in adults. Magnetic nanocarriers may help not only for a targeted delivery of chemotherapeutic agents into the tumor site but also provide contrast enhancing properties for diagnostics using magnetic resonance imaging (MRI). Synthesized hybrid chitosan-dextran superparamagnetic nanoparticles (CS-DX-SPIONs) were characterized using transmission electron microscopy (TEM) and relaxometry studies. Nonlinear magnetic response measurements were employed for confirming the superparamagnetic state of particles. Following in vitro analysis of nanoparticles cellular uptake tumor targeting was assessed in the model of the orthotopic glioma in rodents. CS-DX-SPIONs nanoparticles showed a uniform diameter of 55 nm under TEM and superparamagentic characteristics as determined by T (1)(spin-lattice relaxation time) and T (2)(spin-spin relaxation time) proton relaxation times. Application of the chitosan increased the charge from +8.9 to +19.3 mV of the dextran-based SPIONs. The nonlinear magnetic response at second harmonic of CS-DX-SPIONs following the slow change of stationary magnetic fields with very low hysteresis evidenced superparamagnetic state of particles at ambient temperatures. Confocal microscopy and flow cytometry studies showed an enhanced internalization of the chitosan-based nanoparticles in U87, C6 glioma and HeLa cells as compared to dextran-coated particles. Cytotoxicity assay demonstrated acceptable toxicity profile of the synthesized nanoparticles up to a concentration of 10 μg/ml. Intravenously administered CS-DX-SPIONs in orthotopic C6 gliomas in rats accumulated in the tumor site as shown by high-resolution MRI (11.0 T). Retention of nanoparticles resulted in a significant contrast enhancement of the tumor image that was accompanied with a dramatic drop in T (2)values ( P <0.001). Subsequent histological studies proved the accumulation of the nanoparticles inside glioblastoma cells. Hybrid chitosan-dextran magnetic particles demonstrated high MR contrast enhancing properties for the delineation of the brain tumor. Due to a significant retention of the particles in the tumor an application of the CS-DX-SPIONs could not only improve the tumor imaging but also could allow a targeted delivery of chemotherapeutic agents.\n
\n\n\n\n \n\n \n \n \n \n \n PO-411 Combinatorial therapy with immune checkpoint blockade and theranostic tumor-targeted nanoparticles in eradication of tumours.\n \n \n \n\n\n \n Shevtsov, M.; Stangl, S.; Pitkin, E.; Nikolaev, B.; Marchenko, Y.; Yakovleva, L.; Ryzhov, V.; Margulis, B.; Guzhova, I.; and Multhoff, G.\n\n\n \n\n\n\n ESMO Open, 3: A391. 2018.\n \n\n\n\n
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\n\n\n\n@Article{Shevtsov2018a,\n author = {M. Shevtsov and S. Stangl and E. Pitkin and B. Nikolaev and Y. Marchenko and L. Yakovleva and V. Ryzhov and B. Margulis and I. Guzhova and G. Multhoff},\n journal = {ESMO Open},\n title = {PO-411 Combinatorial therapy with immune checkpoint blockade and theranostic tumor-targeted nanoparticles in eradication of tumours},\n year = {2018},\n issn = {2059-7029},\n pages = {A391},\n volume = {3},\n doi = {10.1136/esmoopen-2018-eacr25.922},\n keywords = {Cancer Research, Oncology},\n publisher = {Elsevier BV},\n}\n\n\n\n \n\n \n \n \n \n \n PO-506 Targeting membrane-bound Hsp70 on cancer cells with functionalized superparamagnetic nanoparticles: new perspectives for early diagnosis and therapy.\n \n \n \n\n\n \n Shevtsov, M.; Stangl, S.; Nikolaev, B.; Marchenko, Y.; Pitkin, E.; Yakovleva, L.; Guzhova, I.; Ryzhov, V.; Chester, K.; and Multhoff, G.\n\n\n \n\n\n\n ESMO Open, 3: A220. 2018.\n \n\n\n\n
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\n\n\n\n@Article{Shevtsov2018b,\n author = {M. Shevtsov and S. Stangl and B. Nikolaev and Y. Marchenko and E. Pitkin and L. Yakovleva and I. Guzhova and V. Ryzhov and K. Chester and G. Multhoff},\n journal = {ESMO Open},\n title = {PO-506 Targeting membrane-bound Hsp70 on cancer cells with functionalized superparamagnetic nanoparticles: new perspectives for early diagnosis and therapy},\n year = {2018},\n issn = {2059-7029},\n pages = {A220},\n volume = {3},\n doi = {10.1136/esmoopen-2018-eacr25.521},\n keywords = {Cancer Research, Oncology},\n publisher = {Elsevier BV},\n}\n\n\n\n \n\n \n \n \n \n \n P04.01 Synergistic antitumor effects of a combined therapy consisting of immune checkpoint inhibitors and tumor-targeting nanoparticles in glioblastoma.\n \n \n \n\n\n \n Shevtsov, M.; Stangl, S.; Nikolaev, B.; Edmond, S.; Yakovleva, L.; Marchenko, Y.; Ryzhov, V.; Margulis, B.; Pitkin, E.; and Multhoff, G.\n\n\n \n\n\n\n Neuro-Oncology, 20(suppl_3): iii277-iii278. 2018.\n \n\n\n\n
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\n\n\n\n@Article{Shevtsov2018c,\n author = {M. Shevtsov and S. Stangl and B. Nikolaev and S. Edmond and L. Yakovleva and Y. Marchenko and V. Ryzhov and B. Margulis and E. Pitkin and G. Multhoff},\n journal = {Neuro-Oncology},\n title = {P04.01 Synergistic antitumor effects of a combined therapy consisting of immune checkpoint inhibitors and tumor-targeting nanoparticles in glioblastoma},\n year = {2018},\n issn = {1522-8517},\n number = {suppl_3},\n pages = {iii277-iii278},\n volume = {20},\n doi = {10.1093/neuonc/noy139.235},\n keywords = {Cancer Research, Neurology (clinical), Oncology},\n publisher = {Oxford University Press (OUP)},\n}\n\n\n\n \n\n \n \n \n \n \n EXOSOMAL MICRO-RNA - POTENTIAL PREDICTIVE MARKER OF BREAST CANCER NEOADJUVANT THERAPY EFFECT.\n \n \n \n\n\n \n Kovalenko, I.; Semiglazov, V.; Bershteyn, L.; Dashyan, G.; Semiglazova, T.; Kamyshinskiy, R.; Tsyrlina, Y.; Shtam, T.; Samsonov, R.; and Malek, A.\n\n\n \n\n\n\n Problems in oncology, 64(6): 758-767. June 2018.\n \n\n\n\n
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\n\n\n\n@Article{Kovalenko2018,\n author = {Irina Kovalenko and Vladimir Semiglazov and Lev Bershteyn and Garik Dashyan and Tatyana Semiglazova and Roman Kamyshinskiy and Yevgeniya Tsyrlina and Tatyana Shtam and Roman Samsonov and Anastasiya Malek},\n journal = {Problems in oncology},\n title = {EXOSOMAL MICRO-RNA - POTENTIAL PREDICTIVE MARKER OF BREAST CANCER NEOADJUVANT THERAPY EFFECT},\n year = {2018},\n issn = {0507-3758},\n month = jun,\n number = {6},\n pages = {758-767},\n volume = {64},\n doi = {10.37469/0507-3758-2018-64-6-758-767},\n keywords = {Cancer Research, Oncology},\n publisher = {Autonomous non-profit scientific and medical organization - Questions of Oncology},\n}\n\n\n\n \n\n \n \n \n \n \n DIAGNOSTIC VALUE OF EXOSOMAL MIRNAS FOR COLORECTAL CANCER.\n \n \n \n\n\n \n Samsonov, R. B.; Tarasov, M. A.; Burdakov, V. S.; Shtam, T. A.; Guljaev, A. M.; Tkachenko, O. B.; Rybakov, E. G.; Filatov, M. V.; Aigner, A. .; and Malek, A. V.\n\n\n \n\n\n\n Koloproktologia, (2): 25-31. June 2018.\n \n\n\n\n
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\n\n\n\n@Article{Samsonov2018,\n author = {R. B. Samsonov and M. A. Tarasov and V. S. Burdakov and T. A. Shtam and A. M. Guljaev and O. B. Tkachenko and E. G. Rybakov and M. V. Filatov and A. . Aigner and A. V. Malek},\n journal = {Koloproktologia},\n title = {DIAGNOSTIC VALUE OF EXOSOMAL MIRNAS FOR COLORECTAL CANCER},\n year = {2018},\n issn = {2686-7303},\n month = jun,\n number = {2},\n pages = {25-31},\n doi = {10.33878/2073-7556-2018-0-2-25-31},\n keywords = {Gastroenterology, Oncology, Surgery},\n publisher = {Russian Association of Coloproctology},\n}\n\n\n\n
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\n \n \n\n \n \n \n \n \n Biodiversity, drug discovery, and the future of global health: Introducing the biodiversity to biomedicine consortium, a call to action.\n \n \n \n\n\n \n Neergheen-Bhujun, V.; Awan, A. T.; Baran, Y.; Bunnefeld, N.; Chan, K.; Dela Cruz, T. E.; Egamberdieva, D.; Elsässer, S.; Johnson, M. V.; Komai, S.; Konevega, A. L.; Malone, J. H.; Mason, P.; Nguon, R.; Piper, R.; Shrestha, U. B.; Pešić, M.; and Kagansky, A.\n\n\n \n\n\n\n Journal of global health, 7: 020304. December 2017.\n \n\n\n\n
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\n\n\n\n@Article{NeergheenBhujun2017,\n author = {Neergheen-Bhujun, Vidushi and Awan, Almas Taj and Baran, Yusuf and Bunnefeld, Nils and Chan, Kit and Dela Cruz, Thomas Edison and Egamberdieva, Dilfuza and Elsässer, Simon and Johnson, Mari-Vaughn V. and Komai, Shoji and Konevega, Andrey L. and Malone, John H. and Mason, Paul and Nguon, Rothsophal and Piper, Ross and Shrestha, Uttam Babu and Pešić, Milica and Kagansky, Alexander},\n journal = {Journal of global health},\n title = {Biodiversity, drug discovery, and the future of global health: Introducing the biodiversity to biomedicine consortium, a call to action.},\n year = {2017},\n issn = {2047-2986},\n month = dec,\n pages = {020304},\n volume = {7},\n citation-subset = {IM},\n completed = {2019-05-17},\n country = {Scotland},\n doi = {10.7189/jogh.07.020304},\n issn-linking = {2047-2978},\n issue = {2},\n keywords = {Biodiversity; Drug Discovery; Forecasting; Global Health, trends; Humans},\n nlm-id = {101578780},\n owner = {NLM},\n pii = {020304},\n pmc = {PMC5735771},\n pmid = {29302312},\n pubmodel = {Print},\n pubstate = {ppublish},\n revised = {2019-05-17},\n}\n\n\n\n \n\n \n \n \n \n \n Klebsazolicin inhibits 70S ribosome by obstructing the peptide exit tunnel.\n \n \n \n\n\n \n Metelev, M.; Osterman, I. A.; Ghilarov, D.; Khabibullina, N. F.; Yakimov, A.; Shabalin, K.; Utkina, I.; Travin, D. Y.; Komarova, E. S.; Serebryakova, M.; Artamonova, T.; Khodorkovskii, M.; Konevega, A. L.; Sergiev, P. V.; Severinov, K.; and Polikanov, Y. S.\n\n\n \n\n\n\n Nature chemical biology, 13: 1129–1136. October 2017.\n \n\n\n\n
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\n\n\n@Article{Metelev2017,\n author = {Metelev, Mikhail and Osterman, Ilya A. and Ghilarov, Dmitry and Khabibullina, Nelli F. and Yakimov, Alexander and Shabalin, Konstantin and Utkina, Irina and Travin, Dmitry Y. and Komarova, Ekaterina S. and Serebryakova, Marina and Artamonova, Tatyana and Khodorkovskii, Mikhail and Konevega, Andrey L. and Sergiev, Petr V. and Severinov, Konstantin and Polikanov, Yury S.},\n journal = {Nature chemical biology},\n title = {Klebsazolicin inhibits 70S ribosome by obstructing the peptide exit tunnel.},\n year = {2017},\n issn = {1552-4469},\n month = oct,\n pages = {1129--1136},\n volume = {13},\n abstract = {Whereas screening of the small-molecule metabolites produced by most cultivatable microorganisms often results in the rediscovery of known compounds, genome-mining programs allow researchers to harness much greater chemical diversity, and result in the discovery of new molecular scaffolds. Here we report the genome-guided identification of a new antibiotic, klebsazolicin (KLB), from Klebsiella pneumoniae that inhibits the growth of sensitive cells by targeting ribosomes. A ribosomally synthesized post-translationally modified peptide (RiPP), KLB is characterized by the presence of a unique N-terminal amidine ring that is essential for its activity. Biochemical in vitro studies indicate that KLB inhibits ribosomes by interfering with translation elongation. Structural analysis of the ribosome-KLB complex showed that the compound binds in the peptide exit tunnel overlapping with the binding sites of macrolides or streptogramin-B. KLB adopts a compact conformation and largely obstructs the tunnel. Engineered KLB fragments were observed to retain in vitro activity, and thus have the potential to serve as a starting point for the development of new bioactive compounds.},\n chemicals = {Anti-Bacterial Agents, Peptides, klebsazolicin},\n citation-subset = {IM},\n completed = {2017-10-09},\n country = {United States},\n doi = {10.1038/nchembio.2462},\n issn-linking = {1552-4450},\n issue = {10},\n keywords = {Anti-Bacterial Agents, chemistry, metabolism, pharmacology; Binding Sites, drug effects; Cloning, Molecular; Klebsiella pneumoniae, chemistry, metabolism; Peptides, chemistry, metabolism, pharmacology; Protein Engineering; Ribosomes, chemistry, drug effects},\n mid = {NIHMS894386},\n nlm-id = {101231976},\n owner = {NLM},\n pii = {nchembio.2462},\n pmc = {PMC5701663},\n pmid = {28846667},\n pubmodel = {Print-Electronic},\n pubstate = {ppublish},\n revised = {2018-11-13},\n}\n\n\n\n Whereas screening of the small-molecule metabolites produced by most cultivatable microorganisms often results in the rediscovery of known compounds, genome-mining programs allow researchers to harness much greater chemical diversity, and result in the discovery of new molecular scaffolds. Here we report the genome-guided identification of a new antibiotic, klebsazolicin (KLB), from Klebsiella pneumoniae that inhibits the growth of sensitive cells by targeting ribosomes. A ribosomally synthesized post-translationally modified peptide (RiPP), KLB is characterized by the presence of a unique N-terminal amidine ring that is essential for its activity. Biochemical in vitro studies indicate that KLB inhibits ribosomes by interfering with translation elongation. Structural analysis of the ribosome-KLB complex showed that the compound binds in the peptide exit tunnel overlapping with the binding sites of macrolides or streptogramin-B. KLB adopts a compact conformation and largely obstructs the tunnel. Engineered KLB fragments were observed to retain in vitro activity, and thus have the potential to serve as a starting point for the development of new bioactive compounds.\n
\n\n\n\n \n\n \n \n \n \n \n Madumycin II inhibits peptide bond formation by forcing the peptidyl transferase center into an inactive state.\n \n \n \n\n\n \n Osterman, I. A.; Khabibullina, N. F.; Komarova, E. S.; Kasatsky, P.; Kartsev, V. G.; Bogdanov, A. A.; Dontsova, O. A.; Konevega, A. L.; Sergiev, P. V.; and Polikanov, Y. S.\n\n\n \n\n\n\n Nucleic acids research, 45: 7507–7514. July 2017.\n \n\n\n\n
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\n\n\n@Article{Osterman2017,\n author = {Osterman, Ilya A. and Khabibullina, Nelli F. and Komarova, Ekaterina S. and Kasatsky, Pavel and Kartsev, Victor G. and Bogdanov, Alexey A. and Dontsova, Olga A. and Konevega, Andrey L. and Sergiev, Petr V. and Polikanov, Yury S.},\n journal = {Nucleic acids research},\n title = {Madumycin II inhibits peptide bond formation by forcing the peptidyl transferase center into an inactive state.},\n year = {2017},\n issn = {1362-4962},\n month = jul,\n pages = {7507--7514},\n volume = {45},\n abstract = {The emergence of multi-drug resistant bacteria is limiting the effectiveness of commonly used antibiotics, which spurs a renewed interest in revisiting older and poorly studied drugs. Streptogramins A is a class of protein synthesis inhibitors that target the peptidyl transferase center (PTC) on the large subunit of the ribosome. In this work, we have revealed the mode of action of the PTC inhibitor madumycin II, an alanine-containing streptogramin A antibiotic, in the context of a functional 70S ribosome containing tRNA substrates. Madumycin II inhibits the ribosome prior to the first cycle of peptide bond formation. It allows binding of the tRNAs to the ribosomal A and P sites, but prevents correct positioning of their CCA-ends into the PTC thus making peptide bond formation impossible. We also revealed a previously unseen drug-induced rearrangement of nucleotides U2506 and U2585 of the 23S rRNA resulting in the formation of the U2506•G2583 wobble pair that was attributed to a catalytically inactive state of the PTC. The structural and biochemical data reported here expand our knowledge on the fundamental mechanisms by which peptidyl transferase inhibitors modulate the catalytic activity of the ribosome.},\n chemicals = {Anti-Bacterial Agents, Bacterial Proteins, Protein Synthesis Inhibitors, RNA, Ribosomal, 23S, Streptogramins, madumycin II, RNA, Transfer, Peptidyl Transferases},\n citation-subset = {IM},\n completed = {2017-10-17},\n country = {England},\n doi = {10.1093/nar/gkx413},\n issn-linking = {0305-1048},\n issue = {12},\n keywords = {Anti-Bacterial Agents, chemistry, pharmacology; Bacterial Proteins, antagonists & inhibitors, chemistry, genetics, metabolism; Binding Sites; Catalytic Domain; Escherichia coli, drug effects, enzymology, genetics; Models, Molecular; Nucleic Acid Conformation; Peptidyl Transferases, antagonists & inhibitors, chemistry, genetics, metabolism; Protein Biosynthesis, drug effects; Protein Synthesis Inhibitors, chemistry, pharmacology; RNA, Ribosomal, 23S, antagonists & inhibitors, chemistry, metabolism; RNA, Transfer, antagonists & inhibitors, chemistry, metabolism; Ribosomes, drug effects, genetics, metabolism; Streptogramins, chemistry, pharmacology; Thermus thermophilus, drug effects, enzymology, genetics},\n nlm-id = {0411011},\n owner = {NLM},\n pii = {3823294},\n pmc = {PMC5499580},\n pmid = {28505372},\n pubmodel = {Print},\n pubstate = {ppublish},\n revised = {2018-11-13},\n}\n\n\n\n The emergence of multi-drug resistant bacteria is limiting the effectiveness of commonly used antibiotics, which spurs a renewed interest in revisiting older and poorly studied drugs. Streptogramins A is a class of protein synthesis inhibitors that target the peptidyl transferase center (PTC) on the large subunit of the ribosome. In this work, we have revealed the mode of action of the PTC inhibitor madumycin II, an alanine-containing streptogramin A antibiotic, in the context of a functional 70S ribosome containing tRNA substrates. Madumycin II inhibits the ribosome prior to the first cycle of peptide bond formation. It allows binding of the tRNAs to the ribosomal A and P sites, but prevents correct positioning of their CCA-ends into the PTC thus making peptide bond formation impossible. We also revealed a previously unseen drug-induced rearrangement of nucleotides U2506 and U2585 of the 23S rRNA resulting in the formation of the U2506•G2583 wobble pair that was attributed to a catalytically inactive state of the PTC. The structural and biochemical data reported here expand our knowledge on the fundamental mechanisms by which peptidyl transferase inhibitors modulate the catalytic activity of the ribosome.\n
\n\n\n\n \n\n \n \n \n \n \n The rare nonsense mutation in p53 triggers alternative splicing to produce a protein capable of inducing apoptosis.\n \n \n \n\n\n \n Makarov, E. M.; Shtam, T. A.; Kovalev, R. A.; Pantina, R. A.; Varfolomeeva, E. Y.; and Filatov, M. V.\n\n\n \n\n\n\n PloS one, 12: e0185126. 2017.\n \n\n\n\n
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\n\n\n@Article{Makarov2017,\n author = {Makarov, Evgeny M. and Shtam, Tatyana A. and Kovalev, Roman A. and Pantina, Rimma A. and Varfolomeeva, Elena Yu and Filatov, Michael V.},\n journal = {PloS one},\n title = {The rare nonsense mutation in p53 triggers alternative splicing to produce a protein capable of inducing apoptosis.},\n year = {2017},\n issn = {1932-6203},\n pages = {e0185126},\n volume = {12},\n abstract = {P53 protein is more frequently mutated in human tumours compared with the other proteins. While the majority of the p53 mutations, especially within its DNA-binding domain, lead to the loss of the wild-type function, there are accumulating data demonstrating that the p53 mutants gain tumour promoting activities; the latter triggers a revitalised interest in functional analysis of the p53 mutants. A systematic screening for p53 mutations in surgical materials from patients with glioma revealed a 378C>G mutation that creates a stop codon at the position of amino acid residue 126. The mutation eliminates the recognition site for the restriction endonuclease Sca I that allowed us to carry out RFLP analysis of DNA extracted from the clinical samples and suggests that this mutation is more frequent than is documented in the p53 databases. Both the ECV-304 and EJ cell lines, that probably originate from the bladder carcinoma T24 cell line, were confirmed to contain the homozygous 378C>G mutation but were shown to produce the p53 protein of expected full-length size detected by Western blotting. We provide evidence that the 378C>G mutation generates an alternative 3' splice site (ss) which is more often used instead of the authentic upstream 3' ss, driving the production of mRNA encoding the protein with the single amino acid deletion (p53ΔY126). Using endogenous expression, we demonstrated that the p53ΔY126 protein is nearly as active as the wild type protein in inducing the p21/Waf1 expression and apoptosis.},\n chemicals = {Codon, Nonsense, DNA, Complementary, TP53 protein, human, Tumor Suppressor Protein p53},\n citation-subset = {IM},\n completed = {2017-11-03},\n country = {United States},\n doi = {10.1371/journal.pone.0185126},\n file = {:Makarov2017 - The Rare Nonsense Mutation in P53 Triggers Alternative Splicing to Produce a Protein Capable of Inducing Apoptosis..pdf:PDF},\n issn-linking = {1932-6203},\n issue = {9},\n keywords = {Alternative Splicing; Apoptosis; Blotting, Western; Cell Line, Tumor; Codon, Nonsense; DNA, Complementary, genetics; Flow Cytometry; Humans; Polymorphism, Restriction Fragment Length; Tumor Suppressor Protein p53, genetics},\n nlm-id = {101285081},\n owner = {NLM},\n pii = {e0185126},\n pmc = {PMC5621691},\n pmid = {28961258},\n pubmodel = {Electronic-eCollection},\n pubstate = {epublish},\n revised = {2018-11-13},\n}\n\n\n\n P53 protein is more frequently mutated in human tumours compared with the other proteins. While the majority of the p53 mutations, especially within its DNA-binding domain, lead to the loss of the wild-type function, there are accumulating data demonstrating that the p53 mutants gain tumour promoting activities; the latter triggers a revitalised interest in functional analysis of the p53 mutants. A systematic screening for p53 mutations in surgical materials from patients with glioma revealed a 378C>G mutation that creates a stop codon at the position of amino acid residue 126. The mutation eliminates the recognition site for the restriction endonuclease Sca I that allowed us to carry out RFLP analysis of DNA extracted from the clinical samples and suggests that this mutation is more frequent than is documented in the p53 databases. Both the ECV-304 and EJ cell lines, that probably originate from the bladder carcinoma T24 cell line, were confirmed to contain the homozygous 378C>G mutation but were shown to produce the p53 protein of expected full-length size detected by Western blotting. We provide evidence that the 378C>G mutation generates an alternative 3' splice site (ss) which is more often used instead of the authentic upstream 3' ss, driving the production of mRNA encoding the protein with the single amino acid deletion (p53ΔY126). Using endogenous expression, we demonstrated that the p53ΔY126 protein is nearly as active as the wild type protein in inducing the p21/Waf1 expression and apoptosis.\n
\n\n\n\n \n\n \n \n \n \n \n AGGREGATION BY LECTIN-METHODICAL APPROACH FOR EFFECTIVE ISOLATION OF EXOSOMES FROM CELL CULTURE SUPERNATANT FOR PROTEOME PROFILING.\n \n \n \n\n\n \n Shtam, T. A.; Burdakov, V. S.; Landa, S. B.; Naryzhny, S. N.; Bairamukov, V. Y.; Malek, A. V.; Orlov, Y. N.; and Filatov, M. V.\n\n\n \n\n\n\n Tsitologiia, 59: 5–12. 2017.\n \n\n\n\n
