Publications by authors named "Vadim M Govorun"

91 Publications

Benchmarking germline CNV calling tools from exome sequencing data.

Sci Rep 2021 Jul 13;11(1):14416. Epub 2021 Jul 13.

Federal Research and Clinical Center of Physical-Chemical Medicine of Federal Medical Biological Agency, Moscow, Russia.

Whole-exome sequencing is an attractive alternative to microarray analysis because of the low cost and potential ability to detect copy number variations (CNV) of various sizes (from 1-2 exons to several Mb). Previous comparison of the most popular CNV calling tools showed a high portion of false-positive calls. Moreover, due to a lack of a gold standard CNV set, the results are limited and incomparable. Here, we aimed to perform a comprehensive analysis of tools capable of germline CNV calling available at the moment using a single CNV standard and reference sample set. Compiling variants from previous studies with Bayesian estimation approach, we constructed an internal standard for NA12878 sample (pilot National Institute of Standards and Technology Reference Material) including 110,050 CNV or non-CNV exons. The standard was used to evaluate the performance of 16 germline CNV calling tools on the NA12878 sample and 10 correlated exomes as a reference set with respect to length distribution, concordance, and efficiency. Each algorithm had a certain range of detected lengths and showed low concordance with other tools. Most tools are focused on detection of a limited number of CNVs one to seven exons long with a false-positive rate below 50%. EXCAVATOR2, exomeCopy, and FishingCNV focused on detection of a wide range of variations but showed low precision. Upon unified comparison, the tools were not equivalent. The analysis performed allows choosing algorithms or ensembles of algorithms most suitable for a specific goal, e.g. population studies or medical genetics.
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http://dx.doi.org/10.1038/s41598-021-93878-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8277855PMC
July 2021

β-N-Methylamino-L-Alanine (BMAA) Causes Severe Stress in sp. PCC 7120 Cells under Diazotrophic Conditions: A Proteomic Study.

Toxins (Basel) 2021 04 30;13(5). Epub 2021 Apr 30.

Scientific-Research Institute of Physical-Chemical Medicine, 119435 Moscow, Russia.

Non-proteinogenic neurotoxic amino acid β-N-methylamino-L-alanine (BMAA) is synthesized by cyanobacteria, diatoms, and dinoflagellates, and is known to be a causative agent of human neurodegenerative diseases. Different phytoplankton organisms' ability to synthesize BMAA could indicate the importance of this molecule in the interactions between microalgae in nature. We were interested in the following: what kinds of mechanisms underline BMAA's action on cyanobacterial cells in different nitrogen supply conditions. Herein, we present a proteomic analysis of filamentous cyanobacteria sp. PCC 7120 cells that underwent BMAA treatment in diazotrophic conditions. In diazotrophic growth conditions, to survive, cyanobacteria can use only biological nitrogen fixation to obtain nitrogen for life. Note that nitrogen fixation is an energy-consuming process. In total, 1567 different proteins of sp. PCC 7120 were identified by using LC-MS/MS spectrometry. Among them, 123 proteins belonging to different functional categories were selected-due to their notable expression differences-for further functional analysis and discussion. The presented proteomic data evidences that BMAA treatment leads to very strong (up to 80%) downregulation of α (NifD) and β (NifK) subunits of molybdenum-iron protein, which is known to be a part of nitrogenase. This enzyme is responsible for catalyzing nitrogen fixation. The genes and are under transcriptional control of a global nitrogen regulator NtcA. In this study, we have found that BMAA impacts in a total of 22 proteins that are under the control of NtcA. Moreover, BMAA downregulates 18 proteins that belong to photosystems I or II and light-harvesting complexes; BMAA treatment under diazotrophic conditions also downregulates five subunits of ATP synthase and enzyme NAD(P)H-quinone oxidoreductase. Therefore, we can conclude that the disbalance in energy and metabolite amounts leads to severe intracellular stress that induces the upregulation of stress-activated proteins, such as starvation-inducible DNA-binding protein, four SOS-response enzymes, and DNA repair enzymes, nine stress-response enzymes, and four proteases. The presented data provide new leads into the ecological impact of BMAA on microalgal communities that can be used in future investigations.
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http://dx.doi.org/10.3390/toxins13050325DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8147232PMC
April 2021

New Insights into Therapy-Induced Progression of Cancer.

Int J Mol Sci 2020 Oct 23;21(21). Epub 2020 Oct 23.

Center for Precision Genome Editing and Genetic Technologies for Biomedicine, Federal Research and Clinical Center of Physical-Chemical Medicine of Federal Medical Biological Agency, 119435 Moscow, Russia.

The malignant tumor is a complex heterogeneous set of cells functioning in a no less heterogeneous microenvironment. Like any dynamic system, cancerous tumors evolve and undergo changes in response to external influences, including therapy. Initially, most tumors are susceptible to treatment. However, remaining cancer cells may rapidly reestablish the tumor after a temporary remission. These new populations of malignant cells usually have increased resistance not only to the first-line agent, but also to the second- and third-line drugs, leading to a significant decrease in patient survival. Multiple studies describe the mechanism of acquired therapy resistance. In past decades, it became clear that, in addition to the simple selection of pre-existing resistant clones, therapy induces a highly complicated and tightly regulated molecular response that allows tumors to adapt to current and even subsequent therapeutic interventions. This review summarizes mechanisms of acquired resistance, such as secondary genetic alterations, impaired function of drug transporters, and autophagy. Moreover, we describe less obvious molecular aspects of therapy resistance in cancers, including epithelial-to-mesenchymal transition, cell cycle alterations, and the role of intercellular communication. Understanding these molecular mechanisms will be beneficial in finding novel therapeutic approaches for cancer therapy.
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http://dx.doi.org/10.3390/ijms21217872DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7660620PMC
October 2020

Identification of Clinically Significant Prostate Cancer by Combined and mRNA Detection in Urine Samples.