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\n\n\n@Article{Shtam2017,\n author = {Shtam, T. A. and Burdakov, V. S. and Landa, S. B. and Naryzhny, S. N. and Bairamukov, V. Yu and Malek, A. V. and Orlov, Yu N. and Filatov, M. V.},\n journal = {Tsitologiia},\n title = {AGGREGATION BY LECTIN-METHODICAL APPROACH FOR EFFECTIVE ISOLATION OF EXOSOMES FROM CELL CULTURE SUPERNATANT FOR PROTEOME PROFILING.},\n year = {2017},\n issn = {0041-3771},\n pages = {5--12},\n volume = {59},\n abstract = {Exosomes are small membrane vesicles secreted by most cell types in vivo and in vitro. Exosomes are found in cell culture media, blood, urine, amniotic fluid, malignant ascite fluids and contain distinct subsets of microRNAs and proteins depending upon the tissue from which they are secreted. Thus exosomes constitute potential biomarkers of human diseases, such as cancer. A major bottleneck in the development of exosome-based diagnostic assays is the challenging purification of these vesicles; this requires time-consuming and instrument-based procedures. Isolation of exosomes can be a tedious, non-specific, and difficult process. Here, we provide a preparative technique for isolation of exosomes based on their ability to aggregate in the presence of lectins. The new method for lectin-based isolation of exosomes from cell culture media was developed as a sample preparation step for exosome-based protein biomarker research.},\n chemicals = {Lectins, Proteome},\n citation-subset = {IM},\n completed = {2018-09-24},\n country = {Russia (Federation)},\n issn-linking = {0041-3771},\n issue = {1},\n keywords = {Exosomes, chemistry, metabolism; HeLa Cells; Humans; Lectins, chemistry; MCF-7 Cells; Proteome, metabolism; Proteomics, methods},\n nlm-id = {0417363},\n owner = {NLM},\n pmid = {30188097},\n pubmodel = {Print},\n pubstate = {ppublish},\n revised = {2018-09-24},\n}\n\n\n\n Exosomes are small membrane vesicles secreted by most cell types in vivo and in vitro. Exosomes are found in cell culture media, blood, urine, amniotic fluid, malignant ascite fluids and contain distinct subsets of microRNAs and proteins depending upon the tissue from which they are secreted. Thus exosomes constitute potential biomarkers of human diseases, such as cancer. A major bottleneck in the development of exosome-based diagnostic assays is the challenging purification of these vesicles; this requires time-consuming and instrument-based procedures. Isolation of exosomes can be a tedious, non-specific, and difficult process. Here, we provide a preparative technique for isolation of exosomes based on their ability to aggregate in the presence of lectins. The new method for lectin-based isolation of exosomes from cell culture media was developed as a sample preparation step for exosome-based protein biomarker research.\n
\n\n\n\n \n\n \n \n \n \n \n \n Exosomes: Some approaches to cancer diagnosis and therapy.\n \n \n \n \n\n\n \n Shtam, T.; Samsonov, R.; Kamyshinsky, R.; Pantina, R.; Verlov, N.; Vasiliev, A.; Konevega, A.; and Malek, A.\n\n\n \n\n\n\n In Physics of Cancer: Interdisciplinary Problems and Clinical Applications, volume 1882, of American Institute of Physics Conference Series, pages 020066, September 2017. \n \n\n\n\n
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\n\n\n@InProceedings{Shtam2017a,\n author = {Shtam, T. and Samsonov, R. and Kamyshinsky, R. and Pantina, R. and Verlov, N. and Vasiliev, A. and Konevega, A.~L. and Malek, A.~V.},\n booktitle = {Physics of Cancer: Interdisciplinary Problems and Clinical Applications},\n title = {Exosomes: Some approaches to cancer diagnosis and therapy},\n year = {2017},\n month = sep,\n pages = {020066},\n series = {American Institute of Physics Conference Series},\n volume = {1882},\n abstract = {Exosomes are membrane-bound, intercellular communication shuttle vesicles that are defined by their endocytic origin and size range of 30-120 nm. Secreted by nearly all mammalian cell types and present in bodily fluids, exosomes confer messages between cells, by transporting functionally relevant proteins, nucleic acids, and lipids. The capability of tumor exosomes to house tumorigenic information and induce cellular responses that promote disease pathogenesis make tumor exosomes an attractive tool in identifying cancer biomarkers and exploiting exosomes for therapy. In this paper, we sum up our previous findings to utilize exosomes as biomarkers for early detection, diagnosis and therapy selection of prostate and thyroid cancer and present our results on exosomes in colon cancer. Some of plasma exosomal miRNAs showed their potential as diagnostic markers for colon cancer. All together, the data suggested the potentials of circulating exosomal miRNAs as liquid biopsy markers for cancer. Here we also present the possibilities of delivering therapeutic molecules by exosomes. Previously, we had demonstrated the potential of exosome-mediated siRNA delivery. Here, we present the possibility of carrying the exogenous p53 protein by exosomes in vitro.},\n doi = {10.1063/1.5001645},\n eid = {020066},\n url = {https://ui.adsabs.harvard.edu/abs/2017AIPC.1882b0066S},\n}\n\n\n\n Exosomes are membrane-bound, intercellular communication shuttle vesicles that are defined by their endocytic origin and size range of 30-120 nm. Secreted by nearly all mammalian cell types and present in bodily fluids, exosomes confer messages between cells, by transporting functionally relevant proteins, nucleic acids, and lipids. The capability of tumor exosomes to house tumorigenic information and induce cellular responses that promote disease pathogenesis make tumor exosomes an attractive tool in identifying cancer biomarkers and exploiting exosomes for therapy. In this paper, we sum up our previous findings to utilize exosomes as biomarkers for early detection, diagnosis and therapy selection of prostate and thyroid cancer and present our results on exosomes in colon cancer. Some of plasma exosomal miRNAs showed their potential as diagnostic markers for colon cancer. All together, the data suggested the potentials of circulating exosomal miRNAs as liquid biopsy markers for cancer. Here we also present the possibilities of delivering therapeutic molecules by exosomes. Previously, we had demonstrated the potential of exosome-mediated siRNA delivery. Here, we present the possibility of carrying the exogenous p53 protein by exosomes in vitro.\n
\n\n\n\n \n\n \n \n \n \n \n P08.54 Targeting brain tumor with mesenchymal stem cells in the experimental model of the orthotopic glioblastoma.\n \n \n \n\n\n \n Timin, G.; Marchenko, Y.; Yakovleva, L.; Nikolaev, B.; Ryzhov, V.; Tolkunova, E.; and Shevtsov, M.\n\n\n \n\n\n\n Neuro-Oncology, 19(suppl_3): iii65-iii66. 2017.\n \n\n\n\n
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\n\n\n\n@Article{Timin2017,\n author = {G. Timin and Y. Marchenko and L. Yakovleva and B. Nikolaev and V. Ryzhov and E. Tolkunova and M. Shevtsov},\n journal = {Neuro-Oncology},\n title = {P08.54 Targeting brain tumor with mesenchymal stem cells in the experimental model of the orthotopic glioblastoma},\n year = {2017},\n issn = {1522-8517},\n number = {suppl_3},\n pages = {iii65-iii66},\n volume = {19},\n doi = {10.1093/neuonc/nox036.243},\n keywords = {Cancer Research, Neurology (clinical), Oncology},\n publisher = {Oxford University Press (OUP)},\n}\n\n\n\n \n\n \n \n \n \n \n P17.14 Connecting radiotherapy with targeted anti-glioma therapy using superparamagnetic nanoparticles conjugated with Granzyme B.\n \n \n \n\n\n \n Shevtsov, M.; Stangl, S.; Sievert, W.; Parr, M.; Nikolaev, B.; Illarionov, R.; Marchenko, Y.; Yakovleva, L.; Ryzhov, V.; and Multhoff, G.\n\n\n \n\n\n\n Neuro-Oncology, 19(suppl_3): iii119-iii119. 2017.\n \n\n\n\n
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\n\n\n\n@Article{Shevtsov2017,\n author = {M. Shevtsov and S. Stangl and W. Sievert and M. Parr and B. Nikolaev and R. Illarionov and Y. Marchenko and L. Yakovleva and V. Ryzhov and G. Multhoff},\n journal = {Neuro-Oncology},\n title = {P17.14 Connecting radiotherapy with targeted anti-glioma therapy using superparamagnetic nanoparticles conjugated with Granzyme B},\n year = {2017},\n issn = {1522-8517},\n number = {suppl_3},\n pages = {iii119-iii119},\n volume = {19},\n doi = {10.1093/neuonc/nox036.460},\n keywords = {Cancer Research, Neurology (clinical), Oncology},\n publisher = {Oxford University Press (OUP)},\n}\n\n\n\n
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\n \n \n\n \n \n \n \n \n The pathway to GTPase activation of elongation factor SelB on the ribosome.\n \n \n \n\n\n \n Fischer, N.; Neumann, P.; Bock, L. V.; Maracci, C.; Wang, Z.; Paleskava, A.; Konevega, A. L.; Schröder, G. F.; Grubmüller, H.; Ficner, R.; Rodnina, M. V.; and Stark, H.\n\n\n \n\n\n\n Nature, 540: 80–85. December 2016.\n \n\n\n\n
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\n\n\n@Article{Fischer2016,\n author = {Fischer, Niels and Neumann, Piotr and Bock, Lars V. and Maracci, Cristina and Wang, Zhe and Paleskava, Alena and Konevega, Andrey L. and Schröder, Gunnar F. and Grubmüller, Helmut and Ficner, Ralf and Rodnina, Marina V. and Stark, Holger},\n journal = {Nature},\n title = {The pathway to GTPase activation of elongation factor SelB on the ribosome.},\n year = {2016},\n issn = {1476-4687},\n month = dec,\n pages = {80--85},\n volume = {540},\n abstract = {In all domains of life, selenocysteine (Sec) is delivered to the ribosome by selenocysteine-specific tRNA (tRNA ) with the help of a specialized translation factor, SelB in bacteria. Sec-tRNA recodes a UGA stop codon next to a downstream mRNA stem-loop. Here we present the structures of six intermediates on the pathway of UGA recoding in Escherichia coli by single-particle cryo-electron microscopy. The structures explain the specificity of Sec-tRNA binding by SelB and show large-scale rearrangements of Sec-tRNA . Upon initial binding of SelB-Sec-tRNA to the ribosome and codon reading, the 30S subunit adopts an open conformation with Sec-tRNA covering the sarcin-ricin loop (SRL) on the 50S subunit. Subsequent codon recognition results in a local closure of the decoding site, which moves Sec-tRNA away from the SRL and triggers a global closure of the 30S subunit shoulder domain. As a consequence, SelB docks on the SRL, activating the GTPase of SelB. These results reveal how codon recognition triggers GTPase activation in translational GTPases.},\n chemicals = {Bacterial Proteins, Codon, Terminator, Fungal Proteins, RNA, Transfer, Amino Acid-Specific, SelB protein, Bacteria, tRNA, selenocysteine-, Selenocysteine, alpha-sarcin, Ricin, Endoribonucleases, GTP Phosphohydrolases},\n citation-subset = {IM},\n completed = {2017-03-16},\n country = {England},\n doi = {10.1038/nature20560},\n issn-linking = {0028-0836},\n issue = {7631},\n keywords = {Bacterial Proteins, chemistry, metabolism, ultrastructure; Binding Sites; Codon, Terminator, chemistry, genetics, metabolism; Cryoelectron Microscopy; Endoribonucleases, metabolism; Enzyme Activation; Escherichia coli, chemistry, genetics, metabolism, ultrastructure; Fungal Proteins, metabolism; GTP Phosphohydrolases, metabolism, ultrastructure; Models, Molecular; Nucleic Acid Conformation; Protein Binding; Protein Biosynthesis; Protein Domains; RNA, Transfer, Amino Acid-Specific, chemistry, genetics, metabolism, ultrastructure; Ribosome Subunits, Large, Bacterial, chemistry, metabolism, ultrastructure; Ribosome Subunits, Small, Bacterial, chemistry, metabolism, ultrastructure; Ribosomes, chemistry, enzymology, metabolism, ultrastructure; Ricin, metabolism; Selenocysteine, metabolism},\n nlm-id = {0410462},\n owner = {NLM},\n pii = {nature20560},\n pmid = {27842381},\n pubmodel = {Print-Electronic},\n pubstate = {ppublish},\n revised = {2018-11-13},\n}\n\n\n\n In all domains of life, selenocysteine (Sec) is delivered to the ribosome by selenocysteine-specific tRNA (tRNA ) with the help of a specialized translation factor, SelB in bacteria. Sec-tRNA recodes a UGA stop codon next to a downstream mRNA stem-loop. Here we present the structures of six intermediates on the pathway of UGA recoding in Escherichia coli by single-particle cryo-electron microscopy. The structures explain the specificity of Sec-tRNA binding by SelB and show large-scale rearrangements of Sec-tRNA . Upon initial binding of SelB-Sec-tRNA to the ribosome and codon reading, the 30S subunit adopts an open conformation with Sec-tRNA covering the sarcin-ricin loop (SRL) on the 50S subunit. Subsequent codon recognition results in a local closure of the decoding site, which moves Sec-tRNA away from the SRL and triggers a global closure of the 30S subunit shoulder domain. As a consequence, SelB docks on the SRL, activating the GTPase of SelB. These results reveal how codon recognition triggers GTPase activation in translational GTPases.\n
\n\n\n\n \n\n \n \n \n \n \n New Fluorescent Macrolide Derivatives for Studying Interactions of Antibiotics and Their Analogs with the Ribosomal Exit Tunnel.\n \n \n \n\n\n \n Tereshchenkov, A. G.; Shishkina, A. V.; Karpenko, V. V.; Chertkov, V. A.; Konevega, A. L.; Kasatsky, P. S.; Bogdanov, A. A.; and Sumbatyan, N. V.\n\n\n \n\n\n\n Biochemistry. Biokhimiia, 81: 1163–1172. October 2016.\n \n\n\n\n
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\n\n\n@Article{Tereshchenkov2016,\n author = {Tereshchenkov, A. G. and Shishkina, A. V. and Karpenko, V. V. and Chertkov, V. A. and Konevega, A. L. and Kasatsky, P. S. and Bogdanov, A. A. and Sumbatyan, N. V.},\n journal = {Biochemistry. Biokhimiia},\n title = {New Fluorescent Macrolide Derivatives for Studying Interactions of Antibiotics and Their Analogs with the Ribosomal Exit Tunnel.},\n year = {2016},\n issn = {1608-3040},\n month = oct,\n pages = {1163--1172},\n volume = {81},\n abstract = {Novel fluorescent derivatives of macrolide antibiotics related to tylosin bearing rhodamine, fluorescein, Alexa Fluor 488, BODIPY FL, and nitrobenzoxadiazole (NBD) residues were synthesized. The formation of complexes of these compounds with 70S E. coli ribosomes was studied by measuring the fluorescence polarization depending on the ribosome amount at constant concentration of the fluorescent substance. With the synthesized fluorescent tylosin derivatives, the dissociation constants for ribosome complexes with several known antibiotics and macrolide analogs previously obtained were determined. It was found that the fluorescent tylosin derivatives containing BODIPY FL and NBD groups could be used to screen the binding of novel antibiotics to bacterial ribosomes in the macrolide-binding site.},\n chemicals = {Fluorescent Dyes, Tylosin},\n citation-subset = {IM},\n completed = {2017-01-12},\n country = {United States},\n doi = {10.1134/S0006297916100138},\n issn-linking = {0006-2979},\n issue = {10},\n keywords = {Escherichia coli, chemistry; Fluorescent Dyes, chemistry; Ribosomes, chemistry; Tylosin, analogs & derivatives, chemistry},\n nlm-id = {0376536},\n owner = {NLM},\n pii = {BCM81101439},\n pmid = {27908240},\n pubmodel = {Print},\n pubstate = {ppublish},\n revised = {2017-01-13},\n}\n\n\n\n Novel fluorescent derivatives of macrolide antibiotics related to tylosin bearing rhodamine, fluorescein, Alexa Fluor 488, BODIPY FL, and nitrobenzoxadiazole (NBD) residues were synthesized. The formation of complexes of these compounds with 70S E. coli ribosomes was studied by measuring the fluorescence polarization depending on the ribosome amount at constant concentration of the fluorescent substance. With the synthesized fluorescent tylosin derivatives, the dissociation constants for ribosome complexes with several known antibiotics and macrolide analogs previously obtained were determined. It was found that the fluorescent tylosin derivatives containing BODIPY FL and NBD groups could be used to screen the binding of novel antibiotics to bacterial ribosomes in the macrolide-binding site.\n
\n\n\n\n \n\n \n \n \n \n \n Plasma exosomal miR-21 and miR-181a differentiates follicular from papillary thyroid cancer.\n \n \n \n\n\n \n Samsonov, R.; Burdakov, V.; Shtam, T.; Radzhabovа, Z.; Vasilyev, D.; Tsyrlina, E.; Titov, S.; Ivanov, M.; Berstein, L.; Filatov, M.; Kolesnikov, N.; Gil-Henn, H.; and Malek, A.\n\n\n \n\n\n\n Tumour biology : the journal of the International Society for Oncodevelopmental Biology and Medicine, 37: 12011–12021. September 2016.\n \n\n\n\n
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\n\n\n@Article{Samsonov2016,\n author = {Samsonov, Roman and Burdakov, Vladimir and Shtam, Tatiana and Radzhabovа, Zamira and Vasilyev, Dmitry and Tsyrlina, Evgenia and Titov, Sergey and Ivanov, Michail and Berstein, Lev and Filatov, Michael and Kolesnikov, Nikolay and Gil-Henn, Hava and Malek, Anastasia},\n journal = {Tumour biology : the journal of the International Society for Oncodevelopmental Biology and Medicine},\n title = {Plasma exosomal miR-21 and miR-181a differentiates follicular from papillary thyroid cancer.},\n year = {2016},\n issn = {1423-0380},\n month = sep,\n pages = {12011--12021},\n volume = {37},\n abstract = {Thyroid cancer (TC) is the most common endocrine malignancy and its incidence has increased over the last few decades. As has been revealed by a number of studies, TC tissue's micro-RNA (miRNA) profile may reflect histological features and the clinical behavior of tumor. However, alteration of the miRNA profile of plasma exosomes associated with TC development has to date not been explored. We isolated exosomes from plasma and assayed their characteristics using laser diffraction particle size analysis, atomic force microscopy, and western blotting. Next, we profiled cancer-associated miRNAs in plasma exosomes obtained from papillary TC patients, before and after surgical removal of the tumor. The diagnostic value of selected miRNAs was evaluated in a large cohort of patients displaying different statuses of thyroid nodule disease. MiRNA assessment was performed by RT-qPCR. In total, 60 patients with different types of thyroid nodal pathology were included in the study. Our results revealed that the development of papillary TC is associated with specific changes in exosomal miRNA profiles; this phenomenon can be used for differential diagnostics. MiRNA-31 was found to be over-represented in the plasma exosomes of patients with papillary TC vs. benign tumors, while miRNA-21 helped to distinguish between benign tumors and follicular TC. MiRNA-21 and MiRNA-181a-5p were found to be expressed reciprocally in the exosomes of patients with papillary and follicular TC, and their comparative assessment may help to distinguish between these types of TC with 100 % sensitivity and 77 % specificity.},\n chemicals = {MIRN21 microRNA, human, MIrn181 microRNA, human, MicroRNAs},\n citation-subset = {IM},\n completed = {2017-02-13},\n country = {Netherlands},\n doi = {10.1007/s13277-016-5065-3},\n issn-linking = {1010-4283},\n issue = {9},\n keywords = {Adenocarcinoma, Follicular, genetics; Adult; Carcinoma, genetics; Carcinoma, Papillary; Diagnosis, Differential; Exosomes, chemistry; Female; Humans; Male; MicroRNAs, blood; Middle Aged; Thyroid Cancer, Papillary; Thyroid Neoplasms, genetics; Diagnostics; Exosomes; MicroRNA; Thyroid cancer},\n nlm-id = {8409922},\n owner = {NLM},\n pii = {10.1007/s13277-016-5065-3},\n pmid = {27164936},\n pubmodel = {Print-Electronic},\n pubstate = {ppublish},\n revised = {2018-12-02},\n}\n\n\n\n Thyroid cancer (TC) is the most common endocrine malignancy and its incidence has increased over the last few decades. As has been revealed by a number of studies, TC tissue's micro-RNA (miRNA) profile may reflect histological features and the clinical behavior of tumor. However, alteration of the miRNA profile of plasma exosomes associated with TC development has to date not been explored. We isolated exosomes from plasma and assayed their characteristics using laser diffraction particle size analysis, atomic force microscopy, and western blotting. Next, we profiled cancer-associated miRNAs in plasma exosomes obtained from papillary TC patients, before and after surgical removal of the tumor. The diagnostic value of selected miRNAs was evaluated in a large cohort of patients displaying different statuses of thyroid nodule disease. MiRNA assessment was performed by RT-qPCR. In total, 60 patients with different types of thyroid nodal pathology were included in the study. Our results revealed that the development of papillary TC is associated with specific changes in exosomal miRNA profiles; this phenomenon can be used for differential diagnostics. MiRNA-31 was found to be over-represented in the plasma exosomes of patients with papillary TC vs. benign tumors, while miRNA-21 helped to distinguish between benign tumors and follicular TC. MiRNA-21 and MiRNA-181a-5p were found to be expressed reciprocally in the exosomes of patients with papillary and follicular TC, and their comparative assessment may help to distinguish between these types of TC with 100 % sensitivity and 77 % specificity.\n
\n\n\n\n \n\n \n \n \n \n \n Lectin-induced agglutination method of urinary exosomes isolation followed by mi-RNA analysis: Application for prostate cancer diagnostic.\n \n \n \n\n\n \n Samsonov, R.; Shtam, T.; Burdakov, V.; Glotov, A.; Tsyrlina, E.; Berstein, L.; Nosov, A.; Evtushenko, V.; Filatov, M.; and Malek, A.\n\n\n \n\n\n\n The Prostate, 76: 68–79. January 2016.\n \n\n\n\n
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\n\n\n@Article{Samsonov2016a,\n author = {Samsonov, Roman and Shtam, Tatiana and Burdakov, Vladimir and Glotov, Andrey and Tsyrlina, Evgenia and Berstein, Lev and Nosov, Alexander and Evtushenko, Vladimir and Filatov, Michael and Malek, Anastasia},\n journal = {The Prostate},\n title = {Lectin-induced agglutination method of urinary exosomes isolation followed by mi-RNA analysis: Application for prostate cancer diagnostic.},\n year = {2016},\n issn = {1097-0045},\n month = jan,\n pages = {68--79},\n volume = {76},\n abstract = {Prostate cancer is the most common cancer in men. Prostate-specific antigen has, however, insufficient diagnostic specificity. Novel complementary diagnostic approaches are greatly needed. MiRNAs are small regulatory RNAs which play an important role in tumorogenesis and are being investigated as a cancer biomarker. In addition to their intracellular regulatory functions, miRNAs are secreted into the extracellular space and can be found in various body fluids, including urine. The stability of extracellular miRNAs is defined by association with proteins, lipoprotein particles, and membrane vesicles. Among the known forms of miRNA packaging, tumour-derived exosome-enclosed miRNAs is thought to reflect the vital activity of cancer cells. The assessment of the exosomal fraction of urinary miRNA may present a new and highly specific method for prostate cancer diagnostics; however, this is challenged by the absence of reliable and inexpensive methods for isolation of exosomes. Prostate cancer (PC) cell lines and urine samples collected from 35 PC patients and 35 healthy donors were used in the study. Lectins, phytohemagglutinin, and concanavalin A were used to induce agglutination of exosomes. The efficiency of isolation process was evaluated by AFM and DLS assays. The protein content of isolated exosomes was analysed by western blotting. Exosomal RNA was assayed by automated electrophoresis and expression level of selected miRNAs was evaluated by RT-qPCR. The diagnostic potency of the urinary exosomal miRNA assessment was estimated by the ROC method. The formation of multi-vesicular agglutinates in urine can be induced by incubation with lectin at a final concentration of 2 mg/ml. These agglutinates contain urinary exosomes and may be pelleted by centrifugation with a relatively low G-force. The analysis of PC-related miRNA in urinary exosomes revealed significant up-regulation of miR-574-3p, miR-141-5p, and miR-21-5p associated with PC. Lectin-induced aggregation is a low-cost and easily performed method for isolation of exosomes from urine. Isolated exosomes can be further analysed in terms of miRNA content. The miRNA profile of urinary exosomes reflects development of prostate cancer and may present a promising diagnostic tool.},\n chemicals = {Biomarkers, Lectins, MicroRNAs},\n citation-subset = {IM},\n completed = {2016-05-25},\n country = {United States},\n doi = {10.1002/pros.23101},\n issn-linking = {0270-4137},\n issue = {1},\n keywords = {Adult; Aged; Agglutination Tests, methods; Biomarkers, urine; Exosomes, metabolism; Humans; Lectins, pharmacology; Male; MicroRNAs, urine; Middle Aged; Neoplasm Grading; Neoplasm Staging; Prostatic Neoplasms, diagnosis, pathology, urine; Reproducibility of Results; Tumor Cells, Cultured; diagnostic; exosomes; lectin; miRNA; prostate cancer},\n nlm-id = {8101368},\n owner = {NLM},\n pmid = {26417675},\n pubmodel = {Print-Electronic},\n pubstate = {ppublish},\n revised = {2016-01-15},\n}\n\n\n\n Prostate cancer is the most common cancer in men. Prostate-specific antigen has, however, insufficient diagnostic specificity. Novel complementary diagnostic approaches are greatly needed. MiRNAs are small regulatory RNAs which play an important role in tumorogenesis and are being investigated as a cancer biomarker. In addition to their intracellular regulatory functions, miRNAs are secreted into the extracellular space and can be found in various body fluids, including urine. The stability of extracellular miRNAs is defined by association with proteins, lipoprotein particles, and membrane vesicles. Among the known forms of miRNA packaging, tumour-derived exosome-enclosed miRNAs is thought to reflect the vital activity of cancer cells. The assessment of the exosomal fraction of urinary miRNA may present a new and highly specific method for prostate cancer diagnostics; however, this is challenged by the absence of reliable and inexpensive methods for isolation of exosomes. Prostate cancer (PC) cell lines and urine samples collected from 35 PC patients and 35 healthy donors were used in the study. Lectins, phytohemagglutinin, and concanavalin A were used to induce agglutination of exosomes. The efficiency of isolation process was evaluated by AFM and DLS assays. The protein content of isolated exosomes was analysed by western blotting. Exosomal RNA was assayed by automated electrophoresis and expression level of selected miRNAs was evaluated by RT-qPCR. The diagnostic potency of the urinary exosomal miRNA assessment was estimated by the ROC method. The formation of multi-vesicular agglutinates in urine can be induced by incubation with lectin at a final concentration of 2 mg/ml. These agglutinates contain urinary exosomes and may be pelleted by centrifugation with a relatively low G-force. The analysis of PC-related miRNA in urinary exosomes revealed significant up-regulation of miR-574-3p, miR-141-5p, and miR-21-5p associated with PC. Lectin-induced aggregation is a low-cost and easily performed method for isolation of exosomes from urine. Isolated exosomes can be further analysed in terms of miRNA content. The miRNA profile of urinary exosomes reflects development of prostate cancer and may present a promising diagnostic tool.\n
\n\n\n\n \n\n \n \n \n \n \n Design of Stable α-Helical Peptides and Thermostable Proteins in Biotechnology and Biomedicine.\n \n \n \n\n\n \n Yakimov, A. P.; Afanaseva, A. S.; Khodorkovskiy, M. A.; and Petukhov, M. G.\n\n\n \n\n\n\n Acta naturae, 8: 70–81. 2016.\n \n\n\n\n
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\n\n\n@Article{Yakimov2016,\n author = {Yakimov, A. P. and Afanaseva, A. S. and Khodorkovskiy, M. A. and Petukhov, M. G.},\n journal = {Acta naturae},\n title = {Design of Stable α-Helical Peptides and Thermostable Proteins in Biotechnology and Biomedicine.},\n year = {2016},\n issn = {2075-8251},\n pages = {70--81},\n volume = {8},\n abstract = {α-Helices are the most frequently occurring elements of the secondary structure in water-soluble globular proteins. Their increased conformational stability is among the main reasons for the high thermal stability of proteins in thermophilic bacteria. In addition, α-helices are often involved in protein interactions with other proteins, nucleic acids, and the lipids of cell membranes. That is why the highly stable α-helical peptides used as highly active and specific inhibitors of protein-protein and other interactions have recently found more applications in medicine. Several different approaches have been developed in recent years to improve the conformational stability of α-helical peptides and thermostable proteins, which will be discussed in this review. We also discuss the methods for improving the permeability of peptides and proteins across cellular membranes and their resistance to intracellular protease activity. Special attention is given to the SEQOPT method (http://mml.spbstu.ru/services/seqopt/), which is used to design conformationally stable short α-helices.},\n country = {Russia (Federation)},\n issn-linking = {2075-8251},\n issue = {4},\n keywords = {conformational stability; factors of thermal stability; membrane permeability; resistance to intracellular proteolysis; α-helix},\n nlm-id = {101525823},\n owner = {NLM},\n pmc = {PMC5199208},\n pmid = {28050268},\n pubmodel = {Print},\n pubstate = {ppublish},\n revised = {2020-10-01},\n season = {Oct-Dec},\n}\n\n\n\n α-Helices are the most frequently occurring elements of the secondary structure in water-soluble globular proteins. Their increased conformational stability is among the main reasons for the high thermal stability of proteins in thermophilic bacteria. In addition, α-helices are often involved in protein interactions with other proteins, nucleic acids, and the lipids of cell membranes. That is why the highly stable α-helical peptides used as highly active and specific inhibitors of protein-protein and other interactions have recently found more applications in medicine. Several different approaches have been developed in recent years to improve the conformational stability of α-helical peptides and thermostable proteins, which will be discussed in this review. We also discuss the methods for improving the permeability of peptides and proteins across cellular membranes and their resistance to intracellular protease activity. Special attention is given to the SEQOPT method (http://mml.spbstu.ru/services/seqopt/), which is used to design conformationally stable short α-helices.\n
\n\n\n\n \n\n \n \n \n \n \n \n Recognition of Specific Uridines in tRNA Substrates by Dihydrouridine Synthases.\n \n \n \n \n\n\n \n Jenkins, H.; Whelan, F.; Peters, D.; Byrne, R.; Konevega, A.; Koonin, E.; and Antson, F.\n\n\n \n\n\n\n Biophysical Journal, 110(3): 239a. February 2016.\n \n\n\n\n
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\n\n\n\n@Article{Jenkins2016,\n author = {Jenkins, Huw and Whelan, Fiona and Peters, Daniel and Byrne, Robert and Konevega, Andrey and Koonin, Eugene and Antson, Fred},\n journal = {Biophysical Journal},\n title = {Recognition of Specific Uridines in tRNA Substrates by Dihydrouridine Synthases},\n year = {2016},\n month = feb,\n number = {3},\n pages = {239a},\n volume = {110},\n doi = {10.1016/j.bpj.2015.11.1319},\n url = {https://ui.adsabs.harvard.edu/abs/2016BpJ...110R.239J},\n}\n\n\n\n \n\n \n \n \n \n \n Detection of experimental myocardium infarction in rats by MRI using heat shock protein 70 conjugated superparamagnetic iron oxide nanoparticle.\n \n \n \n\n\n \n Shevtsov, M. A.; Nikolaev, B. P.; Ryzhov, V. A.; Yakovleva, L. Y.; Dobrodumov, A. V.; Marchenko, Y. Y.; Margulis, B. A.; Pitkin, E.; Mikhrina, A. L.; Guzhova, I. V.; and Multhoff, G.\n\n\n \n\n\n\n Nanomedicine : nanotechnology, biology, and medicine, 12: 611–621. April 2016.\n \n\n\n\n
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\n\n\n@Article{Shevtsov2016,\n author = {Shevtsov, Maxim A. and Nikolaev, Boris P. and Ryzhov, Vyacheslav A. and Yakovleva, Ludmila Y. and Dobrodumov, Anatolii V. and Marchenko, Yaroslav Y. and Margulis, Boris A. and Pitkin, Emil and Mikhrina, Anastasiy L. and Guzhova, Irina V. and Multhoff, Gabriele},\n journal = {Nanomedicine : nanotechnology, biology, and medicine},\n title = {Detection of experimental myocardium infarction in rats by MRI using heat shock protein 70 conjugated superparamagnetic iron oxide nanoparticle.},\n year = {2016},\n issn = {1549-9642},\n month = apr,\n pages = {611--621},\n volume = {12},\n abstract = {Superparamagnetic iron-oxide based contrast agents can provide important diagnostic information regarding the assessment of cardiac inflammatory diseases. The aim of the study was to analyze whether nanoparticles conjugated to recombinant 70-kDa heat shock protein (Hsp70-SPION) can be applied for the detection of acute myocardium infarct by MRI. Cellular experiments demonstrated increased CD40-mediated uptake of Hsp70-SPIONs in comparison to non-conjugated SPIONs. Following induction of an acute infarct in rats by ligation of the left anterior descending artery SPIONs and Hsp70-SPION conjugates were injected intravenously on day 4. The animals underwent sequential MRI that showed the presence of the particles in the infarcted zone. Subsequent biodistribution analyses with the help of method on non-linear magnetic response indicated the preferential accumulation of the Hsp70-SPIONs in the heart tissue that was further confirmed with histological analyses. The study demonstrated that an acute infarct can be visualized by MRI using Hsp70-functionalized SPION conjugates. Superparamagnetic iron oxides nanoparticles (SPIONs) have been studied extensively as a contrast agent for MRI. Their tissue specificity can be further enhanced by conjugation with various ligands. In this study, the authors conjugated superparamagnetic nanoparticles to 70-kDa heat shock protein (Hsp70-SPION) to investigate the feasibility for the detection of acute myocardium infarct. The positive findings would suggest that this approach might be used clinically in the future.},\n chemicals = {Contrast Media, Ferric Compounds, HSP70 Heat-Shock Proteins, Magnetite Nanoparticles, ferric oxide},\n citation-subset = {IM},\n completed = {2016-12-13},\n country = {United States},\n doi = {10.1016/j.nano.2015.10.017},\n issn-linking = {1549-9634},\n issue = {3},\n keywords = {Animals; Contrast Media, chemistry, pharmacokinetics; Ferric Compounds, chemistry, pharmacokinetics; HSP70 Heat-Shock Proteins, chemistry, pharmacokinetics; Magnetic Resonance Imaging, methods; Magnetite Nanoparticles, analysis, chemistry; Male; Myocardial Infarction, diagnostic imaging; Myocardium, pathology; Rats, Wistar; Tissue Distribution; CD40; Hsp70; Magnetic resonance imaging; Myocardial infarction; Superparamagnetic nanoparticles},\n nlm-id = {101233142},\n owner = {NLM},\n pii = {S1549-9634(15)00209-9},\n pmid = {26656626},\n pubmodel = {Print-Electronic},\n pubstate = {ppublish},\n revised = {2022-03-10},\n}\n\n\n\n Superparamagnetic iron-oxide based contrast agents can provide important diagnostic information regarding the assessment of cardiac inflammatory diseases. The aim of the study was to analyze whether nanoparticles conjugated to recombinant 70-kDa heat shock protein (Hsp70-SPION) can be applied for the detection of acute myocardium infarct by MRI. Cellular experiments demonstrated increased CD40-mediated uptake of Hsp70-SPIONs in comparison to non-conjugated SPIONs. Following induction of an acute infarct in rats by ligation of the left anterior descending artery SPIONs and Hsp70-SPION conjugates were injected intravenously on day 4. The animals underwent sequential MRI that showed the presence of the particles in the infarcted zone. Subsequent biodistribution analyses with the help of method on non-linear magnetic response indicated the preferential accumulation of the Hsp70-SPIONs in the heart tissue that was further confirmed with histological analyses. The study demonstrated that an acute infarct can be visualized by MRI using Hsp70-functionalized SPION conjugates. Superparamagnetic iron oxides nanoparticles (SPIONs) have been studied extensively as a contrast agent for MRI. Their tissue specificity can be further enhanced by conjugation with various ligands. In this study, the authors conjugated superparamagnetic nanoparticles to 70-kDa heat shock protein (Hsp70-SPION) to investigate the feasibility for the detection of acute myocardium infarct. The positive findings would suggest that this approach might be used clinically in the future.\n
\n\n\n\n \n\n \n \n \n \n \n P07.20 Combination of the radiotherapy and targeted magnetic nanoparticles in the theranostics of the Hsp70-positive brain tumors.\n \n \n \n\n\n \n Shevtsov, M.; Stangl, S.; Riederer, I.; Sievert, W.; Parr, M.; Marchenko, Y.; Yakovleva, L.; Nikolaev, B.; Ryzhov, V.; and Multhoff, G.\n\n\n \n\n\n\n Neuro-Oncology, 18(suppl_4): iv38-iv39. 2016.\n \n\n\n\n
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\n\n\n\n@Article{Shevtsov2016a,\n author = {M. Shevtsov and S. Stangl and I. Riederer and W. Sievert and M. Parr and Y. Marchenko and L. Yakovleva and B. Nikolaev and V. Ryzhov and G. Multhoff},\n journal = {Neuro-Oncology},\n title = {P07.20 Combination of the radiotherapy and targeted magnetic nanoparticles in the theranostics of the Hsp70-positive brain tumors},\n year = {2016},\n issn = {1523-5866},\n number = {suppl_4},\n pages = {iv38-iv39},\n volume = {18},\n doi = {10.1093/neuonc/now188.131},\n keywords = {Cancer Research, Neurology (clinical), Oncology},\n publisher = {Oxford University Press (OUP)},\n}\n\n\n\n \n\n \n \n \n \n \n Structure of the 70S ribosome with fMetSec-tRNASec in the hybrid pre-translocation state (H).\n \n \n \n\n\n \n Fischer, N.; Neumann, P.; Bock, L. V.; Maracci, C.; Wang, Z.; Paleskava, A.; Konevega, A. L.; Schroeder, G. F.; Grubmueller, H.; Ficner, R.; Rodnina, M. V.; and Stark, H.\n\n\n \n\n\n\n November 2016.\n \n\n\n\n
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\n\n\n\n@Misc{Fischer2016b,\n author = {N. Fischer and P. Neumann and L. V. Bock and C. Maracci and Z. Wang and A. Paleskava and A. L. Konevega and G. F. Schroeder and H. Grubmueller and R. Ficner and M. V. Rodnina and H. Stark},\n month = nov,\n title = {Structure of the 70S ribosome with fMetSec-tRNASec in the hybrid pre-translocation state (H)},\n year = {2016},\n doi = {10.2210/pdb5lzf/pdb},\n publisher = {Worldwide Protein Data Bank},\n}\n\n\n\n \n\n \n \n \n \n \n Structure of SelB-Sec-tRNASec bound to the 70S ribosome in the initial binding state (IB).\n \n \n \n\n\n \n Fischer, N.; Neumann, P.; Bock, L. V.; Maracci, C.; Wang, Z.; Paleskava, A.; Konevega, A. L.; Schroeder, G. F.; Grubmueller, H.; Ficner, R.; Rodnina, M. V.; and Stark, H.\n\n\n \n\n\n\n November 2016.\n \n\n\n\n
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\n\n\n\n@Misc{Fischer2016c,\n author = {N. Fischer and P. Neumann and L. V. Bock and C. Maracci and Z. Wang and A. Paleskava and A. L. Konevega and G. F. Schroeder and H. Grubmueller and R. Ficner and M. V. Rodnina and H. Stark},\n month = nov,\n title = {Structure of SelB-Sec-tRNASec bound to the 70S ribosome in the initial binding state (IB)},\n year = {2016},\n doi = {10.2210/pdb5lzb/pdbx},\n publisher = {Worldwide Protein Data Bank},\n}\n\n\n\n \n\n \n \n \n \n \n Structure of SelB-Sec-tRNASec bound to the 70S ribosome in the GTPase activated state (GA).\n \n \n \n\n\n \n Fischer, N.; Neumann, P.; Bock, L. V.; Maracci, C.; Wang, Z.; Paleskava, A.; Konevega, A. L.; Schroeder, G. F.; Grubmueller, H.; Ficner, R.; Rodnina, M. V.; and Stark, H.\n\n\n \n\n\n\n November 2016.\n \n\n\n\n
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\n\n\n\n@Misc{Fischer2016d,\n author = {N. Fischer and P. Neumann and L. V. Bock and C. Maracci and Z. Wang and A. Paleskava and A. L. Konevega and G. F. Schroeder and H. Grubmueller and R. Ficner and M. V. Rodnina and H. Stark},\n month = nov,\n title = {Structure of SelB-Sec-tRNASec bound to the 70S ribosome in the GTPase activated state (GA)},\n year = {2016},\n doi = {10.2210/pdb5lzd/pdbx},\n publisher = {Worldwide Protein Data Bank},\n}\n\n\n\n \n\n \n \n \n \n \n Structure of the 70S ribosome with Sec-tRNASec in the classical pre-translocation state (C).\n \n \n \n\n\n \n Fischer, N.; Neumann, P.; Bock, L. V.; Maracci, C.; Wang, Z.; Paleskava, A.; Konevega, A. L.; Schroeder, G. F.; Grubmueller, H.; Ficner, R.; Rodnina, M. V.; and Stark, H.\n\n\n \n\n\n\n November 2016.\n \n\n\n\n
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\n\n\n\n@Misc{Fischer2016e,\n author = {N. Fischer and P. Neumann and L. V. Bock and C. Maracci and Z. Wang and A. Paleskava and A. L. Konevega and G. F. Schroeder and H. Grubmueller and R. Ficner and M. V. Rodnina and H. Stark},\n month = nov,\n title = {Structure of the 70S ribosome with Sec-tRNASec in the classical pre-translocation state (C)},\n year = {2016},\n doi = {10.2210/pdb5lze/pdbx},\n publisher = {Worldwide Protein Data Bank},\n}\n\n\n\n \n\n \n \n \n \n \n Structure of the 70S ribosome with SECIS-mRNA and P-site tRNA (Initial complex, IC).\n \n \n \n\n\n \n Fischer, N.; Neumann, P.; Bock, L. V.; Maracci, C.; Wang, Z.; Paleskava, A.; Konevega, A. L.; Schroeder, G. F.; Grubmueller, H.; Ficner, R.; Rodnina, M. V.; and Stark, H.\n\n\n \n\n\n\n November 2016.\n \n\n\n\n
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\n\n\n\n@Misc{Fischer2016f,\n author = {N. Fischer and P. Neumann and L. V. Bock and C. Maracci and Z. Wang and A. Paleskava and A. L. Konevega and G. F. Schroeder and H. Grubmueller and R. Ficner and M. V. Rodnina and H. Stark},\n month = nov,\n title = {Structure of the 70S ribosome with SECIS-mRNA and P-site tRNA (Initial complex, IC)},\n year = {2016},\n doi = {10.2210/pdb5lza/pdbx},\n publisher = {Worldwide Protein Data Bank},\n}\n\n\n\n \n\n \n \n \n \n \n Structure of SelB-Sec-tRNASec bound to the 70S ribosome in the codon reading state (CR).\n \n \n \n\n\n \n Fischer, N.; Neumann, P.; Bock, L. V.; Maracci, C.; Wang, Z.; Paleskava, A.; Konevega, A. L.; Schroeder, G. F.; Grubmueller, H.; Ficner, R.; Rodnina, M. V.; and Stark, H.\n\n\n \n\n\n\n November 2016.\n \n\n\n\n
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\n\n\n\n@Misc{Fischer2016g,\n author = {N. Fischer and P. Neumann and L. V. Bock and C. Maracci and Z. Wang and A. Paleskava and A. L. Konevega and G. F. Schroeder and H. Grubmueller and R. Ficner and M. V. Rodnina and H. Stark},\n month = nov,\n title = {Structure of SelB-Sec-tRNASec bound to the 70S ribosome in the codon reading state (CR)},\n year = {2016},\n doi = {10.2210/pdb5lzc/pdb},\n publisher = {Worldwide Protein Data Bank},\n}\n\n\n\n \n\n \n \n \n \n \n Structure of SelB-Sec-tRNASec bound to the 70S ribosome in the initial binding state (IB).\n \n \n \n\n\n \n Fischer, N.; Neumann, P.; Bock, L. V.; Maracci, C.; Wang, Z.; Paleskava, A.; Konevega, A. L.; Schroeder, G. F.; Grubmueller, H.; Ficner, R.; Rodnina, M. V.; and Stark, H.\n\n\n \n\n\n\n November 2016.\n \n\n\n\n
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\n\n\n\n@Misc{Fischer2016h,\n author = {N. Fischer and P. Neumann and L. V. Bock and C. Maracci and Z. Wang and A. Paleskava and A. L. Konevega and G. F. Schroeder and H. Grubmueller and R. Ficner and M. V. Rodnina and H. Stark},\n month = nov,\n title = {Structure of SelB-Sec-tRNASec bound to the 70S ribosome in the initial binding state (IB)},\n year = {2016},\n doi = {10.2210/pdb5lzb/pdb},\n publisher = {Worldwide Protein Data Bank},\n}\n\n\n\n \n\n \n \n \n \n \n Structure of SelB-Sec-tRNASec bound to the 70S ribosome in the codon reading state (CR).\n \n \n \n\n\n \n Fischer, N.; Neumann, P.; Bock, L. V.; Maracci, C.; Wang, Z.; Paleskava, A.; Konevega, A. L.; Schroeder, G. F.; Grubmueller, H.; Ficner, R.; Rodnina, M. V.; and Stark, H.\n\n\n \n\n\n\n November 2016.\n \n\n\n\n
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\n\n\n\n@Misc{Fischer2016i,\n author = {N. Fischer and P. Neumann and L. V. Bock and C. Maracci and Z. Wang and A. Paleskava and A. L. Konevega and G. F. Schroeder and H. Grubmueller and R. Ficner and M. V. Rodnina and H. Stark},\n month = nov,\n title = {Structure of SelB-Sec-tRNASec bound to the 70S ribosome in the codon reading state (CR)},\n year = {2016},\n doi = {10.2210/pdb5lzc/pdbx},\n publisher = {Worldwide Protein Data Bank},\n}\n\n\n\n \n\n \n \n \n \n \n Structure of SelB-Sec-tRNASec bound to the 70S ribosome in the GTPase activated state (GA).\n \n \n \n\n\n \n Fischer, N.; Neumann, P.; Bock, L. V.; Maracci, C.; Wang, Z.; Paleskava, A.; Konevega, A. L.; Schroeder, G. F.; Grubmueller, H.; Ficner, R.; Rodnina, M. V.; and Stark, H.\n\n\n \n\n\n\n November 2016.\n \n\n\n\n
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\n\n\n\n@Misc{Fischer2016j,\n author = {N. Fischer and P. Neumann and L. V. Bock and C. Maracci and Z. Wang and A. Paleskava and A. L. Konevega and G. F. Schroeder and H. Grubmueller and R. Ficner and M. V. Rodnina and H. Stark},\n month = nov,\n title = {Structure of SelB-Sec-tRNASec bound to the 70S ribosome in the GTPase activated state (GA)},\n year = {2016},\n doi = {10.2210/pdb5lzd/pdb},\n publisher = {Worldwide Protein Data Bank},\n}\n\n\n\n \n\n \n \n \n \n \n Structure of the 70S ribosome with Sec-tRNASec in the classical pre-translocation state (C).\n \n \n \n\n\n \n Fischer, N.; Neumann, P.; Bock, L. V.; Maracci, C.; Wang, Z.; Paleskava, A.; Konevega, A. L.; Schroeder, G. F.; Grubmueller, H.; Ficner, R.; Rodnina, M. V.; and Stark, H.\n\n\n \n\n\n\n November 2016.\n \n\n\n\n
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\n\n\n\n@Misc{Fischer2016a,\n author = {N. Fischer and P. Neumann and L. V. Bock and C. Maracci and Z. Wang and A. Paleskava and A. L. Konevega and G. F. Schroeder and H. Grubmueller and R. Ficner and M. V. Rodnina and H. Stark},\n month = nov,\n title = {Structure of the 70S ribosome with Sec-tRNASec in the classical pre-translocation state (C)},\n year = {2016},\n doi = {10.2210/pdb5lze/pdb},\n publisher = {Worldwide Protein Data Bank},\n}\n\n\n\n \n\n \n \n \n \n \n Lectin-induced agglutination of urinary exosomes followed by mi-RNA analysis: Application for prostate cancer diagnostics.\n \n \n \n\n\n \n Nosov, A.; Reva, S.; Berstein, L.; Tsyrlina, E.; Shtam, T.; Samsonov, R.; and Malek, A.\n\n\n \n\n\n\n European Urology Supplements, 15(5): e1169. 2016.\n \n\n\n\n
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\n\n\n\n@Article{Nosov2016,\n author = {A. Nosov and S. Reva and L. Berstein and E. Tsyrlina and T. Shtam and R. Samsonov and A. Malek},\n journal = {European Urology Supplements},\n title = {Lectin-induced agglutination of urinary exosomes followed by mi-RNA analysis: Application for prostate cancer diagnostics},\n year = {2016},\n issn = {1569-9056},\n number = {5},\n pages = {e1169},\n volume = {15},\n doi = {10.1016/s1569-9056(16)15002-x},\n keywords = {Urology},\n publisher = {Elsevier BV},\n}\n\n\n\n
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\n \n \n\n \n \n \n \n \n Major reorientation of tRNA substrates defines specificity of dihydrouridine synthases.\n \n \n \n\n\n \n Byrne, R. T.; Jenkins, H. T.; Peters, D. T.; Whelan, F.; Stowell, J.; Aziz, N.; Kasatsky, P.; Rodnina, M. V.; Koonin, E. V.; Konevega, A. L.; and Antson, A. A.\n\n\n \n\n\n\n Proceedings of the National Academy of Sciences of the United States of America, 112: 6033–6037. May 2015.\n \n\n\n\n