Res Rep Urol 2020 17;12:403-413. Epub 2020 Sep 17.

Department of Molecular Biology and Genetics, Federal Research and Clinical Center of Physical-Chemical Medicine of Federal Medical Biological Agency, Moscow, Russia.

Purpose: Preclinical evaluation of and transcript simultaneous detection in urine to diagnose clinical significant prostate cancer (prostate cancer with Gleason score ≥7) in a Russian cohort.

Patients And Methods: We analyzed urine samples of patients with a total serum PSA ≥2 ng/mL: 31 men with prostate cancer scheduled for radical prostatectomy, 128 men scheduled for first diagnostic biopsy (prebiopsy cohort). , , and transcripts were detected by multiplex reverse transcription quantitative polymerase chain reaction, and the results were used for scores for calculation and statistical analysis.

Results: There was no significant difference between clinically significant and nonsignificant prostate cancer PCA3 scores. However, there was a significant difference in the AMACR score (patients scheduled for radical prostatectomy =0.0088, prebiopsy cohort =0.029). We estimated AUCs, optimal cutoffs, sensitivities and specificities for PCa and csPCa detection in the prebiopsy cohort by tPSA, PCA3 score, PCPT Risk Calculator and classification models based on tPSA, PCA3 score and AMACR score. In the clinically significant prostate cancer ROC analysis, the PCA3 score AUC was 0.632 (95%CI: 0.511-0.752), the AMACR score AUC was 0.711 (95%CI: 0.617-0.806) and AUC of classification model based on the score, the AMACR score and total PSA was 0.72 (95%CI: 0.58-0.83). In addition, the correlation of the AMACR score with the ratio of total RNA and RNA of prostate cells in urine was shown (tau=0.347, =6.542e-09). Significant amounts of nonprostate RNA in urine may be a limitation for the AMACR score use.

Conclusion: The AMACR score is a good predictor of clinically significant prostate cancer. Significant amounts of nonprostate RNA in urine may be a limitation for the AMACR score use. Evaluation of the AMACR score and classification models based on it for clinically significant prostate cancer detection with larger samples and a follow-up analysis is promising.
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http://dx.doi.org/10.2147/RRU.S262310DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7505712PMC
September 2020

Proteomic Insights into Starvation of Nitrogen-Replete Cells of sp. PCC 7120 under β-N-Methylamino-L-Alanine (BMAA) Treatment.

Toxins (Basel) 2020 06 4;12(6). Epub 2020 Jun 4.

Federal Research and Clinical Centre of Physical-Chemical Medicine, 119435 Moscow, Russia.

All cyanobacteria produce a neurotoxic non-protein amino acid β-N-methylamino-L-alanine (BMAA). However, the biological function of BMAA in the regulation of cyanobacteria metabolism still remains undetermined. It is known that BMAA suppresses the formation of heterocysts in diazotrophic cyanobacteria under nitrogen starvation conditions, and BMAA induces the formation of heterocyst-like cells under nitrogen excess conditions, by causing the expression of heterocyst-specific genes that are usually "silent" under nitrogen-replete conditions, as if these bacteria receive a nitrogen deficiency intracellular molecular signal. In order to find out the molecular mechanisms underlying this unexpected BMAA effect, we studied the proteome of cyanobacterium sp. PCC 7120 grown under BMAA treatment in nitrogen-replete medium. Experiments were performed in two experimental settings: (1) in control samples consisted of cells grown without the BMAA treatment and (2) the treated samples consisted of cells grown with addition of an aqueous solution of BMAA (20 µM). In total, 1567 different proteins of sp. PCC 7120 were identified by LC-MS/MS spectrometry. Among them, 80 proteins belonging to different functional categories were chosen for further functional analysis and interpretation of obtained proteomic data. Here, we provide the evidence that a pleiotropic regulatory effect of BMAA on the proteome of cyanobacterium was largely different under conditions of nitrogen-excess compared to its effect under nitrogen starvation conditions (that was studied in our previous work). The most significant difference in proteome expression between the BMAA-treated and untreated samples under different growth conditions was detected in key regulatory protein PII (GlnB). BMAA downregulates protein PII in nitrogen-starved cells and upregulates this protein in nitrogen-replete conditions. PII protein is a key signal transduction protein and the change in its regulation leads to the change of many other regulatory proteins, including different transcriptional factors, enzymes and transporters. Complex changes in key metabolic and regulatory proteins (RbcL, RbcS, Rca, CmpA, GltS, NodM, thioredoxin 1, RpbD, ClpP, MinD, RecA, etc.), detected in this experimental study, could be a reason for the appearance of the "starvation" state in nitrogen-replete conditions in the presence of BMAA. In addition, 15 proteins identified in this study are encoded by genes, which are under the control of NtcA-a global transcriptional regulator-one of the main protein partners and transcriptional regulators of PII protein. Thereby, this proteomic study gives a possible explanation of cyanobacterium starvation under nitrogen-replete conditions and BMAA treatment. It allows to take a closer look at the regulation of cyanobacteria metabolism affected by this cyanotoxin.
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http://dx.doi.org/10.3390/toxins12060372DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7354497PMC
June 2020

The First Proteomics Study of sp. PCC 7120 Exposed to Cyanotoxin BMAA under Nitrogen Starvation.

Toxins (Basel) 2020 05 9;12(5). Epub 2020 May 9.

Federal Research and Clinical Centre of Physical-Chemical Medicine, 119435 Moscow, Russia.

The oldest prokaryotic photoautotrophic organisms, cyanobacteria, produce many different metabolites. Among them is the water-soluble neurotoxic non-protein amino acid beta-N-methylamino-L-alanine (BMAA), whose biological functions in cyanobacterial metabolism are of fundamental scientific and practical interest. An early BMAA inhibitory effect on nitrogen fixation and heterocyst differentiation was shown in strains of diazotrophic cyanobacteria sp. PCC 7120, PCC 73102 (ATCC 29133), and sp. strain 8963 under conditions of nitrogen starvation. Herein, we present a comprehensive proteomic study of (also called ) sp. PCC 7120 in the heterocyst formation stage affecting by BMAA treatment under nitrogen starvation conditions. BMAA disturbs proteins involved in nitrogen and carbon metabolic pathways, which are tightly co-regulated in cyanobacteria cells. The presented evidence shows that exogenous BMAA affects a key nitrogen regulatory protein, PII (GlnB), and some of its protein partners, as well as glutamyl-tRNA synthetase gltX and other proteins that are involved in protein synthesis, heterocyst differentiation, and nitrogen metabolism. By taking into account the important regulatory role of PII, it becomes clear that BMAA has a severe negative impact on the carbon and nitrogen metabolism of starving sp. PCC 7120 cells. BMAA disturbs carbon fixation and the carbon dioxide concentrating mechanism, photosynthesis, and amino acid metabolism. Stress response proteins and DNA repair enzymes are upregulated in the presence of BMAA, clearly indicating severe intracellular stress. This is the first proteomic study of the effects of BMAA on diazotrophic starving cyanobacteria cells, allowing a deeper insight into the regulation of the intracellular metabolism of cyanobacteria by this non-protein amino acid.
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http://dx.doi.org/10.3390/toxins12050310DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7290344PMC
May 2020

Draft genome sequences of Hirudo medicinalis and salivary transcriptome of three closely related medicinal leeches.

BMC Genomics 2020 Apr 29;21(1):331. Epub 2020 Apr 29.

Federal Research and Clinical Centre of Physical-Chemical Medicine of Federal Medical Biological Agency, 1a Malaya Pirogovskaya Str, Moscow, 119435, Russia.

Background: Salivary cell secretion (SCS) plays a critical role in blood feeding by medicinal leeches, making them of use for certain medical purposes even today.

Results: We annotated the Hirudo medicinalis genome and performed RNA-seq on salivary cells isolated from three closely related leech species, H. medicinalis, Hirudo orientalis, and Hirudo verbana. Differential expression analysis verified by proteomics identified salivary cell-specific gene expression, many of which encode previously unknown salivary components. However, the genes encoding known anticoagulants have been found to be expressed not only in salivary cells. The function-related analysis of the unique salivary cell genes enabled an update of the concept of interactions between salivary proteins and components of haemostasis.

Conclusions: Here we report a genome draft of Hirudo medicinalis and describe identification of novel salivary proteins and new homologs of genes encoding known anticoagulants in transcriptomes of three medicinal leech species. Our data provide new insights in genetics of blood-feeding lifestyle in leeches.
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http://dx.doi.org/10.1186/s12864-020-6748-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7191736PMC
April 2020

Phigaro: high-throughput prophage sequence annotation.

Bioinformatics 2020 06;36(12):3882-3884

Department of Molecular Biology and Genetics, Federal Research and Clinical Centre of Physical-Chemical Medicine, Moscow 119435, Russia.

Summary: Phigaro is a standalone command-line application that is able to detect prophage regions taking raw genome and metagenome assemblies as an input. It also produces dynamic annotated 'prophage genome maps' and marks possible transposon insertion spots inside prophages. It is applicable for mining prophage regions from large metagenomic datasets.

Availability And Implementation: Source code for Phigaro is freely available for download at https://github.com/bobeobibo/phigaro along with test data. The code is written in Python.

Supplementary Information: Supplementary data are available at Bioinformatics online.
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http://dx.doi.org/10.1093/bioinformatics/btaa250DOI Listing
June 2020

Comprehensive Functional Analysis of Ribosomal RNA Methyltransferases.

Front Genet 2020 27;11:97. Epub 2020 Feb 27.

Department of Chemistry, Lomonosov Moscow State University, Moscow, Russia.