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\n\n\n@Article{Byrne2015,\n author = {Byrne, Robert T. and Jenkins, Huw T. and Peters, Daniel T. and Whelan, Fiona and Stowell, James and Aziz, Naveed and Kasatsky, Pavel and Rodnina, Marina V. and Koonin, Eugene V. and Konevega, Andrey L. and Antson, Alfred A.},\n journal = {Proceedings of the National Academy of Sciences of the United States of America},\n title = {Major reorientation of tRNA substrates defines specificity of dihydrouridine synthases.},\n year = {2015},\n issn = {1091-6490},\n month = may,\n pages = {6033--6037},\n volume = {112},\n abstract = {The reduction of specific uridines to dihydrouridine is one of the most common modifications in tRNA. Increased levels of the dihydrouridine modification are associated with cancer. Dihydrouridine synthases (Dus) from different subfamilies selectively reduce distinct uridines, located at spatially unique positions of folded tRNA, into dihydrouridine. Because the catalytic center of all Dus enzymes is conserved, it is unclear how the same protein fold can be reprogrammed to ensure that nucleotides exposed at spatially distinct faces of tRNA can be accommodated in the same active site. We show that the Escherichia coli DusC is specific toward U16 of tRNA. Unexpectedly, crystal structures of DusC complexes with tRNA(Phe) and tRNA(Trp) show that Dus subfamilies that selectively modify U16 or U20 in tRNA adopt identical folds but bind their respective tRNA substrates in an almost reverse orientation that differs by a 160° rotation. The tRNA docking orientation appears to be guided by subfamily-specific clusters of amino acids ("binding signatures") together with differences in the shape of the positively charged tRNA-binding surfaces. tRNA orientations are further constrained by positional differences between the C-terminal "recognition" domains. The exquisite substrate specificity of Dus enzymes is therefore controlled by a relatively simple mechanism involving major reorientation of the whole tRNA molecule. Such reprogramming of the enzymatic specificity appears to be a unique evolutionary solution for altering tRNA recognition by the same protein fold.},\n chemicals = {Amino Acids, Escherichia coli Proteins, RNA-Binding Proteins, RNA, RNA, Transfer, Oxidoreductases, Uridine},\n citation-subset = {IM},\n completed = {2015-08-05},\n country = {United States},\n doi = {10.1073/pnas.1500161112},\n issn-linking = {0027-8424},\n issue = {19},\n keywords = {Amino Acids, chemistry; Catalytic Domain; Crystallography, X-Ray; Escherichia coli, enzymology; Escherichia coli Proteins, chemistry; Evolution, Molecular; Oxidoreductases, chemistry; Protein Binding; Protein Folding; RNA, chemistry; RNA, Transfer, chemistry; RNA-Binding Proteins, chemistry; Substrate Specificity; Uridine, chemistry; X-Ray Diffraction; X-ray crystallography; dihydrouridine synthase; protein–RNA interaction; substrate specificity; tRNA modification},\n nlm-id = {7505876},\n owner = {NLM},\n pii = {1500161112},\n pmc = {PMC4434734},\n pmid = {25902496},\n pubmodel = {Print-Electronic},\n pubstate = {ppublish},\n revised = {2018-11-13},\n}\n\n\n\n The reduction of specific uridines to dihydrouridine is one of the most common modifications in tRNA. Increased levels of the dihydrouridine modification are associated with cancer. Dihydrouridine synthases (Dus) from different subfamilies selectively reduce distinct uridines, located at spatially unique positions of folded tRNA, into dihydrouridine. Because the catalytic center of all Dus enzymes is conserved, it is unclear how the same protein fold can be reprogrammed to ensure that nucleotides exposed at spatially distinct faces of tRNA can be accommodated in the same active site. We show that the Escherichia coli DusC is specific toward U16 of tRNA. Unexpectedly, crystal structures of DusC complexes with tRNA(Phe) and tRNA(Trp) show that Dus subfamilies that selectively modify U16 or U20 in tRNA adopt identical folds but bind their respective tRNA substrates in an almost reverse orientation that differs by a 160° rotation. The tRNA docking orientation appears to be guided by subfamily-specific clusters of amino acids (\"binding signatures\") together with differences in the shape of the positively charged tRNA-binding surfaces. tRNA orientations are further constrained by positional differences between the C-terminal \"recognition\" domains. The exquisite substrate specificity of Dus enzymes is therefore controlled by a relatively simple mechanism involving major reorientation of the whole tRNA molecule. Such reprogramming of the enzymatic specificity appears to be a unique evolutionary solution for altering tRNA recognition by the same protein fold.\n
\n\n\n\n \n\n \n \n \n \n \n Structure of the E. coli ribosome-EF-Tu complex at <3 Å resolution by Cs-corrected cryo-EM.\n \n \n \n\n\n \n Fischer, N.; Neumann, P.; Konevega, A. L.; Bock, L. V.; Ficner, R.; Rodnina, M. V.; and Stark, H.\n\n\n \n\n\n\n Nature, 520: 567–570. April 2015.\n \n\n\n\n
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\n\n\n@Article{Fischer2015,\n author = {Fischer, Niels and Neumann, Piotr and Konevega, Andrey L. and Bock, Lars V. and Ficner, Ralf and Rodnina, Marina V. and Stark, Holger},\n journal = {Nature},\n title = {Structure of the E. coli ribosome-EF-Tu complex at <3 Å resolution by Cs-corrected cryo-EM.},\n year = {2015},\n issn = {1476-4687},\n month = apr,\n pages = {567--570},\n volume = {520},\n abstract = {Single particle electron cryomicroscopy (cryo-EM) has recently made significant progress in high-resolution structure determination of macromolecular complexes due to improvements in electron microscopic instrumentation and computational image analysis. However, cryo-EM structures can be highly non-uniform in local resolution and all structures available to date have been limited to resolutions above 3 Å. Here we present the cryo-EM structure of the 70S ribosome from Escherichia coli in complex with elongation factor Tu, aminoacyl-tRNA and the antibiotic kirromycin at 2.65-2.9 Å resolution using spherical aberration (Cs)-corrected cryo-EM. Overall, the cryo-EM reconstruction at 2.9 Å resolution is comparable to the best-resolved X-ray structure of the E. coli 70S ribosome (2.8 Å), but provides more detailed information (2.65 Å) at the functionally important ribosomal core. The cryo-EM map elucidates for the first time the structure of all 35 rRNA modifications in the bacterial ribosome, explaining their roles in fine-tuning ribosome structure and function and modulating the action of antibiotics. We also obtained atomic models for flexible parts of the ribosome such as ribosomal proteins L9 and L31. The refined cryo-EM-based model presents the currently most complete high-resolution structure of the E. coli ribosome, which demonstrates the power of cryo-EM in structure determination of large and dynamic macromolecular complexes.},\n chemicals = {Anti-Bacterial Agents, Ligands, Pyridones, RNA, Bacterial, RNA, Ribosomal, RNA, Transfer, Peptide Elongation Factor Tu, mocimycin},\n citation-subset = {IM},\n completed = {2015-05-14},\n country = {England},\n doi = {10.1038/nature14275},\n issn-linking = {0028-0836},\n issue = {7548},\n keywords = {Anti-Bacterial Agents, chemistry, metabolism; Cryoelectron Microscopy, methods; Escherichia coli, chemistry, ultrastructure; Ligands; Models, Molecular; Peptide Elongation Factor Tu, chemistry, metabolism, ultrastructure; Pyridones, chemistry, metabolism; RNA, Bacterial, chemistry, metabolism, ultrastructure; RNA, Ribosomal, chemistry, metabolism, ultrastructure; RNA, Transfer, chemistry, metabolism, ultrastructure; Ribosomes, chemistry, metabolism, ultrastructure},\n nlm-id = {0410462},\n owner = {NLM},\n pii = {nature14275},\n pmid = {25707802},\n pubmodel = {Print-Electronic},\n pubstate = {ppublish},\n revised = {2018-11-13},\n}\n\n\n\n Single particle electron cryomicroscopy (cryo-EM) has recently made significant progress in high-resolution structure determination of macromolecular complexes due to improvements in electron microscopic instrumentation and computational image analysis. However, cryo-EM structures can be highly non-uniform in local resolution and all structures available to date have been limited to resolutions above 3 Å. Here we present the cryo-EM structure of the 70S ribosome from Escherichia coli in complex with elongation factor Tu, aminoacyl-tRNA and the antibiotic kirromycin at 2.65-2.9 Å resolution using spherical aberration (Cs)-corrected cryo-EM. Overall, the cryo-EM reconstruction at 2.9 Å resolution is comparable to the best-resolved X-ray structure of the E. coli 70S ribosome (2.8 Å), but provides more detailed information (2.65 Å) at the functionally important ribosomal core. The cryo-EM map elucidates for the first time the structure of all 35 rRNA modifications in the bacterial ribosome, explaining their roles in fine-tuning ribosome structure and function and modulating the action of antibiotics. We also obtained atomic models for flexible parts of the ribosome such as ribosomal proteins L9 and L31. The refined cryo-EM-based model presents the currently most complete high-resolution structure of the E. coli ribosome, which demonstrates the power of cryo-EM in structure determination of large and dynamic macromolecular complexes.\n
\n\n\n\n \n\n \n \n \n \n \n [Histone deacetylase inhibitors cause the TP53-dependent induction of p21/Waf1 in tumor cells carrying mutations in TP53].\n \n \n \n\n\n \n Kovalev, R. A.; Shtam, T. A.; Karelov, D. V.; Burdakov, V. S.; Volnitskiy, A. V.; Makarov, E. M.; and Filatov, M. V.\n\n\n \n\n\n\n Tsitologiia, 57: 204–211. 2015.\n \n\n\n\n
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\n\n\n@Article{Kovalev2015,\n author = {Kovalev, R. A. and Shtam, T. A. and Karelov, D. V. and Burdakov, V. S. and Volnitskiy, A. V. and Makarov, E. M. and Filatov, M. V.},\n journal = {Tsitologiia},\n title = {[Histone deacetylase inhibitors cause the TP53-dependent induction of p21/Waf1 in tumor cells carrying mutations in TP53].},\n year = {2015},\n issn = {0041-3771},\n pages = {204--211},\n volume = {57},\n abstract = {p21/Waf1 protein is one of the main cell cycle arrest regulators and one of the most well-known transcriptional targets of TP53 protein. Here, we demonstrated the activation of expression of the p21/Waf1 gene when the cells were treated to sodium butyrate (NaBu)--one of the natural inhibitors of deacetylase, and investigated whether this phenomenon depends on the presence of functionally active TP53 protein. We compared the effect of the NaBu treatment on the human cell line with different TP53 mutation profile, including: wild-type TP53, single nucleotide substitutions, and the complete absence of TP53 gene. NaBu activated the TP53 protein via hyper acetylation at lysine residue K382, without significant changes in the level of protein expression. Western blotting demonstrated that the addition of NaBu triggers a significant increase in the p21/Waf1 protein level in both the TP53 wild-type cells and in the cells with single nucleotide substitutions in the domain responsible for the binding of TP53 protein to DNA. At the same time, no the p21/Waf1 protein induction was observed in the cells with complete deletion of the TP53 gene. However, NaBu was not able to induce the p2 1/Waf1 production when the expression of TP53 was transiently knocked down by the p53 siRNA. Overall, our results suggest that the NaBu-dependent induction of p21/Waf1 does require the presence of TP53 protein but unexpectedly it can occur regardless of mutational changes in the domain responsible for the TP53 binding to DNA. One of the hypothetical explanations is that NaBu increases the level of TP53 acetylation, and the modified protein is able to establish a new network of protein-protein interactions or trigger some conformational changes affecting the TP53-dependent transcriptional machinery even when its DNA binding ability is impaired.},\n chemicals = {CDKN1A protein, human, Cyclin-Dependent Kinase Inhibitor p21, Histone Deacetylase Inhibitors, RNA, Small Interfering, TP53 protein, human, Tumor Suppressor Protein p53, Butyric Acid, Histone Deacetylases},\n citation-subset = {IM},\n completed = {2015-06-11},\n country = {Russia (Federation)},\n issn-linking = {0041-3771},\n issue = {3},\n keywords = {Acetylation; Butyric Acid, pharmacology; Cell Cycle Checkpoints, drug effects; Cell Line, Tumor; Cyclin-Dependent Kinase Inhibitor p21, agonists, genetics, metabolism; Gene Expression Regulation, Neoplastic; Gene Silencing; Histone Deacetylase Inhibitors, pharmacology; Histone Deacetylases, genetics, metabolism; Humans; Mutation; Polymorphism, Single Nucleotide; Protein Binding; Protein Structure, Tertiary; RNA, Small Interfering, genetics, metabolism; Signal Transduction; Tumor Suppressor Protein p53, antagonists & inhibitors, genetics, metabolism},\n nlm-id = {0417363},\n owner = {NLM},\n pmid = {26021170},\n pubmodel = {Print},\n pubstate = {ppublish},\n revised = {2015-05-29},\n}\n\n\n\n p21/Waf1 protein is one of the main cell cycle arrest regulators and one of the most well-known transcriptional targets of TP53 protein. Here, we demonstrated the activation of expression of the p21/Waf1 gene when the cells were treated to sodium butyrate (NaBu)–one of the natural inhibitors of deacetylase, and investigated whether this phenomenon depends on the presence of functionally active TP53 protein. We compared the effect of the NaBu treatment on the human cell line with different TP53 mutation profile, including: wild-type TP53, single nucleotide substitutions, and the complete absence of TP53 gene. NaBu activated the TP53 protein via hyper acetylation at lysine residue K382, without significant changes in the level of protein expression. Western blotting demonstrated that the addition of NaBu triggers a significant increase in the p21/Waf1 protein level in both the TP53 wild-type cells and in the cells with single nucleotide substitutions in the domain responsible for the binding of TP53 protein to DNA. At the same time, no the p21/Waf1 protein induction was observed in the cells with complete deletion of the TP53 gene. However, NaBu was not able to induce the p2 1/Waf1 production when the expression of TP53 was transiently knocked down by the p53 siRNA. Overall, our results suggest that the NaBu-dependent induction of p21/Waf1 does require the presence of TP53 protein but unexpectedly it can occur regardless of mutational changes in the domain responsible for the TP53 binding to DNA. One of the hypothetical explanations is that NaBu increases the level of TP53 acetylation, and the modified protein is able to establish a new network of protein-protein interactions or trigger some conformational changes affecting the TP53-dependent transcriptional machinery even when its DNA binding ability is impaired.\n
\n\n\n\n \n\n \n \n \n \n \n 2.9A Structure of E. coli ribosome-EF-TU complex by cs-corrected cryo-EM.\n \n \n \n\n\n \n Fischer, N.; Neumann, P.; Konevega, A. L.; Bock, L. V.; Ficner, R.; Rodnina, M. V.; and Stark, H.\n\n\n \n\n\n\n March 2015.\n \n\n\n\n
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\n\n\n\n@Misc{Fischer2015a,\n author = {N. Fischer and P. Neumann and A. L. Konevega and L. V. Bock and R. Ficner and M. V. Rodnina and H. Stark},\n month = mar,\n title = {2.9A Structure of E. coli ribosome-EF-TU complex by cs-corrected cryo-EM},\n year = {2015},\n doi = {10.2210/pdb5afi/pdbx},\n publisher = {Worldwide Protein Data Bank},\n}\n\n\n\n \n\n \n \n \n \n \n 2.9A Structure of E. coli ribosome-EF-TU complex by cs-corrected cryo-EM.\n \n \n \n\n\n \n Fischer, N.; Neumann, P.; Konevega, A. L.; Bock, L. V.; Ficner, R.; Rodnina, M. V.; and Stark, H.\n\n\n \n\n\n\n March 2015.\n \n\n\n\n
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\n\n\n\n@Misc{Fischer2015b,\n author = {N. Fischer and P. Neumann and A. L. Konevega and L. V. Bock and R. Ficner and M. V. Rodnina and H. Stark},\n month = mar,\n title = {2.9A Structure of E. coli ribosome-EF-TU complex by cs-corrected cryo-EM},\n year = {2015},\n doi = {10.2210/pdb5afi/pdb},\n publisher = {Worldwide Protein Data Bank},\n}\n\n\n\n \n\n \n \n \n \n \n Ionizing radiation improves glioma-specific targeting of superparamagnetic iron oxide nanoparticles conjugated with cmHsp70.1 monoclonal antibodies (SPION-cmHsp70.1).\n \n \n \n\n\n \n Shevtsov, M. A.; Nikolaev, B. P.; Ryzhov, V. A.; Yakovleva, L. Y.; Marchenko, Y. Y.; Parr, M. A.; Rolich, V. I.; Mikhrina, A. L.; Dobrodumov, A. V.; Pitkin, E.; and Multhoff, G.\n\n\n \n\n\n\n Nanoscale, 7: 20652–20664. December 2015.\n \n\n\n\n
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\n\n\n@Article{Shevtsov2015,\n author = {Shevtsov, Maxim A. and Nikolaev, Boris P. and Ryzhov, Vyacheslav A. and Yakovleva, Ludmila Y. and Marchenko, Yaroslav Y. and Parr, Marina A. and Rolich, Valerij I. and Mikhrina, Anastasiya L. and Dobrodumov, Anatolii V. and Pitkin, Emil and Multhoff, Gabriele},\n journal = {Nanoscale},\n title = {Ionizing radiation improves glioma-specific targeting of superparamagnetic iron oxide nanoparticles conjugated with cmHsp70.1 monoclonal antibodies (SPION-cmHsp70.1).},\n year = {2015},\n issn = {2040-3372},\n month = dec,\n pages = {20652--20664},\n volume = {7},\n abstract = {The stress-inducible 72 kDa heat shock protein Hsp70 is known to be expressed on the membrane of highly aggressive tumor cells including high-grade gliomas, but not on the corresponding normal cells. Membrane Hsp70 (mHsp70) is rapidly internalized into tumor cells and thus targeting of mHsp70 might provide a promising strategy for theranostics. Superparamagnetic iron oxide nanoparticles (SPIONs) are contrast negative agents that are used for the detection of tumors with MRI. Herein, we conjugated the Hsp70-specific antibody (cmHsp70.1) which is known to recognize mHsp70 to superparamagnetic iron nanoparticles to assess tumor-specific targeting before and after ionizing irradiation. In vitro experiments demonstrated the selectivity of SPION-cmHsp70.1 conjugates to free and mHsp70 in different tumor cell types (C6 glioblastoma, K562 leukemia, HeLa cervix carcinoma) in a dose-dependent manner. High-resolution MRI (11 T) on T(2)-weighted images showed the retention of the conjugates in the C6 glioma model. Accumulation of SPION-cmHsp70.1 nanoparticles in the glioma resulted in a nearly 2-fold drop of T*(2) values in comparison to non-conjugated SPIONs. Biodistribution analysis using NLR-M(2) measurements showed a 7-fold increase in the tumor-to-background (normal brain) uptake ratio of SPION-cmHsp70.1 conjugates in glioma-bearing rats in comparison to SPIONs. This accumulation within Hsp70-positive glioma was further enhanced after a single dose (10 Gy) of ionizing radiation. Elevated accumulation of the magnetic conjugates in the tumor due to radiosensitization proves the combination of radiotherapy and application of Hsp70-targeted agents in brain tumors.},\n chemicals = {Antibodies, Monoclonal, Murine-Derived, HSP70 Heat-Shock Proteins, Magnetite Nanoparticles},\n citation-subset = {IM},\n completed = {2016-10-10},\n country = {England},\n doi = {10.1039/c5nr06521f},\n issn-linking = {2040-3364},\n issue = {48},\n keywords = {Animals; Antibodies, Monoclonal, Murine-Derived, chemistry, pharmacology; Brain Neoplasms, therapy; Chemoradiotherapy, methods; Drug Delivery Systems, methods; Gamma Rays, therapeutic use; Glioma, therapy; HSP70 Heat-Shock Proteins, antagonists & inhibitors, chemistry; HeLa Cells; Humans; K562 Cells; Magnetite Nanoparticles, chemistry; Male; Rats; Rats, Wistar},\n nlm-id = {101525249},\n owner = {NLM},\n pmid = {26599206},\n pubmodel = {Print-Electronic},\n pubstate = {ppublish},\n revised = {2022-03-16},\n}\n\n\n\n The stress-inducible 72 kDa heat shock protein Hsp70 is known to be expressed on the membrane of highly aggressive tumor cells including high-grade gliomas, but not on the corresponding normal cells. Membrane Hsp70 (mHsp70) is rapidly internalized into tumor cells and thus targeting of mHsp70 might provide a promising strategy for theranostics. Superparamagnetic iron oxide nanoparticles (SPIONs) are contrast negative agents that are used for the detection of tumors with MRI. Herein, we conjugated the Hsp70-specific antibody (cmHsp70.1) which is known to recognize mHsp70 to superparamagnetic iron nanoparticles to assess tumor-specific targeting before and after ionizing irradiation. In vitro experiments demonstrated the selectivity of SPION-cmHsp70.1 conjugates to free and mHsp70 in different tumor cell types (C6 glioblastoma, K562 leukemia, HeLa cervix carcinoma) in a dose-dependent manner. High-resolution MRI (11 T) on T(2)-weighted images showed the retention of the conjugates in the C6 glioma model. Accumulation of SPION-cmHsp70.1 nanoparticles in the glioma resulted in a nearly 2-fold drop of T*(2) values in comparison to non-conjugated SPIONs. Biodistribution analysis using NLR-M(2) measurements showed a 7-fold increase in the tumor-to-background (normal brain) uptake ratio of SPION-cmHsp70.1 conjugates in glioma-bearing rats in comparison to SPIONs. This accumulation within Hsp70-positive glioma was further enhanced after a single dose (10 Gy) of ionizing radiation. Elevated accumulation of the magnetic conjugates in the tumor due to radiosensitization proves the combination of radiotherapy and application of Hsp70-targeted agents in brain tumors.\n
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\n \n \n\n \n \n \n \n \n High-efficiency translational bypassing of non-coding nucleotides specified by mRNA structure and nascent peptide.\n \n \n \n\n\n \n Samatova, E.; Konevega, A. L.; Wills, N. M.; Atkins, J. F.; and Rodnina, M. V.\n\n\n \n\n\n\n Nature communications, 5: 4459. July 2014.\n \n\n\n\n
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\n\n\n@Article{Samatova2014,\n author = {Samatova, Ekaterina and Konevega, Andrey L. and Wills, Norma M. and Atkins, John F. and Rodnina, Marina V.},\n journal = {Nature communications},\n title = {High-efficiency translational bypassing of non-coding nucleotides specified by mRNA structure and nascent peptide.},\n year = {2014},\n issn = {2041-1723},\n month = jul,\n pages = {4459},\n volume = {5},\n abstract = {The gene product 60 (gp60) of bacteriophage T4 is synthesized as a single polypeptide chain from a discontinuous reading frame as a result of bypassing of a non-coding mRNA region of 50 nucleotides by the ribosome. To identify the minimum set of signals required for bypassing, we recapitulated efficient translational bypassing in an in vitro reconstituted translation system from Escherichia coli. We find that the signals, which promote efficient and accurate bypassing, are specified by the gene 60 mRNA sequence. Systematic analysis of the mRNA suggests unexpected contributions of sequences upstream and downstream of the non-coding gap region as well as of the nascent peptide. During bypassing, ribosomes glide forward on the mRNA track in a processive way. Gliding may have a role not only for gp60 synthesis, but also during regular mRNA translation for reading frame selection during initiation or tRNA translocation during elongation.},\n chemicals = {RNA, Messenger, RNA, Untranslated, Viral Proteins},\n citation-subset = {IM},\n completed = {2016-04-26},\n country = {England},\n doi = {10.1038/ncomms5459},\n issn-linking = {2041-1723},\n keywords = {Bacteriophage T4, genetics; Base Sequence; Escherichia coli, genetics; Molecular Sequence Data; Protein Biosynthesis; RNA, Messenger, chemistry, genetics; RNA, Untranslated, chemistry; Viral Proteins, genetics},\n nlm-id = {101528555},\n owner = {NLM},\n pii = {ncomms5459},\n pmid = {25041899},\n pubmodel = {Electronic},\n pubstate = {epublish},\n revised = {2014-07-21},\n}\n\n\n\n The gene product 60 (gp60) of bacteriophage T4 is synthesized as a single polypeptide chain from a discontinuous reading frame as a result of bypassing of a non-coding mRNA region of 50 nucleotides by the ribosome. To identify the minimum set of signals required for bypassing, we recapitulated efficient translational bypassing in an in vitro reconstituted translation system from Escherichia coli. We find that the signals, which promote efficient and accurate bypassing, are specified by the gene 60 mRNA sequence. Systematic analysis of the mRNA suggests unexpected contributions of sequences upstream and downstream of the non-coding gap region as well as of the nascent peptide. During bypassing, ribosomes glide forward on the mRNA track in a processive way. Gliding may have a role not only for gp60 synthesis, but also during regular mRNA translation for reading frame selection during initiation or tRNA translocation during elongation.\n
\n\n\n\n \n\n \n \n \n \n \n Amicoumacin a inhibits translation by stabilizing mRNA interaction with the ribosome.\n \n \n \n\n\n \n Polikanov, Y. S.; Osterman, I. A.; Szal, T.; Tashlitsky, V. N.; Serebryakova, M. V.; Kusochek, P.; Bulkley, D.; Malanicheva, I. A.; Efimenko, T. A.; Efremenkova, O. V.; Konevega, A. L.; Shaw, K. J.; Bogdanov, A. A.; Rodnina, M. V.; Dontsova, O. A.; Mankin, A. S.; Steitz, T. A.; and Sergiev, P. V.\n\n\n \n\n\n\n Molecular cell, 56: 531–540. November 2014.\n \n\n\n\n
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\n\n\n@Article{Polikanov2014,\n author = {Polikanov, Yury S. and Osterman, Ilya A. and Szal, Teresa and Tashlitsky, Vadim N. and Serebryakova, Marina V. and Kusochek, Pavel and Bulkley, David and Malanicheva, Irina A. and Efimenko, Tatyana A. and Efremenkova, Olga V. and Konevega, Andrey L. and Shaw, Karen J. and Bogdanov, Alexey A. and Rodnina, Marina V. and Dontsova, Olga A. and Mankin, Alexander S. and Steitz, Thomas A. and Sergiev, Petr V.},\n journal = {Molecular cell},\n title = {Amicoumacin a inhibits translation by stabilizing mRNA interaction with the ribosome.},\n year = {2014},\n issn = {1097-4164},\n month = nov,\n pages = {531--540},\n volume = {56},\n abstract = {We demonstrate that the antibiotic amicoumacin A (AMI) is a potent inhibitor of protein synthesis. Resistance mutations in helix 24 of the 16S rRNA mapped the AMI binding site to the small ribosomal subunit. The crystal structure of bacterial ribosome in complex with AMI solved at 2.4 Å resolution revealed that the antibiotic makes contacts with universally conserved nucleotides of 16S rRNA in the E site and the mRNA backbone. Simultaneous interactions of AMI with 16S rRNA and mRNA and the in vivo experimental evidence suggest that it may inhibit the progression of the ribosome along mRNA. Consistent with this proposal, binding of AMI interferes with translocation in vitro. The inhibitory action of AMI can be partly compensated by mutations in the translation elongation factor G.},\n chemicals = {Anti-Bacterial Agents, Bacterial Proteins, Coumarins, Peptide Elongation Factor G, Protein Synthesis Inhibitors, RNA, Messenger, amicoumacin A},\n citation-subset = {IM},\n completed = {2015-02-26},\n country = {United States},\n doi = {10.1016/j.molcel.2014.09.020},\n issn-linking = {1097-2765},\n issue = {4},\n keywords = {Anti-Bacterial Agents, chemistry, pharmacology; Bacterial Proteins, genetics; Base Sequence; Binding Sites; Coumarins, chemistry, pharmacology; Crystallography, X-Ray; Drug Resistance, Bacterial; Escherichia coli; Microbial Sensitivity Tests; Models, Molecular; Peptide Elongation Factor G, genetics; Protein Biosynthesis, drug effects; Protein Synthesis Inhibitors, chemistry, pharmacology; RNA Stability; RNA, Messenger, metabolism; Ribosome Subunits, Large, Bacterial, chemistry; Ribosome Subunits, Small, Bacterial, chemistry; Staphylococcus aureus, genetics; Thermus thermophilus},\n mid = {NIHMS638536},\n nlm-id = {9802571},\n owner = {NLM},\n pii = {S1097-2765(14)00752-7},\n pmc = {PMC4253140},\n pmid = {25306919},\n pubmodel = {Print-Electronic},\n pubstate = {ppublish},\n revised = {2021-10-21},\n}\n\n\n\n We demonstrate that the antibiotic amicoumacin A (AMI) is a potent inhibitor of protein synthesis. Resistance mutations in helix 24 of the 16S rRNA mapped the AMI binding site to the small ribosomal subunit. The crystal structure of bacterial ribosome in complex with AMI solved at 2.4 Å resolution revealed that the antibiotic makes contacts with universally conserved nucleotides of 16S rRNA in the E site and the mRNA backbone. Simultaneous interactions of AMI with 16S rRNA and mRNA and the in vivo experimental evidence suggest that it may inhibit the progression of the ribosome along mRNA. Consistent with this proposal, binding of AMI interferes with translocation in vitro. The inhibitory action of AMI can be partly compensated by mutations in the translation elongation factor G.\n
\n\n\n\n \n\n \n \n \n \n \n GTP hydrolysis by EF-G synchronizes tRNA movement on small and large ribosomal subunits.\n \n \n \n\n\n \n Holtkamp, W.; Cunha, C. E.; Peske, F.; Konevega, A. L.; Wintermeyer, W.; and Rodnina, M. V.\n\n\n \n\n\n\n The EMBO journal, 33: 1073–1085. May 2014.\n \n\n\n\n
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\n\n\n@Article{Holtkamp2014,\n author = {Holtkamp, Wolf and Cunha, Carlos E. and Peske, Frank and Konevega, Andrey L. and Wintermeyer, Wolfgang and Rodnina, Marina V.},\n journal = {The EMBO journal},\n title = {GTP hydrolysis by EF-G synchronizes tRNA movement on small and large ribosomal subunits.},\n year = {2014},\n issn = {1460-2075},\n month = may,\n pages = {1073--1085},\n volume = {33},\n abstract = {Elongation factor G (EF-G) promotes the movement of two tRNAs and the mRNA through the ribosome in each cycle of peptide elongation. During translocation, the tRNAs transiently occupy intermediate positions on both small (30S) and large (50S) ribosomal subunits. How EF-G and GTP hydrolysis control these movements is still unclear. We used fluorescence labels that specifically monitor movements on either 30S or 50S subunits in combination with EF-G mutants and translocation-specific antibiotics to investigate timing and energetics of translocation. We show that EF-G-GTP facilitates synchronous movements of peptidyl-tRNA on the two subunits into an early post-translocation state, which resembles a chimeric state identified by structural studies. EF-G binding without GTP hydrolysis promotes only partial tRNA movement on the 50S subunit. However, rapid 30S translocation and the concomitant completion of 50S translocation require GTP hydrolysis and a functional domain 4 of EF-G. Our results reveal two distinct modes for utilizing the energy of EF-G binding and GTP hydrolysis and suggest that coupling of GTP hydrolysis to translocation is mediated through rearrangements of the 30S subunit.},\n chemicals = {Peptide Elongation Factor G, Guanosine Triphosphate, RNA, Transfer},\n citation-subset = {IM},\n completed = {2014-07-28},\n country = {England},\n doi = {10.1002/embj.201387465},\n issn-linking = {0261-4189},\n issue = {9},\n keywords = {Escherichia coli, genetics, metabolism; Guanosine Triphosphate, metabolism; Hydrolysis; Kinetics; Movement; Organisms, Genetically Modified; Peptide Elongation Factor G, metabolism; Protein Biosynthesis; RNA Transport; RNA, Transfer, physiology; Ribosome Subunits, Large, Bacterial, metabolism; Ribosome Subunits, Small, Bacterial, metabolism},\n nlm-id = {8208664},\n owner = {NLM},\n pii = {embj.201387465},\n pmc = {PMC4193938},\n pmid = {24614227},\n pubmodel = {Print-Electronic},\n pubstate = {ppublish},\n revised = {2021-10-21},\n}\n\n\n\n Elongation factor G (EF-G) promotes the movement of two tRNAs and the mRNA through the ribosome in each cycle of peptide elongation. During translocation, the tRNAs transiently occupy intermediate positions on both small (30S) and large (50S) ribosomal subunits. How EF-G and GTP hydrolysis control these movements is still unclear. We used fluorescence labels that specifically monitor movements on either 30S or 50S subunits in combination with EF-G mutants and translocation-specific antibiotics to investigate timing and energetics of translocation. We show that EF-G-GTP facilitates synchronous movements of peptidyl-tRNA on the two subunits into an early post-translocation state, which resembles a chimeric state identified by structural studies. EF-G binding without GTP hydrolysis promotes only partial tRNA movement on the 50S subunit. However, rapid 30S translocation and the concomitant completion of 50S translocation require GTP hydrolysis and a functional domain 4 of EF-G. Our results reveal two distinct modes for utilizing the energy of EF-G binding and GTP hydrolysis and suggest that coupling of GTP hydrolysis to translocation is mediated through rearrangements of the 30S subunit.\n
\n\n\n\n \n\n \n \n \n \n \n [Aberrant expression of sox2 gene in malignant gliomas].\n \n \n \n\n\n \n Volnitskiĭ, A. V.; Semenova, E. V.; Shtam, T. A.; Kovalev, R. A.; and Filatov, M. V.\n\n\n \n\n\n\n Tsitologiia, 56: 504–510. 2014.\n \n\n\n\n
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\n\n\n@Article{Volnitskii2014,\n author = {Volnitskiĭ, A. V. and Semenova, E. V. and Shtam, T. A. and Kovalev, R. A. and Filatov, M. V.},\n journal = {Tsitologiia},\n title = {[Aberrant expression of sox2 gene in malignant gliomas].},\n year = {2014},\n issn = {0041-3771},\n pages = {504--510},\n volume = {56},\n abstract = {Both genetic and epigenetic changes underlite the mechanisms of tumor initiation and progression. In the present study we analyze sox2 gene expression and its epigenetic regulation in primary cultures of malignant gliomas. The sox2 expression was detected in the vast majority (74%) of the investigated gliomas and absent in morphologically normal brain tissue. This indicates the process of glioma malignant transformation. We have also shown that the association of different areas of the sox2 gene with important epigenetic markers, posttranslational modifications of H3 histone H3K4ac and H3K9met3, does not correlate with the sox2 expression. However, this may indicate the stochastic nature of the regulation of sox2 gene expression in malignant gliomas.},\n chemicals = {Histones, SOX2 protein, human, SOXB1 Transcription Factors},\n citation-subset = {IM},\n completed = {2015-03-17},\n country = {Russia (Federation)},\n issn-linking = {0041-3771},\n issue = {7},\n keywords = {Brain Neoplasms, genetics, metabolism, pathology; Cell Line, Tumor; Cell Transformation, Neoplastic, genetics, metabolism, pathology; Epigenesis, Genetic; Gene Expression Regulation, Neoplastic; Glioma, genetics, metabolism, pathology; Histones, genetics, metabolism; Humans; Methylation; Primary Cell Culture; Protein Processing, Post-Translational; SOXB1 Transcription Factors, genetics, metabolism; Tumor Microenvironment, genetics},\n nlm-id = {0417363},\n owner = {NLM},\n pmid = {25696994},\n pubmodel = {Print},\n pubstate = {ppublish},\n revised = {2015-02-20},\n}\n\n\n\n Both genetic and epigenetic changes underlite the mechanisms of tumor initiation and progression. In the present study we analyze sox2 gene expression and its epigenetic regulation in primary cultures of malignant gliomas. The sox2 expression was detected in the vast majority (74%) of the investigated gliomas and absent in morphologically normal brain tissue. This indicates the process of glioma malignant transformation. We have also shown that the association of different areas of the sox2 gene with important epigenetic markers, posttranslational modifications of H3 histone H3K4ac and H3K9met3, does not correlate with the sox2 expression. However, this may indicate the stochastic nature of the regulation of sox2 gene expression in malignant gliomas.\n
\n\n\n\n \n\n \n \n \n \n \n Study of low-frequency dynamics of short peptides by Brillouin light scattering and Monte-Carlo global energy minimization.\n \n \n \n\n\n \n Vashchenkov, V. E.; Fedoseev, A. I.; Petukhov, M. G.; Khavinson, V. K.; Savvateeva-Popova, E. V.; and Lushnikov, S. G.\n\n\n \n\n\n\n Journal of Physics: Conference Series, 572: 012015. 2014.\n \n\n\n\n
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\n\n\n\n@Article{Vashchenkov2014,\n author = {V. E. Vashchenkov and A. I. Fedoseev and M. G. Petukhov and V. Kh Khavinson and E. V. Savvateeva-Popova and S. G. Lushnikov},\n journal = {Journal of Physics: Conference Series},\n title = {Study of low-frequency dynamics of short peptides by Brillouin light scattering and Monte-Carlo global energy minimization},\n year = {2014},\n issn = {1742-6588},\n pages = {012015},\n volume = {572},\n doi = {10.1088/1742-6596/572/1/012015},\n keywords = {General Physics and Astronomy},\n publisher = {IOP Publishing},\n}\n\n\n\n \n\n \n \n \n \n \n Aberrant expression of the sox2 gene in malignant gliomas.\n \n \n \n\n\n \n Volnitskiy, A. V.; Semenova, E. V.; Shtam, T. A.; Kovalev, R. A.; and Filatov, M. V.\n\n\n \n\n\n\n Cell and Tissue Biology, 8(5): 368-373. 2014.\n \n\n\n\n
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\n\n\n\n@Article{Volnitskiy2014,\n author = {A. V. Volnitskiy and E. V. Semenova and T. A. Shtam and R. A. Kovalev and M. V. Filatov},\n journal = {Cell and Tissue Biology},\n title = {Aberrant expression of the sox2 gene in malignant gliomas},\n year = {2014},\n issn = {1990-519X},\n number = {5},\n pages = {368-373},\n volume = {8},\n doi = {10.1134/s1990519x14050101},\n keywords = {Cell Biology},\n publisher = {Pleiades Publishing Ltd},\n}\n\n\n\n
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\n \n \n\n \n \n \n \n \n tRNA tKUUU, tQUUG, and tEUUC wobble position modifications fine-tune protein translation by promoting ribosome A-site binding.\n \n \n \n\n\n \n Rezgui, V. A. N.; Tyagi, K.; Ranjan, N.; Konevega, A. L.; Mittelstaet, J.; Rodnina, M. V.; Peter, M.; and Pedrioli, P. G. A.\n\n\n \n\n\n\n Proceedings of the National Academy of Sciences of the United States of America, 110: 12289–12294. July 2013.\n \n\n\n\n
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\n\n\n@Article{Rezgui2013,\n author = {Rezgui, Vanessa Anissa Nathalie and Tyagi, Kshitiz and Ranjan, Namit and Konevega, Andrey L. and Mittelstaet, Joerg and Rodnina, Marina V. and Peter, Matthias and Pedrioli, Patrick G. A.},\n journal = {Proceedings of the National Academy of Sciences of the United States of America},\n title = {tRNA tKUUU, tQUUG, and tEUUC wobble position modifications fine-tune protein translation by promoting ribosome A-site binding.},\n year = {2013},\n issn = {1091-6490},\n month = jul,\n pages = {12289--12294},\n volume = {110},\n abstract = {tRNA modifications are crucial to ensure translation efficiency and fidelity. In eukaryotes, the URM1 and ELP pathways increase cellular resistance to various stress conditions, such as nutrient starvation and oxidative agents, by promoting thiolation and methoxycarbonylmethylation, respectively, of the wobble uridine of cytoplasmic (tK(UUU)), (tQ(UUG)), and (tE(UUC)). Although in vitro experiments have implicated these tRNA modifications in modulating wobbling capacity and translation efficiency, their exact in vivo biological roles remain largely unexplored. Using a combination of quantitative proteomics and codon-specific translation reporters, we find that translation of a specific gene subset enriched for AAA, CAA, and GAA codons is impaired in the absence of URM1- and ELP-dependent tRNA modifications. Moreover, in vitro experiments using native tRNAs demonstrate that both modifications enhance binding of tK(UUU) to the ribosomal A-site. Taken together, our data suggest that tRNA thiolation and methoxycarbonylmethylation regulate translation of genes with specific codon content.},\n chemicals = {Codon, Proteins, RNA, Messenger, RNA, Transfer},\n citation-subset = {IM},\n completed = {2013-10-17},\n country = {United States},\n doi = {10.1073/pnas.1300781110},\n issn-linking = {0027-8424},\n issue = {30},\n keywords = {Binding Sites; Codon; Protein Biosynthesis; Proteins, genetics; RNA, Messenger, genetics; RNA, Transfer, chemistry, metabolism; Ribosomes, metabolism; SILAC; systems biology; translation regulation},\n nlm-id = {7505876},\n owner = {NLM},\n pii = {1300781110},\n pmc = {PMC3725067},\n pmid = {23836657},\n pubmodel = {Print-Electronic},\n pubstate = {ppublish},\n revised = {2021-10-21},\n}\n\n\n\n tRNA modifications are crucial to ensure translation efficiency and fidelity. In eukaryotes, the URM1 and ELP pathways increase cellular resistance to various stress conditions, such as nutrient starvation and oxidative agents, by promoting thiolation and methoxycarbonylmethylation, respectively, of the wobble uridine of cytoplasmic (tK(UUU)), (tQ(UUG)), and (tE(UUC)). Although in vitro experiments have implicated these tRNA modifications in modulating wobbling capacity and translation efficiency, their exact in vivo biological roles remain largely unexplored. Using a combination of quantitative proteomics and codon-specific translation reporters, we find that translation of a specific gene subset enriched for AAA, CAA, and GAA codons is impaired in the absence of URM1- and ELP-dependent tRNA modifications. Moreover, in vitro experiments using native tRNAs demonstrate that both modifications enhance binding of tK(UUU) to the ribosomal A-site. Taken together, our data suggest that tRNA thiolation and methoxycarbonylmethylation regulate translation of genes with specific codon content.\n
\n\n\n\n \n\n \n \n \n \n \n A kinetic safety gate controlling the delivery of unnatural amino acids to the ribosome.\n \n \n \n\n\n \n Mittelstaet, J.; Konevega, A. L.; and Rodnina, M. V.\n\n\n \n\n\n\n Journal of the American Chemical Society, 135: 17031–17038. November 2013.\n \n\n\n\n
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\n\n\n@Article{Mittelstaet2013,\n author = {Mittelstaet, Joerg and Konevega, Andrey L. and Rodnina, Marina V.},\n journal = {Journal of the American Chemical Society},\n title = {A kinetic safety gate controlling the delivery of unnatural amino acids to the ribosome.},\n year = {2013},\n issn = {1520-5126},\n month = nov,\n pages = {17031--17038},\n volume = {135},\n abstract = {Improving the yield of unnatural amino acid incorporation is an important challenge in producing novel designer proteins with unique chemical properties. Here we examine the mechanisms that restrict the incorporation of the fluorescent unnatural amino acid εNH2-Bodipy576/589-lysine (BOP-Lys) into a model protein. While the delivery of BOP-Lys-tRNA(Lys) to the ribosome is limited by its poor binding to elongation factor Tu (EF-Tu), the yield of incorporation into peptide is additionally controlled at the step of BOP-Lys-tRNA release from EF-Tu into the ribosome. The unnatural amino acid appears to disrupt the interactions that balance the strength of tRNA binding to EF-Tu-GTP with the velocity of tRNA dissociation from EF-Tu-GDP on the ribosome, which ensure uniform incorporation of standard amino acids. Circumventing this potential quality control checkpoint that specifically prevents incorporation of unnatural amino acids into proteins may provide a new strategy to increase yields of unnatural polymers.},\n chemicals = {4,4-difluoro-4-bora-3a,4a-diaza-s-indacene, Bacterial Proteins, Boron Compounds, Fluorescent Dyes, Guanosine Triphosphate, RNA, Transfer, Peptide Elongation Factor Tu, Lysine},\n citation-subset = {IM},\n completed = {2014-06-17},\n country = {United States},\n doi = {10.1021/ja407511q},\n issn-linking = {0002-7863},\n issue = {45},\n keywords = {Bacterial Proteins, chemistry, metabolism; Boron Compounds, chemistry; Escherichia coli, chemistry, metabolism; Fluorescent Dyes, chemistry; Guanosine Triphosphate, metabolism; Kinetics; Lysine, analogs & derivatives; Models, Molecular; Peptide Elongation Factor Tu, chemistry, metabolism; RNA, Transfer, metabolism; Ribosomes, metabolism; Thermus thermophilus, chemistry, metabolism},\n nlm-id = {7503056},\n owner = {NLM},\n pmid = {24079513},\n pubmodel = {Print-Electronic},\n pubstate = {ppublish},\n revised = {2013-11-13},\n}\n\n\n\n Improving the yield of unnatural amino acid incorporation is an important challenge in producing novel designer proteins with unique chemical properties. Here we examine the mechanisms that restrict the incorporation of the fluorescent unnatural amino acid εNH2-Bodipy576/589-lysine (BOP-Lys) into a model protein. While the delivery of BOP-Lys-tRNA(Lys) to the ribosome is limited by its poor binding to elongation factor Tu (EF-Tu), the yield of incorporation into peptide is additionally controlled at the step of BOP-Lys-tRNA release from EF-Tu into the ribosome. The unnatural amino acid appears to disrupt the interactions that balance the strength of tRNA binding to EF-Tu-GTP with the velocity of tRNA dissociation from EF-Tu-GDP on the ribosome, which ensure uniform incorporation of standard amino acids. Circumventing this potential quality control checkpoint that specifically prevents incorporation of unnatural amino acids into proteins may provide a new strategy to increase yields of unnatural polymers.\n
\n\n\n\n \n\n \n \n \n \n \n Exosomes are natural carriers of exogenous siRNA to human cells in vitro.\n \n \n \n\n\n \n Shtam, T. A.; Kovalev, R. A.; Varfolomeeva, E. Y.; Makarov, E. M.; Kil, Y. V.; and Filatov, M. V.\n\n\n \n\n\n\n Cell communication and signaling : CCS, 11: 88. November 2013.\n \n\n\n\n
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\n\n\n@Article{Shtam2013,\n author = {Shtam, Tatyana A. and Kovalev, Roman A. and Varfolomeeva, Elena Yu and Makarov, Evgeny M. and Kil, Yury V. and Filatov, Michael V.},\n journal = {Cell communication and signaling : CCS},\n title = {Exosomes are natural carriers of exogenous siRNA to human cells in vitro.},\n year = {2013},\n issn = {1478-811X},\n month = nov,\n pages = {88},\n volume = {11},\n abstract = {Exosomes are nano-sized vesicles of endocytic origin that are involved in cell-to-cell communication including shuttle RNA, mainly mRNA and microRNA. As exosomes naturally carry RNA between cells, these particles might be useful in gene cancer therapy to deliver therapeutic short interfering RNA (siRNA) to the target cells. Despite the promise of RNA interference (RNAi) for use in therapy, several technical obstacles must be overcome. Exogenous siRNA is prone to degradation, has a limited ability to cross cell membranes and may induce an immune response. Naturally occurring RNA carriers, such as exosomes, might provide an untapped source of effective delivery strategies. This study demonstrates that exosomes can deliver siRNA to recipient cells in vitro. The different strategies were used to introduce siRNAs into human exosomes of various origins. The delivery of fluorescently labeled siRNA via exosomes to cells was confirmed using confocal microscopy and flow cytometry. Two different siRNAs against RAD51 and RAD52 were used to transfect into the exosomes for therapeutic delivery into target cells. The exosome-delivered siRNAs were effective at causing post-transcriptional gene silencing in recipient cells. Moreover, the exosome-delivered siRNA against RAD51 was functional and caused the massive reproductive cell death of recipient cancer cells. The results strongly suggest that exosomes effectively delivered the siRNA into the target cells. The therapeutic potential of exosome-mediated siRNA delivery was demonstrated in vitro by the strong knockdown of RAD51, a prospective therapeutic target for cancer cells. The results give an additional evidence of the ability to use human exosomes as vectors in cancer therapy, including RNAi-based gene therapy.},\n chemicals = {RAD52 protein, human, RNA, Small Interfering, Rad52 DNA Repair and Recombination Protein, RAD51 protein, human, Rad51 Recombinase},\n citation-subset = {IM},\n completed = {2014-02-21},\n country = {England},\n doi = {10.1186/1478-811X-11-88},\n issn-linking = {1478-811X},\n keywords = {Ascitic Fluid, cytology; Cell Line, Tumor; Exosomes; Gene Transfer Techniques; Humans; RNA, Small Interfering, administration & dosage; Rad51 Recombinase, genetics; Rad52 DNA Repair and Recombination Protein, genetics},\n nlm-id = {101170464},\n owner = {NLM},\n pii = {1478-811X-11-88},\n pmc = {PMC3895799},\n pmid = {24245560},\n pubmodel = {Electronic},\n pubstate = {epublish},\n revised = {2022-03-10},\n}\n\n\n\n Exosomes are nano-sized vesicles of endocytic origin that are involved in cell-to-cell communication including shuttle RNA, mainly mRNA and microRNA. As exosomes naturally carry RNA between cells, these particles might be useful in gene cancer therapy to deliver therapeutic short interfering RNA (siRNA) to the target cells. Despite the promise of RNA interference (RNAi) for use in therapy, several technical obstacles must be overcome. Exogenous siRNA is prone to degradation, has a limited ability to cross cell membranes and may induce an immune response. Naturally occurring RNA carriers, such as exosomes, might provide an untapped source of effective delivery strategies. This study demonstrates that exosomes can deliver siRNA to recipient cells in vitro. The different strategies were used to introduce siRNAs into human exosomes of various origins. The delivery of fluorescently labeled siRNA via exosomes to cells was confirmed using confocal microscopy and flow cytometry. Two different siRNAs against RAD51 and RAD52 were used to transfect into the exosomes for therapeutic delivery into target cells. The exosome-delivered siRNAs were effective at causing post-transcriptional gene silencing in recipient cells. Moreover, the exosome-delivered siRNA against RAD51 was functional and caused the massive reproductive cell death of recipient cancer cells. The results strongly suggest that exosomes effectively delivered the siRNA into the target cells. The therapeutic potential of exosome-mediated siRNA delivery was demonstrated in vitro by the strong knockdown of RAD51, a prospective therapeutic target for cancer cells. The results give an additional evidence of the ability to use human exosomes as vectors in cancer therapy, including RNAi-based gene therapy.\n