Ribosomal RNAs in all organisms are methylated. The functional role of the majority of modified nucleotides is unknown. We systematically questioned the influence of rRNA methylation in on a number of characteristics of bacterial cells with the help of a set of rRNA methyltransferase (MT) gene knockout strains from the Keio collection. Analysis of ribosomal subunits sedimentation profiles of the knockout strains revealed a surprisingly small number of rRNA MT that significantly affected ribosome assembly. Accumulation of the assembly intermediates was observed only for the knockout strain whose growth was retarded most significantly among other rRNA MT knockout strains. Accumulation of the 17S rRNA precursor was observed for () knockout cells as well as for cells devoid of functional and genes. Significant differences were found among the WT and the majority of rRNA MT knockout strains in their ability to sustain exogenous protein overexpression. While the majority of the rRNA MT knockout strains supported suboptimal reporter gene expression, the strain devoid of the gene demonstrated a moderate increase in the yield of ectopic gene expression. Comparative 2D protein gel analysis of rRNA MT knockout strains revealed only minor perturbations of the proteome.
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http://dx.doi.org/10.3389/fgene.2020.00097DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7056703PMC
February 2020

Identification of Antimicrobial Peptides from Novel Lactobacillus fermentum Strain.

Protein J 2020 02;39(1):73-84

Laboratory of Molecular Genetics of Microorganisms, Institute of Fundamental Medicine and Biology, Kazan Federal University, 18 Kremlyovskaya Street, Kazan, Republic of Tatarstan, Russia, 420008.

Antimicrobial peptides (AMPs) are natural antagonistic tools of many bacteria and are considered as attractive antimicrobial agents for the treatment of bacteria with multidrug resistance. Lactic acid bacteria from the gastrointestinal tract of animals and human produce various AMPs inhibiting the growth of pathogens. Here we report the isolation and identification of novel Lactobacillus fermentum strain HF-D1 from the human gut producing AMPs which prevents the growth of P. aeruginosa and S. marcescens. The active fraction of peptides was obtained from the culture liquid by precipitation at 80% saturation of ammonium sulphate. For peptides identification, the precipitate was treated with guanidine hydrochloride to desorb from proteins, separated with ultrafiltration on spin columns with 10,000 MWCO, desalted with a reversed-phase chromatography and subjected to LC-MS/MS analysis. The in silico analysis of the identified 1111 peptides by using ADAM, CAMPR3 and AMPA prediction servers led to identification of the linear peptide with highly probable antimicrobial activity and further investigation of its antibacterial activity mechanism is promising. By using the dereplication algorithm, the peptide highly similar to non-ribosomal cyclic AMPs originally isolated from Staphylococcus epidermidis has been identified. This indicates that L. fermentum HF-D1 represents a novel strain producing antimicrobial peptides targeting P. aeruginosa and S. marcescens.
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http://dx.doi.org/10.1007/s10930-019-09879-8DOI Listing
February 2020

Long-term impact of fecal transplantation in healthy volunteers.

BMC Microbiol 2019 12 30;19(1):312. Epub 2019 Dec 30.

R.M.Gorbacheva Memorial Institute of Oncology, Hematology and Transplantation, Pavlov First Saint Petersburg State Medical University, St. Petersburg, Russian Federation.

Background: Fecal microbiota transplantation (FMT) has been recently approved by FDA for the treatment of refractory recurrent clostridial colitis (rCDI). Success of FTM in treatment of rCDI led to a number of studies investigating the effectiveness of its application in the other gastrointestinal diseases. However, in the majority of studies the effects of FMT were evaluated on the patients with initially altered microbiota. The aim of our study was to estimate effects of FMT on the gut microbiota composition in healthy volunteers and to monitor its long-term outcomes.

Results: We have performed a combined analysis of three healthy volunteers before and after capsule FMT by evaluating their general condition, adverse clinical effects, changes of basic laboratory parameters, and several immune markers. Intestinal microbiota samples were evaluated by 16S rRNA gene and shotgun sequencing. The data analysis demonstrated profound shift towards the donor microbiota taxonomic composition in all volunteers. Following FMT, all the volunteers exhibited gut colonization with donor gut bacteria and persistence of this effect for almost ∼1 year of observation. Transient changes of immune parameters were consistent with suppression of T-cell cytotoxicity. FMT was well tolerated with mild gastrointestinal adverse events, however, one volunteer developed a systemic inflammatory response syndrome.

Conclusions: The FMT leads to significant long-term changes of the gut microbiota in healthy volunteers with the shift towards donor microbiota composition and represents a relatively safe procedure to the recipients without long-term adverse events.
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http://dx.doi.org/10.1186/s12866-019-1689-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6938016PMC
December 2019

Challenges of the Human Proteome Project: 10-Year Experience of the Russian Consortium.

J Proteome Res 2019 12 28;18(12):4206-4214. Epub 2019 Oct 28.

Institute of Biomedical Chemistry , Moscow 119435 , Russia.

This manuscript collects all the efforts of the Russian Consortium, bottlenecks revealed in the course of the C-HPP realization, and ways of their overcoming. One of the main bottlenecks in the C-HPP is the insufficient sensitivity of proteomic technologies, hampering the detection of low- and ultralow-copy number proteins forming the "dark part" of the human proteome. In the frame of MP-Challenge, to increase proteome coverage we suggest an experimental workflow based on a combination of shotgun technology and selected reaction monitoring with two-dimensional alkaline fractionation. Further, to detect proteins that cannot be identified by such technologies, nanotechnologies such as combined atomic force microscopy with molecular fishing and/or nanowire detection may be useful. These technologies provide a powerful tool for single molecule analysis, by analogy with nanopore sequencing during genome analysis. To systematically analyze the functional features of some proteins (CP50 Challenge), we created a mathematical model that predicts the number of proteins differing in amino acid sequence: proteoforms. According to our data, we should expect about 100 000 different proteoforms in the liver tissue and a little more in the HepG2 cell line. The variety of proteins forming the whole human proteome significantly exceeds these results due to post-translational modifications (PTMs). As PTMs determine the functional specificity of the protein, we propose using a combination of gene-centric transcriptome-proteomic analysis with preliminary fractionation by two-dimensional electrophoresis to identify chemically modified proteoforms. Despite the complexity of the proposed solutions, such integrative approaches could be fruitful for MP50 and CP50 Challenges in the framework of the C-HPP.
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http://dx.doi.org/10.1021/acs.jproteome.9b00358DOI Listing
December 2019

Shifts in the Human Gut Microbiota Structure Caused by Quadruple Eradication Therapy.

Front Microbiol 2019 27;10:1902. Epub 2019 Aug 27.

Federal Research and Clinical Centre of Physical-Chemical Medicine of Federal Medical Biological Agency, Moscow, Russia.

The human gut microbiome plays an important role both in health and disease. Use of antibiotics can alter gut microbiota composition, which can lead to various deleterious events. Here we report a whole genome sequencing metagenomic/genomic study of the intestinal microbiota changes caused by (HP) eradication therapy. Using approaches for metagenomic data analysis we revealed a statistically significant decrease in alpha-diversity and relative abundance of due to HP eradication therapy, while the relative abundance of increased. We have detected changes in general metagenome resistome profiles as well: after HP eradication therapy, the group, and genes were overrepresented, while and genes were underrepresented. We have confirmed these results with genome-resolved metagenomic approaches. MAG (metagenome-assembled genomes) abundance profiles have changed dramatically after HP eradication therapy. Focusing on gene conferring resistance to macrolides, which were included in the HP eradication therapy scheme, we have shown a connection between antibiotic resistance genes (ARGs) and some overrepresented MAGs. Moreover, some strains isolated from stool samples obtained after HP eradication have manifested greater antibiotic resistance in comparison to other isolates, as well as the higher number of ARGs conferring resistance to macrolides and tetracyclines.
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http://dx.doi.org/10.3389/fmicb.2019.01902DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6718723PMC
August 2019

The A-allele of the FTO Gene rs9939609 Polymorphism Is Associated With Decreased Proportion of Slow Oxidative Muscle Fibers and Over-represented in Heavier Athletes.

J Strength Cond Res 2019 Mar;33(3):691-700

Laboratory of Applied Nutrition and Metabolism, Department of Biodynamics of the Human Body Movement, School of Physical Education and Sport, University of Sao Paulo, São Paulo, Brazil.

Guilherme, JPLF, Egorova, ES, Semenova, EA, Kostryukova, ES, Kulemin, NA, Borisov, OV, Khabibova, SA, Larin, AK, Ospanova, EA, Pavlenko, AV, Lyubaeva, EV, Popov, DV, Lysenko, EA, Vepkhvadze, TF, Lednev, EM, Govorun, VM, Generozov, EV, Ahmetov, II, and Lancha Junior, AH. The A-allele of the FTO gene rs9939609 polymorphism is associated with decreased proportion of slow oxidative muscle fibers and over-represented in heavier athletes. J Strength Cond Res 33(3): 691-700, 2019-The purpose of this study was to explore the frequency of the FTO T > A (rs9939609) polymorphism in elite athletes from 2 cohorts (Brazil and Russia), as well as to find a relationship between FTO genotypes and muscle fiber composition. A total of 677 athletes and 652 nonathletes were evaluated in the Brazilian cohort, whereas a total of 920 athletes and 754 nonathletes were evaluated in the Russian cohort. It was found a trend for a lower frequency of A/A genotype in long-distance athletes compared with nonathletes (odds ratio [OR]: 0.65; p = 0.054). By contrast, it was found an increased frequency of the A-allele in Russian power athletes. The presence of the T/A + A/A genotypes rather than T/T increased the OR of being a Russian power athlete compared with matched nonathletes (OR: 1.45; p = 0.002). Different from that observed in combat sports athletes of lighter weight categories, the A-allele was also over-represented in combat sports athletes of heavier weight categories. The presence of the T/A + A/A genotypes rather than T/T increased the OR of being a combat sports athlete of heavier weight categories compared with nonathletes (OR: 1.79; p = 0.018). Regarding the muscle fibers, we found that carriers of the A/A genotype had less slow-twitch muscle fibers than T-allele carriers (p = 0.029). In conclusion, the A/A genotype of the FTO T > A polymorphism is under-represented in athletes more reliant on a lean phenotype and associated with decreased proportion of slow-twitch muscle fibers, while is over-represented in strength and heavier athletes.
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http://dx.doi.org/10.1519/JSC.0000000000003032DOI Listing
March 2019

Genetic diversity of Escherichia coli in gut microbiota of patients with Crohn's disease discovered using metagenomic and genomic analyses.

BMC Genomics 2018 Dec 27;19(1):968. Epub 2018 Dec 27.

Federal Research and Clinical Centre of Physical-Chemical Medicine, Malaya Pirogovskaya 1a, Moscow, 119435, Russia.

Background: Crohn's disease is associated with gut dysbiosis. Independent studies have shown an increase in the abundance of certain bacterial species, particularly Escherichia coli with the adherent-invasive pathotype, in the gut. The role of these species in this disease needs to be elucidated.