\n\n\n\n \n\n \n \n \n \n \n Crystal structure of E. coli dihydrouridine synthase C (DusC).\n \n \n \n\n\n \n Byrne, R. T.; Whelan, F.; Konevega, A.; Aziz, N.; Rodnina, M.; and Antson, A. A.\n\n\n \n\n\n\n November 2013.\n \n\n\n\n
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\n\n\n\n@Misc{Byrne2013,\n author = {R. T. Byrne and F. Whelan and A. Konevega and N. Aziz and M. Rodnina and A. A. Antson},\n month = nov,\n title = {Crystal structure of E. coli dihydrouridine synthase C (DusC)},\n year = {2013},\n doi = {10.2210/pdb4bfa/pdb},\n publisher = {Worldwide Protein Data Bank},\n}\n\n\n\n \n\n \n \n \n \n \n Crystal structure of E. coli dihydrouridine synthase C (DusC) ( selenomethionine derivative).\n \n \n \n\n\n \n Byrne, R. T.; Whelan, F.; Konevega, A.; Aziz, N.; Rodnina, M.; and Antson, A. A.\n\n\n \n\n\n\n November 2013.\n \n\n\n\n
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\n\n\n\n@Misc{Byrne2013a,\n author = {R. T. Byrne and F. Whelan and A. Konevega and N. Aziz and M. Rodnina and A. A. Antson},\n month = nov,\n title = {Crystal structure of E. coli dihydrouridine synthase C (DusC) ( selenomethionine derivative)},\n year = {2013},\n doi = {10.2210/pdb4bf9/pdb},\n publisher = {Worldwide Protein Data Bank},\n}\n\n\n\n
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\n \n \n\n \n \n \n \n \n Large-scale conformational flexibility determines the properties of AAA+ TIP49 ATPases.\n \n \n \n\n\n \n Petukhov, M.; Dagkessamanskaja, A.; Bommer, M.; Barrett, T.; Tsaneva, I.; Yakimov, A.; Quéval, R.; Shvetsov, A.; Khodorkovskiy, M.; Käs, E.; and Grigoriev, M.\n\n\n \n\n\n\n Structure (London, England : 1993), 20: 1321–1331. August 2012.\n \n\n\n\n
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\n\n\n@Article{Petukhov2012,\n author = {Petukhov, Michael and Dagkessamanskaja, Adilia and Bommer, Martin and Barrett, Tracey and Tsaneva, Irina and Yakimov, Alexander and Quéval, Richard and Shvetsov, Alexey and Khodorkovskiy, Mikhail and Käs, Emmanuel and Grigoriev, Mikhail},\n journal = {Structure (London, England : 1993)},\n title = {Large-scale conformational flexibility determines the properties of AAA+ TIP49 ATPases.},\n year = {2012},\n issn = {1878-4186},\n month = aug,\n pages = {1321--1331},\n volume = {20},\n abstract = {The TIP49a and TIP49b proteins belong to the family of AAA+ ATPases and play essential roles in vital processes such as transcription, DNA repair, snoRNP biogenesis, and chromatin remodeling. We report the crystal structure of a TIP49b hexamer and the comparative analysis of large-scale conformational flexibility of TIP49a, TIP49b, and TIP49a/TIP49b complexes using molecular modeling and molecular dynamics simulations in a water environment. Our results establish key principles of domain mobility that affect protein conformation and biochemical properties, including a mechanistic basis for the downregulation of ATPase activity upon protein hexamerization. These approaches, applied to the lik-TIP49b mutant reported to possess enhanced DNA-independent ATPase activity, help explain how a three-amino acid insertion remotely affects the structure and conformational dynamics of the ATP binding and hydrolysis pocket while uncoupling ATP hydrolysis from DNA binding. This might be similar to the effects of conformations adopted by TIP49 heterohexamers.},\n chemicals = {Carrier Proteins, Adenosine Triphosphate, ATPases Associated with Diverse Cellular Activities, DNA Helicases, RUVBL1 protein, human, RUVBL2 protein, human},\n citation-subset = {IM},\n completed = {2012-12-26},\n country = {United States},\n doi = {10.1016/j.str.2012.05.012},\n issn-linking = {0969-2126},\n issue = {8},\n keywords = {ATPases Associated with Diverse Cellular Activities; Adenosine Triphosphate, chemistry; Carrier Proteins, chemistry; Catalytic Domain; Crystallography, X-Ray; DNA Helicases, chemistry; Enzyme Stability; Humans; Hydrogen Bonding; Hydrolysis; Molecular Dynamics Simulation; Protein Binding; Protein Structure, Quaternary; Protein Structure, Secondary},\n nlm-id = {101087697},\n owner = {NLM},\n pii = {S0969-2126(12)00216-X},\n pmid = {22748767},\n pubmodel = {Print-Electronic},\n pubstate = {ppublish},\n revised = {2021-10-21},\n}\n\n\n\n The TIP49a and TIP49b proteins belong to the family of AAA+ ATPases and play essential roles in vital processes such as transcription, DNA repair, snoRNP biogenesis, and chromatin remodeling. We report the crystal structure of a TIP49b hexamer and the comparative analysis of large-scale conformational flexibility of TIP49a, TIP49b, and TIP49a/TIP49b complexes using molecular modeling and molecular dynamics simulations in a water environment. Our results establish key principles of domain mobility that affect protein conformation and biochemical properties, including a mechanistic basis for the downregulation of ATPase activity upon protein hexamerization. These approaches, applied to the lik-TIP49b mutant reported to possess enhanced DNA-independent ATPase activity, help explain how a three-amino acid insertion remotely affects the structure and conformational dynamics of the ATP binding and hydrolysis pocket while uncoupling ATP hydrolysis from DNA binding. This might be similar to the effects of conformations adopted by TIP49 heterohexamers.\n
\n\n\n\n \n\n \n \n \n \n \n Thermodynamics of the GTP-GDP-operated conformational switch of selenocysteine-specific translation factor SelB.\n \n \n \n\n\n \n Paleskava, A.; Konevega, A. L.; and Rodnina, M. V.\n\n\n \n\n\n\n The Journal of biological chemistry, 287: 27906–27912. August 2012.\n \n\n\n\n
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\n\n\n@Article{Paleskava2012,\n author = {Paleskava, Alena and Konevega, Andrey L. and Rodnina, Marina V.},\n journal = {The Journal of biological chemistry},\n title = {Thermodynamics of the GTP-GDP-operated conformational switch of selenocysteine-specific translation factor SelB.},\n year = {2012},\n issn = {1083-351X},\n month = aug,\n pages = {27906--27912},\n volume = {287},\n abstract = {SelB is a specialized translation factor that binds GTP and GDP and delivers selenocysteyl-tRNA (Sec-tRNA(Sec)) to the ribosome. By analogy to elongation factor Tu (EF-Tu), SelB is expected to control the delivery and release of Sec-tRNA(Sec) to the ribosome by the structural switch between GTP- and GDP-bound conformations. However, crystal structures of SelB suggested a similar domain arrangement in the apo form and GDP- and GTP-bound forms of the factor, raising the question of how SelB can fulfill its delivery function. Here, we studied the thermodynamics of guanine nucleotide binding to SelB by isothermal titration calorimetry in the temperature range between 10 and 25 °C using GTP, GDP, and two nonhydrolyzable GTP analogs, guanosine 5'-O-(γ-thio)triphosphate (GTPγS) and guanosine 5'-(β,γ-imido)-triphosphate (GDPNP). The binding of SelB to either guanine nucleotide is characterized by a large heat capacity change (-621, -467, -235, and -275 cal × mol(-1) × K(-1), with GTP, GTPγS, GDPNP, and GDP, respectively), associated with compensatory changes in binding entropy and enthalpy. Changes in heat capacity indicate a large decrease of the solvent-accessible surface area in SelB, amounting to 43 or 32 amino acids buried upon binding of GTP or GTPγS, respectively, and 15-19 amino acids upon binding GDP or GDPNP. The similarity of the GTP and GDP forms in the crystal structures can be attributed to the use of GDPNP, which appears to induce a structure of SelB that is more similar to the GDP than to the GTP-bound form.},\n chemicals = {Bacterial Proteins, Escherichia coli Proteins, Peptide Elongation Factors, SelB protein, Bacteria, Guanosine Diphosphate, Guanosine Triphosphate},\n citation-subset = {IM},\n completed = {2012-11-05},\n country = {United States},\n doi = {10.1074/jbc.M112.366120},\n issn-linking = {0021-9258},\n issue = {33},\n keywords = {Bacterial Proteins, chemistry; Escherichia coli, chemistry; Escherichia coli Proteins, chemistry; Guanosine Diphosphate, analogs & derivatives, chemistry; Guanosine Triphosphate, analogs & derivatives, chemistry; Peptide Elongation Factors, chemistry; Protein Conformation; Thermodynamics},\n nlm-id = {2985121R},\n owner = {NLM},\n pii = {S0021-9258(20)47813-5},\n pmc = {PMC3431659},\n pmid = {22740700},\n pubmodel = {Print-Electronic},\n pubstate = {ppublish},\n revised = {2021-10-21},\n}\n\n\n\n SelB is a specialized translation factor that binds GTP and GDP and delivers selenocysteyl-tRNA (Sec-tRNA(Sec)) to the ribosome. By analogy to elongation factor Tu (EF-Tu), SelB is expected to control the delivery and release of Sec-tRNA(Sec) to the ribosome by the structural switch between GTP- and GDP-bound conformations. However, crystal structures of SelB suggested a similar domain arrangement in the apo form and GDP- and GTP-bound forms of the factor, raising the question of how SelB can fulfill its delivery function. Here, we studied the thermodynamics of guanine nucleotide binding to SelB by isothermal titration calorimetry in the temperature range between 10 and 25 °C using GTP, GDP, and two nonhydrolyzable GTP analogs, guanosine 5'-O-(γ-thio)triphosphate (GTPγS) and guanosine 5'-(β,γ-imido)-triphosphate (GDPNP). The binding of SelB to either guanine nucleotide is characterized by a large heat capacity change (-621, -467, -235, and -275 cal × mol(-1) × K(-1), with GTP, GTPγS, GDPNP, and GDP, respectively), associated with compensatory changes in binding entropy and enthalpy. Changes in heat capacity indicate a large decrease of the solvent-accessible surface area in SelB, amounting to 43 or 32 amino acids buried upon binding of GTP or GTPγS, respectively, and 15-19 amino acids upon binding GDP or GDPNP. The similarity of the GTP and GDP forms in the crystal structures can be attributed to the use of GDPNP, which appears to induce a structure of SelB that is more similar to the GDP than to the GTP-bound form.\n
\n\n\n\n \n\n \n \n \n \n \n Purification and in vitro analysis of exosomes secreted by malignantly transformed human cells.\n \n \n \n\n\n \n Shtam, T. A.; Naryzhny, S. N.; Landa, S. B.; Burdakov, V. S.; Artamonova, T. O.; and Filatov, M. V.\n\n\n \n\n\n\n Cell and Tissue Biology, 6(4): 317-325. 2012.\n \n\n\n\n
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\n\n\n\n@Article{Shtam2012,\n author = {T. A. Shtam and S. N. Naryzhny and S. B. Landa and V. S. Burdakov and T. O. Artamonova and M. V. Filatov},\n journal = {Cell and Tissue Biology},\n title = {Purification and in vitro analysis of exosomes secreted by malignantly transformed human cells},\n year = {2012},\n issn = {1990-519X},\n number = {4},\n pages = {317-325},\n volume = {6},\n doi = {10.1134/s1990519x12040116},\n keywords = {Cell Biology},\n publisher = {Pleiades Publishing Ltd},\n}\n\n\n\n
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\n \n \n\n \n \n \n \n \n Evolutionary optimization of speed and accuracy of decoding on the ribosome.\n \n \n \n\n\n \n Wohlgemuth, I.; Pohl, C.; Mittelstaet, J.; Konevega, A. L.; and Rodnina, M. V.\n\n\n \n\n\n\n Philosophical transactions of the Royal Society of London. Series B, Biological sciences, 366: 2979–2986. October 2011.\n \n\n\n\n
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\n\n\n@Article{Wohlgemuth2011,\n author = {Wohlgemuth, Ingo and Pohl, Corinna and Mittelstaet, Joerg and Konevega, Andrey L. and Rodnina, Marina V.},\n journal = {Philosophical transactions of the Royal Society of London. Series B, Biological sciences},\n title = {Evolutionary optimization of speed and accuracy of decoding on the ribosome.},\n year = {2011},\n issn = {1471-2970},\n month = oct,\n pages = {2979--2986},\n volume = {366},\n abstract = {Speed and accuracy of protein synthesis are fundamental parameters for the fitness of living cells, the quality control of translation, and the evolution of ribosomes. The ribosome developed complex mechanisms that allow for a uniform recognition and selection of any cognate aminoacyl-tRNA (aa-tRNA) and discrimination against any near-cognate aa-tRNA, regardless of the nature or position of the mismatch. This review describes the principles of the selection-kinetic partitioning and induced fit-and discusses the relationship between speed and accuracy of decoding, with a focus on bacterial translation. The translational machinery apparently has evolved towards high speed of translation at the cost of fidelity.},\n chemicals = {Bacterial Proteins, Codon, Peptides, RNA, Transfer, Amino Acyl, Guanosine Triphosphate, GTP Phosphohydrolases, Peptide Elongation Factor Tu},\n citation-subset = {IM},\n completed = {2012-01-17},\n country = {England},\n doi = {10.1098/rstb.2011.0138},\n issn-linking = {0962-8436},\n issue = {1580},\n keywords = {Bacterial Proteins, chemistry; Catalytic Domain; Codon, chemistry; Enzyme Activation; Escherichia coli, chemistry, genetics; Evolution, Molecular; GTP Phosphohydrolases, chemistry; Guanosine Triphosphate, chemistry; Hydrolysis; Kinetics; Peptide Elongation Factor Tu, chemistry; Peptides, chemistry; Protein Biosynthesis; RNA, Transfer, Amino Acyl, chemistry; Ribosomes, chemistry, genetics; Time Factors},\n nlm-id = {7503623},\n owner = {NLM},\n pii = {366/1580/2979},\n pmc = {PMC3158919},\n pmid = {21930591},\n pubmodel = {Print},\n pubstate = {ppublish},\n revised = {2021-10-20},\n}\n\n\n\n Speed and accuracy of protein synthesis are fundamental parameters for the fitness of living cells, the quality control of translation, and the evolution of ribosomes. The ribosome developed complex mechanisms that allow for a uniform recognition and selection of any cognate aminoacyl-tRNA (aa-tRNA) and discrimination against any near-cognate aa-tRNA, regardless of the nature or position of the mismatch. This review describes the principles of the selection-kinetic partitioning and induced fit-and discusses the relationship between speed and accuracy of decoding, with a focus on bacterial translation. The translational machinery apparently has evolved towards high speed of translation at the cost of fidelity.\n
\n\n\n\n \n\n \n \n \n \n \n Distortion of tRNA upon near-cognate codon recognition on the ribosome.\n \n \n \n\n\n \n Mittelstaet, J.; Konevega, A. L.; and Rodnina, M. V.\n\n\n \n\n\n\n The Journal of biological chemistry, 286: 8158–8164. March 2011.\n \n\n\n\n
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\n\n\n@Article{Mittelstaet2011,\n author = {Mittelstaet, Joerg and Konevega, Andrey L. and Rodnina, Marina V.},\n journal = {The Journal of biological chemistry},\n title = {Distortion of tRNA upon near-cognate codon recognition on the ribosome.},\n year = {2011},\n issn = {1083-351X},\n month = mar,\n pages = {8158--8164},\n volume = {286},\n abstract = {The accurate decoding of the genetic information by the ribosome relies on the communication between the decoding center of the ribosome, where the tRNA anticodon interacts with the codon, and the GTPase center of EF-Tu, where GTP hydrolysis takes place. In the A/T state of decoding, the tRNA undergoes a large conformational change that results in a more open, distorted tRNA structure. Here we use a real-time transient fluorescence quenching approach to monitor the timing and the extent of the tRNA distortion upon reading cognate or near-cognate codons. The tRNA is distorted upon codon recognition and remains in that conformation until the tRNA is released from EF-Tu, although the extent of distortion gradually changes upon transition from the pre- to the post-hydrolysis steps of decoding. The timing and extent of the rearrangement is similar on cognate and near-cognate codons, suggesting that the tRNA distortion alone does not provide a specific switch for the preferential activation of GTP hydrolysis on the cognate codon. Thus, although the tRNA plays an active role in signal transmission between the decoding and GTPase centers, other regulators of signaling must be involved.},\n chemicals = {Codon, RNA, Fungal, Guanosine Triphosphate, RNA, Transfer, Peptide Elongation Factor Tu},\n citation-subset = {IM},\n completed = {2011-05-11},\n country = {United States},\n doi = {10.1074/jbc.M110.210021},\n issn-linking = {0021-9258},\n issue = {10},\n keywords = {Cell-Free System, chemistry, metabolism; Codon, chemistry, metabolism; Guanosine Triphosphate, chemistry, metabolism; Nucleic Acid Conformation; Peptide Elongation Factor Tu, chemistry, metabolism; RNA, Fungal, chemistry, metabolism; RNA, Transfer, chemistry, metabolism; Ribosomes, chemistry, metabolism; Saccharomyces cerevisiae, chemistry, metabolism},\n nlm-id = {2985121R},\n owner = {NLM},\n pii = {S0021-9258(20)53960-4},\n pmc = {PMC3048702},\n pmid = {21212264},\n pubmodel = {Print-Electronic},\n pubstate = {ppublish},\n revised = {2021-10-20},\n}\n\n\n\n The accurate decoding of the genetic information by the ribosome relies on the communication between the decoding center of the ribosome, where the tRNA anticodon interacts with the codon, and the GTPase center of EF-Tu, where GTP hydrolysis takes place. In the A/T state of decoding, the tRNA undergoes a large conformational change that results in a more open, distorted tRNA structure. Here we use a real-time transient fluorescence quenching approach to monitor the timing and the extent of the tRNA distortion upon reading cognate or near-cognate codons. The tRNA is distorted upon codon recognition and remains in that conformation until the tRNA is released from EF-Tu, although the extent of distortion gradually changes upon transition from the pre- to the post-hydrolysis steps of decoding. The timing and extent of the rearrangement is similar on cognate and near-cognate codons, suggesting that the tRNA distortion alone does not provide a specific switch for the preferential activation of GTP hydrolysis on the cognate codon. Thus, although the tRNA plays an active role in signal transmission between the decoding and GTPase centers, other regulators of signaling must be involved.\n
\n\n\n\n \n\n \n \n \n \n \n The structure of helix 89 of 23S rRNA is important for peptidyl transferase function of Escherichia coli ribosome.\n \n \n \n\n\n \n Burakovsky, D. E.; Sergiev, P. V.; Steblyanko, M. A.; Konevega, A. L.; Bogdanov, A. A.; and Dontsova, O. A.\n\n\n \n\n\n\n FEBS letters, 585: 3073–3078. October 2011.\n \n\n\n\n
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\n\n\n@Article{Burakovsky2011,\n author = {Burakovsky, Dmitry E. and Sergiev, Petr V. and Steblyanko, Maria A. and Konevega, Andrey L. and Bogdanov, Alexey A. and Dontsova, Olga A.},\n journal = {FEBS letters},\n title = {The structure of helix 89 of 23S rRNA is important for peptidyl transferase function of Escherichia coli ribosome.},\n year = {2011},\n issn = {1873-3468},\n month = oct,\n pages = {3073--3078},\n volume = {585},\n abstract = {Helix 89 of the 23S rRNA connects ribosomal peptidyltransferase center and elongation factor binding site. Secondary structure of helix 89 determined by X-ray structural analysis involves less base pairs then could be drawn for the helix of the same primary structure. It can be that alternative secondary structure might be realized at some stage of translation. Here by means of site-directed mutagenesis we stabilized either the "X-ray" structure or the structure with largest number of paired nucleotides. Mutation UU2492-3C which aimed to provide maximal pairing of the helix 89 of the 23S rRNA was lethal. Mutant ribosomes were unable to catalyze peptide transfer independently either with aminoacyl-tRNA or puromycin.},\n chemicals = {Dipeptides, Protein Synthesis Inhibitors, RNA, Ribosomal, 23S, RNA, Transfer, Amino Acyl, Puromycin, Peptidyl Transferases},\n citation-subset = {IM},\n completed = {2011-12-27},\n country = {England},\n doi = {10.1016/j.febslet.2011.08.030},\n issn-linking = {0014-5793},\n issue = {19},\n keywords = {Base Sequence; Crystallography, X-Ray; Dipeptides, biosynthesis; Escherichia coli, genetics, metabolism; Molecular Sequence Data; Mutagenesis, Site-Directed; Nucleic Acid Conformation; Peptidyl Transferases, genetics, metabolism; Protein Biosynthesis; Protein Structure, Secondary; Protein Synthesis Inhibitors, metabolism; Puromycin, metabolism; RNA, Ribosomal, 23S, chemistry, genetics, metabolism; RNA, Transfer, Amino Acyl, chemistry, genetics, metabolism; Ribosomes, genetics, metabolism},\n nlm-id = {0155157},\n owner = {NLM},\n pii = {S0014-5793(11)00632-6},\n pmid = {21875584},\n pubmodel = {Print-Electronic},\n pubstate = {ppublish},\n revised = {2013-11-21},\n}\n\n\n\n Helix 89 of the 23S rRNA connects ribosomal peptidyltransferase center and elongation factor binding site. Secondary structure of helix 89 determined by X-ray structural analysis involves less base pairs then could be drawn for the helix of the same primary structure. It can be that alternative secondary structure might be realized at some stage of translation. Here by means of site-directed mutagenesis we stabilized either the \"X-ray\" structure or the structure with largest number of paired nucleotides. Mutation UU2492-3C which aimed to provide maximal pairing of the helix 89 of the 23S rRNA was lethal. Mutant ribosomes were unable to catalyze peptide transfer independently either with aminoacyl-tRNA or puromycin.\n
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\n \n \n\n \n \n \n \n \n The crystal structure of unmodified tRNAPhe from Escherichia coli.\n \n \n \n\n\n \n Byrne, R. T.; Konevega, A. L.; Rodnina, M. V.; and Antson, A. A.\n\n\n \n\n\n\n Nucleic acids research, 38: 4154–4162. July 2010.\n \n\n\n\n
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\n\n\n@Article{Byrne2010,\n author = {Byrne, Robert T. and Konevega, Andrey L. and Rodnina, Marina V. and Antson, Alfred A.},\n journal = {Nucleic acids research},\n title = {The crystal structure of unmodified tRNAPhe from Escherichia coli.},\n year = {2010},\n issn = {1362-4962},\n month = jul,\n pages = {4154--4162},\n volume = {38},\n abstract = {Post-transcriptional nucleoside modifications fine-tune the biophysical and biochemical properties of transfer RNA (tRNA) so that it is optimized for participation in cellular processes. Here we report the crystal structure of unmodified tRNA(Phe) from Escherichia coli at a resolution of 3 A. We show that in the absence of modifications the overall fold of the tRNA is essentially the same as that of mature tRNA. However, there are a number of significant structural differences, such as rearrangements in a triplet base pair and a widened angle between the acceptor and anticodon stems. Contrary to previous observations, the anticodon adopts the same conformation as seen in mature tRNA.},\n chemicals = {Anticodon, Metals, RNA, Transfer, Phe},\n citation-subset = {IM},\n completed = {2010-07-28},\n country = {England},\n doi = {10.1093/nar/gkq133},\n issn-linking = {0305-1048},\n issue = {12},\n keywords = {Anticodon, chemistry; Crystallography, X-Ray; Escherichia coli, genetics; Metals, chemistry; Models, Molecular; Nucleic Acid Conformation; RNA, Transfer, Phe, chemistry},\n nlm-id = {0411011},\n owner = {NLM},\n pii = {gkq133},\n pmc = {PMC2896525},\n pmid = {20203084},\n pubmodel = {Print-Electronic},\n pubstate = {ppublish},\n revised = {2019-10-08},\n}\n\n\n\n Post-transcriptional nucleoside modifications fine-tune the biophysical and biochemical properties of transfer RNA (tRNA) so that it is optimized for participation in cellular processes. Here we report the crystal structure of unmodified tRNA(Phe) from Escherichia coli at a resolution of 3 A. We show that in the absence of modifications the overall fold of the tRNA is essentially the same as that of mature tRNA. However, there are a number of significant structural differences, such as rearrangements in a triplet base pair and a widened angle between the acceptor and anticodon stems. Contrary to previous observations, the anticodon adopts the same conformation as seen in mature tRNA.\n