Methods: We performed a metagenomic study investigating the gut microbiota of patients with Crohn's disease. A metagenomic reconstruction of the consensus genome content of the species was used to assess the genetic variability.

Results: The abnormal shifts in the microbial community structures in Crohn's disease were heterogeneous among the patients. The metagenomic data suggested the existence of multiple E. coli strains within individual patients. We discovered that the genetic diversity of the species was high and that only a few samples manifested similarity to the adherent-invasive varieties. The other species demonstrated genetic diversity comparable to that observed in the healthy subjects. Our results were supported by a comparison of the sequenced genomes of isolates from the same microbiota samples and a meta-analysis of published gut metagenomes.

Conclusions: The genomic diversity of Crohn's disease-associated E. coli within and among the patients paves the way towards an understanding of the microbial mechanisms underlying the onset and progression of the Crohn's disease and the development of new strategies for the prevention and treatment of this disease.
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http://dx.doi.org/10.1186/s12864-018-5306-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6307143PMC
December 2018

BAC-BROWSER: The Tool for Visualization and Analysis of Prokaryotic Genomes.

Front Microbiol 2018 21;9:2827. Epub 2018 Nov 21.

Federal Research and Clinical Centre of Physical-Chemical Medicine, Moscow, Russia.

Prokaryotes are actively studied objects in the scope of genomic regulation. Microbiologists need special tools for complex analysis of data to study and identification of regulatory mechanism in bacteria and archaea. We developed a tool BAC-BROWSER, specifically for visualization and analysis of small prokaryotic genomes. BAC-BROWSER provides tools for different types of analysis to study a wide set of regulatory mechanisms of prokaryotes: -transcriptional regulation by transcription factors (TFs), analysis of TFs, their targets, and binding sites.-other regulatory motifs, promoters, terminators and ribosome binding sites-transcriptional regulation by variation of operon structure, alternative starts or ends of transcription.-non-coding RNAs, antisense RNAs-RNA secondary structure, riboswitches-GC content, GC skew, codon usage BAC-browser incorporated free programs accelerating the verification of obtained results: primer design and oligocalculator, vector visualization, the tool for synthetic gene construction. The program is designed for Windows operating system and freely available for download in http://smdb.rcpcm.org/tools/index.html.
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http://dx.doi.org/10.3389/fmicb.2018.02827DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6258810PMC
November 2018

AGTR2 and sprint/power performance: a case-control replication study for rs11091046 polymorphism in two ethnicities.

Biol Sport 2018 Jun 23;35(2):105-109. Epub 2017 Nov 23.

Graduate School of Health and Sports Science, Juntendo University, Chiba, Japan.

We aimed to replicate, in a specific athletic event cohort (only track and field) and in two different ethnicities (Japanese and East European, i.e. Russian and Polish), original findings showing the association of the angiotensin-II receptor type-2 gene () rs11091046 A>C polymorphism with athlete status. We compared genotypic frequencies of the rs11091046 polymorphism among 282 track and field sprint/power athletes (200 men and 82 women), including several national record holders and Olympic medallists (214 Japanese, 68 Russian and Polish), and 2024 control subjects (842 men and 1182 women) (804 Japanese, 1220 Russian and Polish). In men, a meta-analysis from the two combined cohorts showed a significantly higher frequency of the C allele in athletes than in controls (odds ratio: 1.62, =0.008, heterogeneity index =0%). With regard to respective cohorts, C allele frequency was higher in Japanese male athletes than in controls (67.7% vs. 55.9%, =0.022), but not in Russian/Polish male athletes (61.9% vs. 51.0%, =0.172). In women, no significant results were obtained by meta-analysis for the two cohorts combination (=0.850). The AC genotype frequency was significantly higher in Russian/Polish women athletes than in controls (69.2% vs. 42.1%, =0.022), but not in Japanese women athletes (=0.226). Our results, in contrast to previous findings, suggested by meta-analysis that the C allele of the rs11091046 polymorphism is associated with sprint/power track and field athlete status in men, but not in women.
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http://dx.doi.org/10.5114/biolsport.2018.71599DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6234304PMC
June 2018

The Cyanotoxin BMAA Induces Heterocyst Specific Gene Expression in sp. PCC 7120 under Repressive Conditions.

Toxins (Basel) 2018 Nov 16;10(11). Epub 2018 Nov 16.

Institute of Molecular Genetics, Russian Academy of Sciences, Kurchatov Square, 2, 123182 Moscow, Russia.

Cyanobacteria synthesize neurotoxic β--methylamino-l-alanine (BMAA). The roles of this non-protein amino acid in cyanobacterial cells are insufficiently studied. During diazotrophic growth, filamentous cyanobacteria form single differentiated cells, called heterocysts, which are separated by approximately 12⁻15 vegetative cells. When combined nitrogen is available, heterocyst formation is blocked and cyanobacterial filaments contain only vegetative cells. In the present study, we discovered that exogenous BMAA induces the process of heterocyst formation in filamentous cyanobacteria under nitrogen-replete conditions that normally repress cell differentiation. BMAA treated cyanobacteria form heterocyst-like dark non-fluorescent non-functional cells. It was found that glutamate eliminates the BMAA mediated derepression. Quantitative polymerase chain reaction (qPCR) permitted to detect the BMAA impact on the transcriptional activity of several genes that are implicated in nitrogen assimilation and heterocyst formation in sp. PCC 7120. We demonstrated that the expression of several essential genes increases in the BMAA presence under repressive conditions.
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http://dx.doi.org/10.3390/toxins10110478DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6266585PMC
November 2018

ACI-1 beta-lactamase is widespread across human gut microbiomes in Negativicutes due to transposons harboured by tailed prophages.

Environ Microbiol 2018 06 7;20(6):2288-2300. Epub 2018 Aug 7.

Department of Genetic Medicine and Development, University of Geneva Medical School and Swiss Institute of Bioinformatics, Geneva, Switzerland.

Antibiotic resistance is increasing among pathogens, and the human microbiome contains a reservoir of antibiotic resistance genes. Acidaminococcus intestini is the first Negativicute bacterium (Gram-negative Firmicute) shown to be resistant to beta-lactam antibiotics. Resistance is conferred by the aci1 gene, but its evolutionary history and prevalence remain obscure. We discovered that ACI-1 proteins are phylogenetically distinct from beta-lactamases of Gram-positive Firmicutes and that aci1 occurs in bacteria scattered across the Negativicute clade, suggesting lateral gene transfer. In the reference A. intestini RyC-MR95 genome, we found transposons residing within a tailed prophage context are likely vehicles for aci1's mobility. We found aci1 in 56 (4.4%) of 1,267 human gut metagenomes, mostly hosted within A. intestini, and, where could be determined, mostly within a consistent mobile element constellation. These samples are from Europe, China and the USA, showing that aci1 is distributed globally. We found that for most Negativicute assemblies with aci1, the prophage observed in A. instestini is absent, but in all cases aci1 is flanked by varying transposons. The chimeric mobile elements we identify here likely have a complex evolutionary history and potentially provide multiple complementary mechanisms for antibiotic resistance gene transfer both within and between cells.
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http://dx.doi.org/10.1111/1462-2920.14276DOI Listing
June 2018

Therapy-induced stress response is associated with downregulation of pre-mRNA splicing in cancer cells.

Genome Med 2018 06 27;10(1):49. Epub 2018 Jun 27.

Laboratory of Proteomics, Shemyakin-Ovchinnikov Institute of Bioorganic Chemistry of the Russian Academy of Sciences, Moscow, 117997, Russia.

Background: Abnormal pre-mRNA splicing regulation is common in cancer, but the effects of chemotherapy on this process remain unclear.

Methods: To evaluate the effect of chemotherapy on slicing regulation, we performed meta-analyses of previously published transcriptomic, proteomic, phosphoproteomic, and secretome datasets. Our findings were verified by LC-MS/MS, western blotting, immunofluorescence, and FACS analyses of multiple cancer cell lines treated with cisplatin and pladienolide B.

Results: Our results revealed that different types of chemotherapy lead to similar changes in alternative splicing by inducing intron retention in multiple genes. To determine the mechanism underlying this effect, we analyzed gene expression in 101 cell lines affected by ɣ-irradiation, hypoxia, and 10 various chemotherapeutic drugs. Strikingly, оnly genes involved in the cell cycle and pre-mRNA splicing regulation were changed in a similar manner in all 335 tested samples regardless of stress stimuli. We revealed significant downregulation of gene expression levels in these two pathways, which could be explained by the observed decrease in splicing efficiency and global intron retention. We showed that the levels of active spliceosomal proteins might be further post-translationally decreased by phosphorylation and export into the extracellular space. To further explore these bioinformatics findings, we performed proteomic analysis of cisplatin-treated ovarian cancer cells. Finally, we demonstrated that the splicing inhibitor pladienolide B impairs the cellular response to DNA damage and significantly increases the sensitivity of cancer cells to chemotherapy.

Conclusions: Decreased splicing efficiency and global intron retention is a novel stress response mechanism that may promote survival of malignant cells following therapy. We found that this mechanism can be inhibited by pladienolide B, which significantly increases the sensitivity of cancer cells to cisplatin which makes it a good candidate drug for improving the efficiency of cancer therapy.
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http://dx.doi.org/10.1186/s13073-018-0557-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6020472PMC
June 2018

Stress effects of cyanotoxin β-methylamino-L-alanine (BMAA) on cyanobacterial heterocyst formation and functionality.

Environ Microbiol Rep 2018 06 6;10(3):369-377. Epub 2018 May 6.

Institute of Molecular Genetics, Russian Academy of Sciences, Kurchatov Square, 2, 123182 Moscow, Russia.

Various species of cyanobacteria, diatoms and dinoflagellates are capable of synthesizing the non-proteinogenic neurotoxic amino acid β-N-methylamino-L-alanine (BMAA), which is known to be a causative agent of human neurodegeneration. Similar to most cyanotoxins, the biological and ecological functions of BMAA in cyanobacteria are unknown. In this study, we show for the first time that BMAA, in micromolar amounts, inhibits the formation of heterocysts (specialized nitrogen-fixing cells) in heterocystous, diazotrophic cyanobacteria [Anabaena sp. PCC 7120, Nostoc punctiforme PCC 73102 (ATCC 29133), Nostoc sp. strain 8963] under conditions of nitrogen starvation. The inhibitory effect of BMAA is abolished by the addition of glutamate. To understand the genetic reason for the observed phenomenon, we used qPCR to study the expression of key genes involved in cell differentiation and nitrogen metabolism in the model cyanobacterium Anabaena sp. PCC 7120. We observed that in the presence of BMAA, Anabaena sp. PCC 7120 does not express two essential genes associated with heterocyst differentiation, namely, hetR and hepA. We also found that addition of BMAA to cyanobacterial cultures with mature heterocysts inhibits nifH gene expression and nitrogenase activity.
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http://dx.doi.org/10.1111/1758-2229.12647DOI Listing
June 2018

Identification of unusual peptides with new Cys frameworks in the venom of the cold-water sea anemone Cnidopus japonicus.