\n\n\n\n \n\n \n \n \n \n \n The ribosome-bound initiation factor 2 recruits initiator tRNA to the 30S initiation complex.\n \n \n \n\n\n \n Milon, P.; Carotti, M.; Konevega, A. L.; Wintermeyer, W.; Rodnina, M. V.; and Gualerzi, C. O.\n\n\n \n\n\n\n EMBO reports, 11: 312–316. April 2010.\n \n\n\n\n
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\n\n\n@Article{Milon2010,\n author = {Milon, Pohl and Carotti, Marcello and Konevega, Andrey L. and Wintermeyer, Wolfgang and Rodnina, Marina V. and Gualerzi, Claudio O.},\n journal = {EMBO reports},\n title = {The ribosome-bound initiation factor 2 recruits initiator tRNA to the 30S initiation complex.},\n year = {2010},\n issn = {1469-3178},\n month = apr,\n pages = {312--316},\n volume = {11},\n abstract = {Bacterial translation initiation factor 2 (IF2) is a GTPase that promotes the binding of the initiator fMet-tRNA(fMet) to the 30S ribosomal subunit. It is often assumed that IF2 delivers fMet-tRNA(fMet) to the ribosome in a ternary complex, IF2.GTP.fMet-tRNA(fMet). By using rapid kinetic techniques, we show here that binding of IF2.GTP to the 30S ribosomal subunit precedes and is independent of fMet-tRNA(fMet) binding. The ternary complex formed in solution by IF2.GTP and fMet-tRNA is unstable and dissociates before IF2.GTP and, subsequently, fMet-tRNA(fMet) bind to the 30S subunit. Ribosome-bound IF2 might accelerate the recruitment of fMet-tRNA(fMet) to the 30S initiation complex by providing anchoring interactions or inducing a favourable ribosome conformation. The mechanism of action of IF2 seems to be different from that of tRNA carriers such as EF-Tu, SelB and eukaryotic initiation factor 2 (eIF2), instead resembling that of eIF5B, the eukaryotic subunit association factor.},\n chemicals = {Prokaryotic Initiation Factor-2, RNA, Transfer, Met, fMet-tRNA(fMet)},\n citation-subset = {IM},\n completed = {2010-06-30},\n country = {England},\n doi = {10.1038/embor.2010.12},\n issn-linking = {1469-221X},\n issue = {4},\n keywords = {Fluorescence Resonance Energy Transfer; Kinetics; Models, Biological; Prokaryotic Initiation Factor-2, metabolism; RNA, Transfer, Met, metabolism; Ribosome Subunits, Small, Bacterial, metabolism; Ribosomes, metabolism},\n nlm-id = {100963049},\n owner = {NLM},\n pii = {embor201012},\n pmc = {PMC2854590},\n pmid = {20224578},\n pubmodel = {Print-Electronic},\n pubstate = {ppublish},\n revised = {2020-09-30},\n}\n\n\n\n Bacterial translation initiation factor 2 (IF2) is a GTPase that promotes the binding of the initiator fMet-tRNA(fMet) to the 30S ribosomal subunit. It is often assumed that IF2 delivers fMet-tRNA(fMet) to the ribosome in a ternary complex, IF2.GTP.fMet-tRNA(fMet). By using rapid kinetic techniques, we show here that binding of IF2.GTP to the 30S ribosomal subunit precedes and is independent of fMet-tRNA(fMet) binding. The ternary complex formed in solution by IF2.GTP and fMet-tRNA is unstable and dissociates before IF2.GTP and, subsequently, fMet-tRNA(fMet) bind to the 30S subunit. Ribosome-bound IF2 might accelerate the recruitment of fMet-tRNA(fMet) to the 30S initiation complex by providing anchoring interactions or inducing a favourable ribosome conformation. The mechanism of action of IF2 seems to be different from that of tRNA carriers such as EF-Tu, SelB and eukaryotic initiation factor 2 (eIF2), instead resembling that of eIF5B, the eukaryotic subunit association factor.\n
\n\n\n\n \n\n \n \n \n \n \n Ribosome dynamics and tRNA movement by time-resolved electron cryomicroscopy.\n \n \n \n\n\n \n Fischer, N.; Konevega, A. L.; Wintermeyer, W.; Rodnina, M. V.; and Stark, H.\n\n\n \n\n\n\n Nature, 466: 329–333. July 2010.\n \n\n\n\n
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\n\n\n@Article{Fischer2010,\n author = {Fischer, Niels and Konevega, Andrey L. and Wintermeyer, Wolfgang and Rodnina, Marina V. and Stark, Holger},\n journal = {Nature},\n title = {Ribosome dynamics and tRNA movement by time-resolved electron cryomicroscopy.},\n year = {2010},\n issn = {1476-4687},\n month = jul,\n pages = {329--333},\n volume = {466},\n abstract = {The translocation step of protein synthesis entails large-scale rearrangements of the ribosome-transfer RNA (tRNA) complex. Here we have followed tRNA movement through the ribosome during translocation by time-resolved single-particle electron cryomicroscopy (cryo-EM). Unbiased computational sorting of cryo-EM images yielded 50 distinct three-dimensional reconstructions, showing the tRNAs in classical, hybrid and various novel intermediate states that provide trajectories and kinetic information about tRNA movement through the ribosome. The structures indicate how tRNA movement is coupled with global and local conformational changes of the ribosome, in particular of the head and body of the small ribosomal subunit, and show that dynamic interactions between tRNAs and ribosomal residues confine the path of the tRNAs through the ribosome. The temperature dependence of ribosome dynamics reveals a surprisingly flat energy landscape of conformational variations at physiological temperature. The ribosome functions as a Brownian machine that couples spontaneous conformational changes driven by thermal energy to directed movement.},\n chemicals = {RNA, Transfer},\n citation-subset = {IM},\n completed = {2010-08-30},\n country = {England},\n doi = {10.1038/nature09206},\n issn-linking = {0028-0836},\n issue = {7304},\n keywords = {Cryoelectron Microscopy; Escherichia coli; Kinetics; Models, Molecular; Molecular Conformation; Movement; Protein Biosynthesis; RNA, Transfer, genetics, metabolism; Ribosome Subunits, Large, Bacterial, chemistry, metabolism; Ribosome Subunits, Small, Bacterial, chemistry, metabolism; Ribosomes, chemistry, metabolism; Temperature; Thermodynamics; Time Factors},\n nlm-id = {0410462},\n owner = {NLM},\n pii = {nature09206},\n pmid = {20631791},\n pubmodel = {Print},\n pubstate = {ppublish},\n revised = {2021-10-20},\n}\n\n\n\n The translocation step of protein synthesis entails large-scale rearrangements of the ribosome-transfer RNA (tRNA) complex. Here we have followed tRNA movement through the ribosome during translocation by time-resolved single-particle electron cryomicroscopy (cryo-EM). Unbiased computational sorting of cryo-EM images yielded 50 distinct three-dimensional reconstructions, showing the tRNAs in classical, hybrid and various novel intermediate states that provide trajectories and kinetic information about tRNA movement through the ribosome. The structures indicate how tRNA movement is coupled with global and local conformational changes of the ribosome, in particular of the head and body of the small ribosomal subunit, and show that dynamic interactions between tRNAs and ribosomal residues confine the path of the tRNAs through the ribosome. The temperature dependence of ribosome dynamics reveals a surprisingly flat energy landscape of conformational variations at physiological temperature. The ribosome functions as a Brownian machine that couples spontaneous conformational changes driven by thermal energy to directed movement.\n
\n\n\n\n \n\n \n \n \n \n \n The crystal structure of unmodified tRNAPhe from Escherichia coli.\n \n \n \n\n\n \n Byrne, R. T.; Konevega, A. L.; Rodnina, M. V.; and Antson, A. A.\n\n\n \n\n\n\n March 2010.\n \n\n\n\n
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\n\n\n\n@Misc{Byrne2010a,\n author = {R. T. Byrne and A. L. Konevega and M. V. Rodnina and A. A. Antson},\n month = mar,\n title = {The crystal structure of unmodified tRNAPhe from Escherichia coli},\n year = {2010},\n doi = {10.2210/pdb3l0u/pdb},\n publisher = {Worldwide Protein Data Bank},\n}\n\n\n\n \n\n \n \n \n \n \n Thermodynamic and kinetic framework of selenocysteyl-tRNASec recognition by elongation factor SelB.\n \n \n \n\n\n \n Paleskava, A.; Konevega, A. L.; and Rodnina, M. V.\n\n\n \n\n\n\n The Journal of biological chemistry, 285: 3014–3020. January 2010.\n \n\n\n\n
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\n\n\n@Article{Paleskava2010,\n author = {Paleskava, Alena and Konevega, Andrey L. and Rodnina, Marina V.},\n journal = {The Journal of biological chemistry},\n title = {Thermodynamic and kinetic framework of selenocysteyl-tRNASec recognition by elongation factor SelB.},\n year = {2010},\n issn = {1083-351X},\n month = jan,\n pages = {3014--3020},\n volume = {285},\n abstract = {SelB is a specialized translation elongation factor that delivers selenocysteyl-tRNA(Sec) (Sec-tRNA(Sec)) to the ribosome. Here we show that Sec-tRNA(Sec) binds to SelB.GTP with an extraordinary high affinity (K(d) = 0.2 pm). The tight binding is driven enthalpically and involves the net formation of four ion pairs, three of which may involve the Sec residue. The dissociation of tRNA from the ternary complex SelB.GTP.Sec-tRNA(Sec) is very slow (0.3 h(-1)), and GTP hydrolysis accelerates the release of Sec-tRNA(Sec) by more than a million-fold (to 240 s(-1)). The affinities of Sec-tRNA(Sec) to SelB in the GDP or apoforms, or Ser-tRNA(Sec) and tRNA(Sec) to SelB in any form, are similar (K(d) = 0.5 microm). Thermodynamic coupling in binding of Sec-tRNA(Sec) and GTP to SelB ensures at the same time the specificity of Sec- versus Ser-tRNA(Sec) selection and rapid release of Sec-tRNA(Sec) from SelB after GTP cleavage on the ribosome. SelB provides an example for the evolution of a highly specialized protein-RNA complex toward recognition of unique set of identity elements. The mode of tRNA recognition by SelB is reminiscent of another specialized factor, eIF2, rather than of EF-Tu, the common delivery factor for all other aminoacyl-tRNAs, in line with a common evolutionary ancestry of SelB and eIF2.},\n chemicals = {Bacterial Proteins, Codon, Ions, RNA, Transfer, Amino Acyl, SelB protein, Bacteria, selenocysteinyl-tRNA, Guanosine Diphosphate, Guanosine Triphosphate, RNA, Transfer, Peptide Elongation Factor Tu},\n citation-subset = {IM},\n completed = {2010-02-25},\n country = {United States},\n doi = {10.1074/jbc.M109.081380},\n issn-linking = {0021-9258},\n issue = {5},\n keywords = {Bacterial Proteins, chemistry; Codon; Dose-Response Relationship, Drug; Escherichia coli, metabolism; Guanosine Diphosphate, chemistry; Guanosine Triphosphate, chemistry; Hydrolysis; Ions; Kinetics; Peptide Elongation Factor Tu, chemistry; Protein Binding; RNA, Transfer, chemistry; RNA, Transfer, Amino Acyl, metabolism; Static Electricity; Thermodynamics},\n nlm-id = {2985121R},\n owner = {NLM},\n pii = {S0021-9258(20)64796-2},\n pmc = {PMC2823455},\n pmid = {19940162},\n pubmodel = {Print-Electronic},\n pubstate = {ppublish},\n revised = {2021-10-20},\n}\n\n\n\n SelB is a specialized translation elongation factor that delivers selenocysteyl-tRNA(Sec) (Sec-tRNA(Sec)) to the ribosome. Here we show that Sec-tRNA(Sec) binds to SelB.GTP with an extraordinary high affinity (K(d) = 0.2 pm). The tight binding is driven enthalpically and involves the net formation of four ion pairs, three of which may involve the Sec residue. The dissociation of tRNA from the ternary complex SelB.GTP.Sec-tRNA(Sec) is very slow (0.3 h(-1)), and GTP hydrolysis accelerates the release of Sec-tRNA(Sec) by more than a million-fold (to 240 s(-1)). The affinities of Sec-tRNA(Sec) to SelB in the GDP or apoforms, or Ser-tRNA(Sec) and tRNA(Sec) to SelB in any form, are similar (K(d) = 0.5 microm). Thermodynamic coupling in binding of Sec-tRNA(Sec) and GTP to SelB ensures at the same time the specificity of Sec- versus Ser-tRNA(Sec) selection and rapid release of Sec-tRNA(Sec) from SelB after GTP cleavage on the ribosome. SelB provides an example for the evolution of a highly specialized protein-RNA complex toward recognition of unique set of identity elements. The mode of tRNA recognition by SelB is reminiscent of another specialized factor, eIF2, rather than of EF-Tu, the common delivery factor for all other aminoacyl-tRNAs, in line with a common evolutionary ancestry of SelB and eIF2.\n
\n\n\n\n \n\n \n \n \n \n \n Mutations at the accommodation gate of the ribosome impair RF2-dependent translation termination.\n \n \n \n\n\n \n Burakovsky, D. E.; Sergiev, P. V.; Steblyanko, M. A.; Kubarenko, A. V.; Konevega, A. L.; Bogdanov, A. A.; Rodnina, M. V.; and Dontsova, O. A.\n\n\n \n\n\n\n RNA (New York, N.Y.), 16: 1848–1853. September 2010.\n \n\n\n\n
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\n\n\n@Article{Burakovsky2010,\n author = {Burakovsky, Dmitry E. and Sergiev, Petr V. and Steblyanko, Maria A. and Kubarenko, Andriy V. and Konevega, Andrey L. and Bogdanov, Alexey A. and Rodnina, Marina V. and Dontsova, Olga A.},\n journal = {RNA (New York, N.Y.)},\n title = {Mutations at the accommodation gate of the ribosome impair RF2-dependent translation termination.},\n year = {2010},\n issn = {1469-9001},\n month = sep,\n pages = {1848--1853},\n volume = {16},\n abstract = {During protein synthesis, aminoacyl-tRNA (aa-tRNA) and release factors 1 and 2 (RF1 and RF2) have to bind at the catalytic center of the ribosome on the 50S subunit where they take part in peptide bond formation or peptidyl-tRNA hydrolysis, respectively. Computer simulations of aa-tRNA movement into the catalytic site (accommodation) suggested that three nucleotides of 23S rRNA, U2492, C2556, and C2573, form a "gate" at which aa-tRNA movement into the A site is retarded. Here we examined the role of nucleotides C2573 of 23S rRNA, a part of the putative accommodation gate, and of the neighboring A2572 for aa-tRNA binding followed by peptide bond formation and for the RF2-dependent peptide release. Mutations at the two positions did not affect aa-tRNA accommodation, peptide bond formation, or the fidelity of aa-tRNA selection, but impaired RF2-catalyzed peptide release. The data suggest that the ribosome is a robust machine that allows rapid aa-tRNA accommodation despite the defects at the accommodation gate. In comparison, peptide release by RF2 appears more sensitive to these mutations, due to slower accommodation of the factor or effects on RF2 positioning in the A site.},\n chemicals = {Escherichia coli Proteins, Peptide Termination Factors, RNA, Ribosomal, 23S, peptide chain termination release factor 2, RNA, Transfer},\n citation-subset = {IM},\n completed = {2010-09-21},\n country = {United States},\n doi = {10.1261/rna.2185710},\n issn-linking = {1355-8382},\n issue = {9},\n keywords = {Escherichia coli, metabolism; Escherichia coli Proteins, metabolism; Mutagenesis, Site-Directed; Mutation; Peptide Chain Termination, Translational; Peptide Termination Factors, metabolism; Protein Biosynthesis; RNA, Ribosomal, 23S, genetics, metabolism; RNA, Transfer, metabolism; Ribosomes, metabolism},\n medline = {9509184},\n nlm-id = {9509184},\n owner = {NLM},\n pii = {rna.2185710},\n pmc = {PMC2924543},\n pmid = {20668033},\n pubmodel = {Print-Electronic},\n pubstate = {ppublish},\n revised = {2021-10-20},\n}\n\n\n\n During protein synthesis, aminoacyl-tRNA (aa-tRNA) and release factors 1 and 2 (RF1 and RF2) have to bind at the catalytic center of the ribosome on the 50S subunit where they take part in peptide bond formation or peptidyl-tRNA hydrolysis, respectively. Computer simulations of aa-tRNA movement into the catalytic site (accommodation) suggested that three nucleotides of 23S rRNA, U2492, C2556, and C2573, form a \"gate\" at which aa-tRNA movement into the A site is retarded. Here we examined the role of nucleotides C2573 of 23S rRNA, a part of the putative accommodation gate, and of the neighboring A2572 for aa-tRNA binding followed by peptide bond formation and for the RF2-dependent peptide release. Mutations at the two positions did not affect aa-tRNA accommodation, peptide bond formation, or the fidelity of aa-tRNA selection, but impaired RF2-catalyzed peptide release. The data suggest that the ribosome is a robust machine that allows rapid aa-tRNA accommodation despite the defects at the accommodation gate. In comparison, peptide release by RF2 appears more sensitive to these mutations, due to slower accommodation of the factor or effects on RF2 positioning in the A site.\n
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\n \n \n\n \n \n \n \n \n Kinetic checkpoint at a late step in translation initiation.\n \n \n \n\n\n \n Milon, P.; Konevega, A. L.; Gualerzi, C. O.; and Rodnina, M. V.\n\n\n \n\n\n\n Molecular cell, 30: 712–720. June 2008.\n \n\n\n\n
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\n\n\n@Article{Milon2008,\n author = {Milon, Pohl and Konevega, Andrey L. and Gualerzi, Claudio O. and Rodnina, Marina V.},\n journal = {Molecular cell},\n title = {Kinetic checkpoint at a late step in translation initiation.},\n year = {2008},\n issn = {1097-4164},\n month = jun,\n pages = {712--720},\n volume = {30},\n abstract = {The translation initiation efficiency of a given mRNA is determined by its translation initiation region (TIR). mRNAs are selected into 30S initiation complexes according to the strengths of the secondary structure of the TIR, the pairing of the Shine-Dalgarno sequence with 16S rRNA, and the interaction between initiator tRNA and the start codon. Here, we show that the conversion of the 30S initiation complex into the translating 70S ribosome constitutes another important mRNA control checkpoint. Kinetic analysis reveals that 50S subunit joining and dissociation of IF3 are strongly influenced by the nature of the codon used for initiation and the structural elements of the TIR. Coupling between the TIR and the rate of 70S initiation complex formation involves IF3- and IF1-induced rearrangements of the 30S subunit, providing a mechanism by which the ribosome senses the TIR and determines the efficiency of translational initiation of a particular mRNA.},\n chemicals = {Codon, Peptide Initiation Factors, Prokaryotic Initiation Factor-2, RNA, Messenger, RNA, Ribosomal, 18S},\n citation-subset = {IM},\n completed = {2008-08-01},\n country = {United States},\n doi = {10.1016/j.molcel.2008.04.014},\n issn-linking = {1097-2765},\n issue = {6},\n keywords = {Codon, genetics, metabolism; Kinetics; Peptide Chain Initiation, Translational; Peptide Initiation Factors, genetics, metabolism; Prokaryotic Initiation Factor-2, metabolism; Protein Biosynthesis; RNA, Messenger, chemistry, genetics; RNA, Ribosomal, 18S, genetics; Ribosomes, genetics, metabolism},\n nlm-id = {9802571},\n owner = {NLM},\n pii = {S1097-2765(08)00298-0},\n pmid = {18570874},\n pubmodel = {Print},\n pubstate = {ppublish},\n revised = {2008-06-23},\n}\n\n\n\n The translation initiation efficiency of a given mRNA is determined by its translation initiation region (TIR). mRNAs are selected into 30S initiation complexes according to the strengths of the secondary structure of the TIR, the pairing of the Shine-Dalgarno sequence with 16S rRNA, and the interaction between initiator tRNA and the start codon. Here, we show that the conversion of the 30S initiation complex into the translating 70S ribosome constitutes another important mRNA control checkpoint. Kinetic analysis reveals that 50S subunit joining and dissociation of IF3 are strongly influenced by the nature of the codon used for initiation and the structural elements of the TIR. Coupling between the TIR and the rate of 70S initiation complex formation involves IF3- and IF1-induced rearrangements of the 30S subunit, providing a mechanism by which the ribosome senses the TIR and determines the efficiency of translational initiation of a particular mRNA.\n
\n\n\n\n \n\n \n \n \n \n \n Structure of ratcheted ribosomes with tRNAs in hybrid states.\n \n \n \n\n\n \n Julián, P.; Konevega, A. L.; Scheres, S. H. W.; Lázaro, M.; Gil, D.; Wintermeyer, W.; Rodnina, M. V.; and Valle, M.\n\n\n \n\n\n\n Proceedings of the National Academy of Sciences of the United States of America, 105: 16924–16927. November 2008.\n \n\n\n\n
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\n\n\n@Article{Julian2008,\n author = {Julián, Patricia and Konevega, Andrey L. and Scheres, Sjors H. W. and Lázaro, Melisa and Gil, David and Wintermeyer, Wolfgang and Rodnina, Marina V. and Valle, Mikel},\n journal = {Proceedings of the National Academy of Sciences of the United States of America},\n title = {Structure of ratcheted ribosomes with tRNAs in hybrid states.},\n year = {2008},\n issn = {1091-6490},\n month = nov,\n pages = {16924--16927},\n volume = {105},\n abstract = {During protein synthesis, tRNAs and mRNA move through the ribosome between aminoacyl (A), peptidyl (P), and exit (E) sites of the ribosome in a process called translocation. Translocation is accompanied by the displacement of the tRNAs on the large ribosomal subunit toward the hybrid A/P and P/E states and by a rotational movement (ratchet) of the ribosomal subunits relative to one another. So far, the structure of the ratcheted state has been observed only when translation factors were bound to the ribosome. Using cryo-electron microscopy and classification, we show here that ribosomes can spontaneously adopt a ratcheted conformation with tRNAs in their hybrid states. The peptidyl-tRNA molecule in the A/P state, which is visualized here, is not distorted compared with the A/A state except for slight adjustments of its acceptor end, suggesting that the displacement of the A-site tRNA on the 50S subunit is passive and is induced by the 30S subunit rotation. Simultaneous subunit ratchet and formation of the tRNA hybrid states precede and may promote the subsequent rapid and coordinated tRNA translocation on the 30S subunit catalyzed by elongation factor G.},\n chemicals = {Peptide Elongation Factor G, RNA, Transfer, Amino Acyl, tRNA, peptidyl-, RNA, Transfer},\n citation-subset = {IM},\n completed = {2008-12-22},\n country = {United States},\n doi = {10.1073/pnas.0809587105},\n issn-linking = {0027-8424},\n issue = {44},\n keywords = {Cryoelectron Microscopy; Models, Molecular; Nucleic Acid Conformation; Peptide Elongation Factor G, chemistry, metabolism; RNA, Transfer, chemistry, metabolism; RNA, Transfer, Amino Acyl, chemistry, metabolism; Ribosomes, chemistry, metabolism},\n nlm-id = {7505876},\n owner = {NLM},\n pii = {0809587105},\n pmc = {PMC2579354},\n pmid = {18971332},\n pubmodel = {Print-Electronic},\n pubstate = {ppublish},\n revised = {2018-11-13},\n}\n\n\n\n During protein synthesis, tRNAs and mRNA move through the ribosome between aminoacyl (A), peptidyl (P), and exit (E) sites of the ribosome in a process called translocation. Translocation is accompanied by the displacement of the tRNAs on the large ribosomal subunit toward the hybrid A/P and P/E states and by a rotational movement (ratchet) of the ribosomal subunits relative to one another. So far, the structure of the ratcheted state has been observed only when translation factors were bound to the ribosome. Using cryo-electron microscopy and classification, we show here that ribosomes can spontaneously adopt a ratcheted conformation with tRNAs in their hybrid states. The peptidyl-tRNA molecule in the A/P state, which is visualized here, is not distorted compared with the A/A state except for slight adjustments of its acceptor end, suggesting that the displacement of the A-site tRNA on the 50S subunit is passive and is induced by the 30S subunit rotation. Simultaneous subunit ratchet and formation of the tRNA hybrid states precede and may promote the subsequent rapid and coordinated tRNA translocation on the 30S subunit catalyzed by elongation factor G.\n
\n\n\n\n \n\n \n \n \n \n \n Genetic Reconstruction of One Hereditary Nonpolyposis Colorectal Cancer History with Multiple Initiations of the Disease.\n \n \n \n\n\n \n Vostrukhina, O. A.; Shtam, T. A.; Gulyaev, A. V.; Pozharisski, K. M.; and Lanzov, V. A.\n\n\n \n\n\n\n The Open Environmental & Biological Monitoring Journal, 1(1): 43-47. 2008.\n \n\n\n\n
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\n\n\n\n@Article{Vostrukhina2008,\n author = {Olga A. Vostrukhina and Tatyana A. Shtam and Alexey V. Gulyaev and Kazimir M. Pozharisski and Vladislav A. Lanzov},\n journal = {The Open Environmental & Biological Monitoring Journal},\n title = {Genetic Reconstruction of One Hereditary Nonpolyposis Colorectal Cancer History with Multiple Initiations of the Disease},\n year = {2008},\n issn = {1875-0400},\n number = {1},\n pages = {43-47},\n volume = {1},\n doi = {10.2174/1875040000801010043},\n publisher = {Bentham Science Publishers Ltd.},\n}\n\n\n\n \n\n \n \n \n \n \n Role of human RAD51 recombinase in the cycle checkpoint and survival of a cell.\n \n \n \n\n\n \n Shtam, T. A.; Varfolomeeva, E. Y.; Semenova, E. V.; and Filatov, M. V.\n\n\n \n\n\n\n Cell and Tissue Biology, 2(5): 463-467. 2008.\n \n\n\n\n
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\n\n\n\n@Article{Shtam2008,\n author = {T. A. Shtam and E. Yu. Varfolomeeva and E. V. Semenova and M. V. Filatov},\n journal = {Cell and Tissue Biology},\n title = {Role of human RAD51 recombinase in the cycle checkpoint and survival of a cell},\n year = {2008},\n issn = {1990-519X},\n number = {5},\n pages = {463-467},\n volume = {2},\n doi = {10.1134/s1990519x08050027},\n keywords = {Cell Biology},\n publisher = {Pleiades Publishing Ltd},\n}\n\n\n\n
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\n \n \n\n \n \n \n \n \n Towards understanding selenocysteine incorporation into bacterial proteins.\n \n \n \n\n\n \n Fischer, N.; Paleskava, A.; Gromadski, K. B.; Konevega, A. L.; Wahl, M. C.; Stark, H.; and Rodnina, M. V.\n\n\n \n\n\n\n Biological chemistry, 388: 1061–1067. October 2007.\n \n\n\n\n
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\n\n\n@Article{Fischer2007,\n author = {Fischer, Niels and Paleskava, Alena and Gromadski, Kirill B. and Konevega, Andrey L. and Wahl, Markus C. and Stark, Holger and Rodnina, Marina V.},\n journal = {Biological chemistry},\n title = {Towards understanding selenocysteine incorporation into bacterial proteins.},\n year = {2007},\n issn = {1431-6730},\n month = oct,\n pages = {1061--1067},\n volume = {388},\n abstract = {In bacteria, UGA stop codons can be recoded to direct the incorporation of selenocysteine into proteins on the ribosome. Recoding requires a selenocysteine incorporation sequence (SECIS) downstream of the UGA codon, a specialized translation factor SelB, and the non-canonical Sec-tRNASec, which is formed from Ser-tRNASec by selenocysteine synthase, SelA, using selenophosphate as selenium donor. Here we describe a rapid-kinetics approach to study the mechanism of selenocysteine insertion into proteins on the ribosome. Labeling of SelB, Sec-tRNASec and other components of the translational machinery allows direct observation of the formation or dissociation of complexes by monitoring changes in the fluorescence of single dyes or fluorescence resonance energy transfer between two fluorophores. Furthermore, the structure of SelA was studied by electron cryomicroscopy (cryo-EM). We report that intact SelA from the thermophilic bacterium Moorella thermoacetica (mthSelA) can be vitrified for cryo-EM using a controlled-environment vitrification system. Two-dimensional image analysis of vitrified mthSelA images shows that SelA can adopt the wide range of orientations required for high-resolution structure determination by cryo-EM. The results indicate that mthSelA forms a homodecamer that has a ring-like structure with five bilobed wings, similar to the structure of the E. coli complex determined previously.},\n chemicals = {Bacterial Proteins, RNA, Transfer, Amino Acid-Specific, tRNA, selenocysteine-, Selenocysteine, Transferases, selenium transferase},\n citation-subset = {IM},\n completed = {2008-01-03},\n country = {Germany},\n doi = {10.1515/BC.2007.108},\n issn-linking = {1431-6730},\n issue = {10},\n keywords = {Bacterial Proteins, chemistry, isolation & purification, metabolism; Cryoelectron Microscopy; Kinetics; Models, Biological; RNA, Transfer, Amino Acid-Specific, chemistry, metabolism; Selenocysteine, chemistry, metabolism; Thermoanaerobacter, enzymology, metabolism; Transferases, chemistry, metabolism, ultrastructure},\n nlm-id = {9700112},\n owner = {NLM},\n pmid = {17937620},\n pubmodel = {Print},\n pubstate = {ppublish},\n revised = {2013-11-21},\n}\n\n\n\n In bacteria, UGA stop codons can be recoded to direct the incorporation of selenocysteine into proteins on the ribosome. Recoding requires a selenocysteine incorporation sequence (SECIS) downstream of the UGA codon, a specialized translation factor SelB, and the non-canonical Sec-tRNASec, which is formed from Ser-tRNASec by selenocysteine synthase, SelA, using selenophosphate as selenium donor. Here we describe a rapid-kinetics approach to study the mechanism of selenocysteine insertion into proteins on the ribosome. Labeling of SelB, Sec-tRNASec and other components of the translational machinery allows direct observation of the formation or dissociation of complexes by monitoring changes in the fluorescence of single dyes or fluorescence resonance energy transfer between two fluorophores. Furthermore, the structure of SelA was studied by electron cryomicroscopy (cryo-EM). We report that intact SelA from the thermophilic bacterium Moorella thermoacetica (mthSelA) can be vitrified for cryo-EM using a controlled-environment vitrification system. Two-dimensional image analysis of vitrified mthSelA images shows that SelA can adopt the wide range of orientations required for high-resolution structure determination by cryo-EM. The results indicate that mthSelA forms a homodecamer that has a ring-like structure with five bilobed wings, similar to the structure of the E. coli complex determined previously.\n
\n\n\n\n \n\n \n \n \n \n \n Spontaneous reverse movement of mRNA-bound tRNA through the ribosome.\n \n \n \n\n\n \n Konevega, A. L.; Fischer, N.; Semenkov, Y. P.; Stark, H.; Wintermeyer, W.; and Rodnina, M. V.\n\n\n \n\n\n\n Nature structural & molecular biology, 14: 318–324. April 2007.\n \n\n\n\n
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\n\n\n\n\n\n \n\n\n\n \n\n \n \n doi\n \n \n\n \n link\n \n \n\n bibtex\n \n\n \n \n \n abstract \n \n\n \n\n \n \n \n \n \n \n \n\n \n \n \n \n \n \n \n \n \n \n \n \n \n \n \n \n \n \n \n \n \n \n \n \n \n \n \n \n \n \n \n \n \n \n \n \n \n\n\n\n
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\n\n\n@Article{Konevega2007,\n author = {Konevega, Andrey L. and Fischer, Niels and Semenkov, Yuri P. and Stark, Holger and Wintermeyer, Wolfgang and Rodnina, Marina V.},\n journal = {Nature structural & molecular biology},\n title = {Spontaneous reverse movement of mRNA-bound tRNA through the ribosome.},\n year = {2007},\n issn = {1545-9993},\n month = apr,\n pages = {318--324},\n volume = {14},\n abstract = {During the translocation step of protein synthesis, a complex of two transfer RNAs bound to messenger RNA (tRNA-mRNA) moves through the ribosome. The reaction is promoted by an elongation factor, called EF-G in bacteria, which, powered by GTP hydrolysis, induces an open, unlocked conformation of the ribosome that allows for spontaneous tRNA-mRNA movement. Here we show that, in the absence of EF-G, there is spontaneous backward movement, or retrotranslocation, of two tRNAs bound to mRNA. Retrotranslocation is driven by the gain in affinity when a cognate E-site tRNA moves into the P site, which compensates the affinity loss accompanying the movement of peptidyl-tRNA from the P to the A site. These results lend support to the diffusion model of tRNA movement during translocation. In the cell, tRNA movement is biased in the forward direction by EF-G, which acts as a Brownian ratchet and prevents backward movement.},\n chemicals = {RNA, Bacterial, RNA, Messenger, RNA, Transfer, Amino Acyl, tRNA, peptidyl-, RNA, Transfer},\n citation-subset = {IM},\n completed = {2007-05-30},\n country = {United States},\n doi = {10.1038/nsmb1221},\n issn-linking = {1545-9985},\n issue = {4},\n keywords = {Cryoelectron Microscopy; Escherichia coli, metabolism; Models, Molecular; Movement; Protein Biosynthesis; RNA, Bacterial, metabolism, ultrastructure; RNA, Messenger, metabolism, ultrastructure; RNA, Transfer, metabolism, ultrastructure; RNA, Transfer, Amino Acyl, metabolism; Ribosomes, metabolism, ultrastructure},\n nlm-id = {101186374},\n owner = {NLM},\n pii = {nsmb1221},\n pmid = {17369838},\n pubmodel = {Print-Electronic},\n pubstate = {ppublish},\n revised = {2007-04-05},\n}\n\n\n\n During the translocation step of protein synthesis, a complex of two transfer RNAs bound to messenger RNA (tRNA-mRNA) moves through the ribosome. The reaction is promoted by an elongation factor, called EF-G in bacteria, which, powered by GTP hydrolysis, induces an open, unlocked conformation of the ribosome that allows for spontaneous tRNA-mRNA movement. Here we show that, in the absence of EF-G, there is spontaneous backward movement, or retrotranslocation, of two tRNAs bound to mRNA. Retrotranslocation is driven by the gain in affinity when a cognate E-site tRNA moves into the P site, which compensates the affinity loss accompanying the movement of peptidyl-tRNA from the P to the A site. These results lend support to the diffusion model of tRNA movement during translocation. In the cell, tRNA movement is biased in the forward direction by EF-G, which acts as a Brownian ratchet and prevents backward movement.\n
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\n\n \n \n 2006\n \n \n (2)\n \n \n
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\n \n \n\n \n \n \n \n \n [The effect of modification of tRNA nucleotide-37 on the tRNA interaction with the P- and A-site of the 70S ribosome Escherichia coli].\n \n \n \n\n\n \n Konevega, A. L.; Soboleva, N. G.; Makhno, V. I.; Peshekhonov, A. V.; and Katunin, V. I.\n\n\n \n\n\n\n Molekuliarnaia biologiia, 40: 669–683. 2006.\n \n\n\n\n
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\n\n\n@Article{Konevega2006,\n author = {Konevega, A. L. and Soboleva, N. G. and Makhno, V. I. and Peshekhonov, A. V. and Katunin, V. I.},\n journal = {Molekuliarnaia biologiia},\n title = {[The effect of modification of tRNA nucleotide-37 on the tRNA interaction with the P- and A-site of the 70S ribosome Escherichia coli].},\n year = {2006},\n issn = {0026-8984},\n pages = {669--683},\n volume = {40},\n abstract = {A modified nucleotide on the 3'-side of the anticodon loop of tRNA is one of the most important structure element regulating codon-anticodone interaction on the ribosome owing to the stacking interaction with the stack of codon-anticodon bases. The presence and identity (pyrimidine, purine or modified purine) of this nucleotide has an essential influence on the energy of the stacking interaction on A- and P-sites of the ribosome. There is a significant influence of the 37-modification by itself on the P-site, whereas there is no such one on the A-site of the ribosome. Comparison of binding enthalpies of tRNA interactions on the P- or A-site of the ribosome with the binding enthalpies of the complex of two tRNAs with the complementary anticodones suggests that the ribosome by itself significantly endows in the thermodynamics of codon-anticodon complex formation. It happens by additional ribosomal interactions with the molecule of tRNA or indirectly by the stabilization of codon-anticodon conformation. In addition to the stacking, tRNA binding in the A and P sites is futher stabilized by the interactions involving some magnesium ions. The number of them involved in those interactions strongly depends on the nucleotide identity in the 37-position of tRNA anticodon loop.},\n chemicals = {Cations, Divalent, Codon, Nucleotides, RNA, Bacterial, RNA, Transfer, Magnesium},\n citation-subset = {IM},\n completed = {2006-09-29},\n country = {Russia (Federation)},\n issn-linking = {0026-8984},\n issue = {4},\n keywords = {Acetylation; Binding Sites; Cations, Divalent, metabolism; Codon; Escherichia coli, genetics, metabolism; Magnesium, metabolism; Models, Molecular; Nucleotides, chemistry; RNA, Bacterial, chemistry, metabolism; RNA, Transfer, chemistry, metabolism; Ribosomes, metabolism; Thermodynamics},\n nlm-id = {0105454},\n owner = {NLM},\n pmid = {16913226},\n pubmodel = {Print},\n pubstate = {ppublish},\n references = {58},\n revised = {2020-12-09},\n season = {Jul-Aug},\n}\n\n\n\n A modified nucleotide on the 3'-side of the anticodon loop of tRNA is one of the most important structure element regulating codon-anticodone interaction on the ribosome owing to the stacking interaction with the stack of codon-anticodon bases. The presence and identity (pyrimidine, purine or modified purine) of this nucleotide has an essential influence on the energy of the stacking interaction on A- and P-sites of the ribosome. There is a significant influence of the 37-modification by itself on the P-site, whereas there is no such one on the A-site of the ribosome. Comparison of binding enthalpies of tRNA interactions on the P- or A-site of the ribosome with the binding enthalpies of the complex of two tRNAs with the complementary anticodones suggests that the ribosome by itself significantly endows in the thermodynamics of codon-anticodon complex formation. It happens by additional ribosomal interactions with the molecule of tRNA or indirectly by the stabilization of codon-anticodon conformation. In addition to the stacking, tRNA binding in the A and P sites is futher stabilized by the interactions involving some magnesium ions. The number of them involved in those interactions strongly depends on the nucleotide identity in the 37-position of tRNA anticodon loop.\n
\n\n\n\n \n\n \n \n \n \n \n Single-step purification of specific tRNAs by hydrophobic tagging.\n \n \n \n\n\n \n Kothe, U.; Paleskava, A.; Konevega, A. L.; and Rodnina, M. V.\n\n\n \n\n\n\n Analytical biochemistry, 356: 148–150. September 2006.\n \n\n\n\n
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\n\n\n\n@Article{Kothe2006,\n author = {Kothe, Ute and Paleskava, Alena and Konevega, Andrey L. and Rodnina, Marina V.},\n journal = {Analytical biochemistry},\n title = {Single-step purification of specific tRNAs by hydrophobic tagging.},\n year = {2006},\n issn = {0003-2697},\n month = sep,\n pages = {148--150},\n volume = {356},\n chemicals = {Amino Acids, Fluorenes, N(alpha)-fluorenylmethyloxycarbonylamino acids, RNA, Bacterial, RNA, Transfer, Ala, RNA, Transfer, Amino Acid-Specific, tRNA, selenocysteine-, RNA, Transfer},\n citation-subset = {IM},\n completed = {2006-10-16},\n country = {United States},\n doi = {10.1016/j.ab.2006.04.038},\n issn-linking = {0003-2697},\n issue = {1},\n keywords = {Amino Acids; Chromatography, High Pressure Liquid, methods; Escherichia coli, chemistry; Fluorenes; Hydrophobic and Hydrophilic Interactions; RNA, Bacterial, isolation & purification; RNA, Transfer, chemistry, isolation & purification; RNA, Transfer, Ala, isolation & purification; RNA, Transfer, Amino Acid-Specific, isolation & purification},\n nlm-id = {0370535},\n owner = {NLM},\n pii = {S0003-2697(06)00305-8},\n pmid = {16750812},\n pubmodel = {Print-Electronic},\n pubstate = {ppublish},\n revised = {2010-11-18},\n}\n\n\n\n
\n\n \n \n 2004\n \n \n (2)\n \n \n
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\n \n \n\n \n \n \n \n \n Mechanizm stabilizacii kodon-antikodonovogo vazimodejstvija v A sajte 70S ribosom Escherichia coli, induciruemyj purinovym osnovaniem v 37 položenii tRNK.\n \n \n \n\n\n \n Konevega, A. L.,\n editor.\n \n\n\n \n\n\n\n of PreprintGatčina, 2004.\n Engl. Zsfassung u.d.T.: Purine bases at position 37 of tRNA stabilize codon-anticodon interaction in the ribosomal A site by stacking and Mg 2+ -dependent interactions\n\n\n\n
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\n\n\n\n@Book{Konevega2004,\n editor = {A. L. Konevega},\n title = {Mechanizm stabilizacii kodon-antikodonovogo vazimodejstvija v A sajte 70S ribosom Escherichia coli, induciruemyj purinovym osnovaniem v 37 položenii tRNK},\n year = {2004},\n address = {Gatčina},\n note = {Engl. Zsfassung u.d.T.: Purine bases at position 37 of tRNA stabilize codon-anticodon interaction in the ribosomal A site by stacking and Mg 2+ -dependent interactions},\n number = {2555},\n series = {Preprint},\n pagetotal = {34},\n ppn_gvk = {74948313X},\n}\n\n\n\n \n\n \n \n \n \n \n Genetic Lesions during Progression of Hereditary Non-polypous Colorectal Cancer.\n \n \n \n\n\n \n Shtam, T. A.; Vostryukhina, O. A.; Gulyaev, A. V.; Pozharissky, K. M.; and Lantsov, V. A.\n\n\n \n\n\n\n Doklady Biochemistry and Biophysics, 395(1-6): 69-74. 2004.\n \n\n\n\n
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\n\n\n\n@Article{Shtam2004,\n author = {T. A. Shtam and O. A. Vostryukhina and A. V. Gulyaev and K. M. Pozharissky and V. A. Lantsov},\n journal = {Doklady Biochemistry and Biophysics},\n title = {Genetic Lesions during Progression of Hereditary Non-polypous Colorectal Cancer},\n year = {2004},\n issn = {1607-6729},\n number = {1-6},\n pages = {69-74},\n volume = {395},\n doi = {10.1023/b:dobi.0000025549.84403.b5},\n keywords = {General Chemistry, Biochemistry, General Medicine, Biophysics},\n publisher = {Springer Science and Business Media LLC},\n}\n\n\n\n
\n\n \n \n 2003\n \n \n (1)\n \n \n
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\n \n \n\n \n \n \n \n \n The Effect of Modification of Nucleotide-37 on the Interaction of Aminoacyl-tRNA with the A Site of the 70S Ribosome.\n \n \n \n\n\n \n Soboleva, N. G.; Makhno, V. I.; Konevega, A. L.; Semenkov, Y. P.; and Katunin, V. I.\n\n\n \n\n\n\n Molecular Biology, 37(1): 110-115. 2003.\n \n\n\n\n
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\n\n\n@Article{Soboleva2003,\n author = {N. G. Soboleva and V. I. Makhno and A. L. Konevega and Yu. P. Semenkov and V. I. Katunin},\n journal = {Molecular Biology},\n title = {The Effect of Modification of Nucleotide-37 on the Interaction of Aminoacyl-tRNA with the A Site of the 70S Ribosome},\n year = {2003},\n issn = {0026-8933},\n number = {1},\n pages = {110-115},\n volume = {37},\n abstract = {To estimate the effect of modified nucleotide 37, the interaction of two yeast aminoacyl-tRNAs (Phe-tRNAPhe +Y and Phe-tRNAPhe –Y) with the A site of complex [70S · poly(U) · deacylated tRNAPhe in the P site] was assayed at 0–20°C. As comparisons with native Phe-tRNAPhe +Y showed, removal of the Y base decreased the association constant of Phe-tRNAPhe –Y and the complex by an order of magnitude at every temperature tested, and increased the enthalpy of their interaction by 23 kJ/mol. When the Y base was present in the anticodon loop of deacylated tRNAPhe bound to the P site of the 70S ribosome, twice higher affinity for the A site was observed for Phe-tRNAPhe –Y but not for Phe-tRNAPhe +Y. Thus, the modified nucleotide 3" of the Phe-tRNAPhe anticodon stabilized the codon–anticodon interaction both in the A and P sites of the 70S ribosome.},\n doi = {10.1023/a:1022345115927},\n file = {:Soboleva2003 - The Effect of Modification of Nucleotide 37 on the Interaction of Aminoacyl TRNA with the a Site of the 70S Ribosome.html:URL},\n keywords = {Structural Biology, Biophysics},\n publisher = {Springer Science and Business Media LLC},\n}\n\n\n\n To estimate the effect of modified nucleotide 37, the interaction of two yeast aminoacyl-tRNAs (Phe-tRNAPhe +Y and Phe-tRNAPhe –Y) with the A site of complex [70S · poly(U) · deacylated tRNAPhe in the P site] was assayed at 0–20°C. As comparisons with native Phe-tRNAPhe +Y showed, removal of the Y base decreased the association constant of Phe-tRNAPhe –Y and the complex by an order of magnitude at every temperature tested, and increased the enthalpy of their interaction by 23 kJ/mol. When the Y base was present in the anticodon loop of deacylated tRNAPhe bound to the P site of the 70S ribosome, twice higher affinity for the A site was observed for Phe-tRNAPhe –Y but not for Phe-tRNAPhe +Y. Thus, the modified nucleotide 3\" of the Phe-tRNAPhe anticodon stabilized the codon–anticodon interaction both in the A and P sites of the 70S ribosome.\n
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\n\n\n\n\n \n \n 1999\n \n \n (1)\n \n \n
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\n \n \n\n \n \n \n \n \n Local water bridges and protein conformational stability.\n \n \n \n\n\n \n Petukhov, M.; Cregut, D.; Soares, C. M.; and Serrano, L.\n\n\n \n\n\n\n Protein science : a publication of the Protein Society, 8: 1982–1989. October 1999.\n \n\n\n\n
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\n\n\n@Article{Petukhov1999,\n author = {Petukhov, M. and Cregut, D. and Soares, C. M. and Serrano, L.},\n journal = {Protein science : a publication of the Protein Society},\n title = {Local water bridges and protein conformational stability.},\n year = {1999},\n issn = {0961-8368},\n month = oct,\n pages = {1982--1989},\n volume = {8},\n abstract = {Recent studies have pointed out the important role of local water structures in protein conformational stability. Here, we present an accurate and computationally effective way to estimate the free energy contribution of the simplest water structure motif--the water bridge. Based on the combination of empirical parameters for accessible protein surface area and the explicit consideration of all possible water bridges with the protein, we introduce an improved protein solvation model. We find that accounting for water bridge formation in our model is essential to understand the conformational behavior of polypeptides in water. The model formulation, in fact, does not depend on the polypeptide nature of the solute and is therefore applicable to other flexible biomolecules (i.e., DNAs, RNAs, polysaccharides, etc.).},\n chemicals = {Water},\n citation-subset = {IM},\n completed = {2000-02-11},\n country = {United States},\n doi = {10.1110/ps.8.10.1982},\n issn-linking = {0961-8368},\n issue = {10},\n keywords = {Hydrogen Bonding; Protein Conformation; Thermodynamics; Water, chemistry},\n nlm-id = {9211750},\n owner = {NLM},\n pmc = {PMC2144129},\n pmid = {10548043},\n pubmodel = {Print},\n pubstate = {ppublish},\n revised = {2018-11-13},\n}\n\n\n\n Recent studies have pointed out the important role of local water structures in protein conformational stability. Here, we present an accurate and computationally effective way to estimate the free energy contribution of the simplest water structure motif–the water bridge. Based on the combination of empirical parameters for accessible protein surface area and the explicit consideration of all possible water bridges with the protein, we introduce an improved protein solvation model. We find that accounting for water bridge formation in our model is essential to understand the conformational behavior of polypeptides in water. The model formulation, in fact, does not depend on the polypeptide nature of the solute and is therefore applicable to other flexible biomolecules (i.e., DNAs, RNAs, polysaccharides, etc.).\n
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