Sci Rep 2017 11 6;7(1):14534. Epub 2017 Nov 6.

Federal Research and Clinical Centre of Physical-Chemical Medicine, Moscow, 119435, Russia.

Sea anemones (Actiniaria) are intensely popular objects of study in venomics. Order Actiniaria includes more than 1,000 species, thus presenting almost unlimited opportunities for the discovery of novel biologically active molecules. The venoms of cold-water sea anemones are studied far less than the venoms of tropical sea anemones. In this work, we analysed the molecular venom composition of the cold-water sea anemone Cnidopus japonicus. Two sets of NGS data from two species revealed molecules belonging to a variety of structural classes, including neurotoxins, toxin-like molecules, linear polypeptides (Cys-free), enzymes, and cytolytics. High-throughput proteomic analyses identified 27 compounds that were present in the venoms. Some of the toxin-like polypeptides exhibited novel Cys frameworks. To characterise their function in the venom, we heterologously expressed 3 polypeptides with unusual Cys frameworks (designated CjTL7, CjTL8, and AnmTx Cj 1c-1) in E. coli. Toxicity tests revealed that the CjTL8 polypeptide displays strong crustacean-specific toxicity, while AnmTx Cj 1c-1 is toxic to both crustaceans and insects. Thus, an improved NGS data analysis algorithm assisted in the identification of toxins with unusual Cys frameworks showing no homology according to BLAST. Our study shows the advantage of combining omics analysis with functional tests for active polypeptide discovery.
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http://dx.doi.org/10.1038/s41598-017-14961-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5673964PMC
November 2017

Links of gut microbiota composition with alcohol dependence syndrome and alcoholic liver disease.

Microbiome 2017 10 17;5(1):141. Epub 2017 Oct 17.

Moscow Institute of Physics and Technology, Institutskiy per. 9, Dolgoprudny, Moscow Region, 141700, Russia.

Background: Alcohol abuse has deleterious effects on human health by disrupting the functions of many organs and systems. Gut microbiota has been implicated in the pathogenesis of alcohol-related liver diseases, with its composition manifesting expressed dysbiosis in patients suffering from alcoholic dependence. Due to its inherent plasticity, gut microbiota is an important target for prevention and treatment of these diseases. Identification of the impact of alcohol abuse with associated psychiatric symptoms on the gut community structure is confounded by the liver dysfunction. In order to differentiate the effects of these two factors, we conducted a comparative "shotgun" metagenomic survey of 99 patients with the alcohol dependence syndrome represented by two cohorts-with and without liver cirrhosis. The taxonomic and functional composition of the gut microbiota was subjected to a multifactor analysis including comparison with the external control group.

Results: Alcoholic dependence and liver cirrhosis were associated with profound shifts in gut community structures and metabolic potential across the patients. The specific effects on species-level community composition were remarkably different between cohorts with and without liver cirrhosis. In both cases, the commensal microbiota was found to be depleted. Alcoholic dependence was inversely associated with the levels of butyrate-producing species from the Clostridiales order, while the cirrhosis-with multiple members of the Bacteroidales order. The opportunist pathogens linked to alcoholic dependence included pro-inflammatory Enterobacteriaceae, while the hallmarks of cirrhosis included an increase of oral microbes in the gut and more frequent occurrence of abnormal community structures. Interestingly, each of the two factors was associated with the expressed enrichment in many Bifidobacterium and Lactobacillus-but the exact set of the species was different between alcoholic dependence and liver cirrhosis. At the level of functional potential, the patients showed different patterns of increase in functions related to alcohol metabolism and virulence factors, as well as pathways related to inflammation.

Conclusions: Multiple shifts in the community structure and metabolic potential suggest strong negative influence of alcohol dependence and associated liver dysfunction on gut microbiota. The identified differences in patterns of impact between these two factors are important for planning of personalized treatment and prevention of these pathologies via microbiota modulation. Particularly, the expansion of Bifidobacterium and Lactobacillus suggests that probiotic interventions for patients with alcohol-related disorders using representatives of the same taxa should be considered with caution. Taxonomic and functional analysis shows an increased propensity of the gut microbiota to synthesis of the toxic acetaldehyde, suggesting higher risk of colorectal cancer and other pathologies in alcoholics.
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http://dx.doi.org/10.1186/s40168-017-0359-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5645934PMC
October 2017

Genome analysis of E. coli isolated from Crohn's disease patients.

BMC Genomics 2017 07 19;18(1):544. Epub 2017 Jul 19.

Federal Research and Clinical Center of Physical-Chemical Medicine of Federal Medical Biological Agency, Moscow, Russia.

Background: Escherichia coli (E. coli) has been increasingly implicated in the pathogenesis of Crohn's disease (CD). The phylogeny of E. coli isolated from Crohn's disease patients (CDEC) was controversial, and while genotyping results suggested heterogeneity, the sequenced strains of E. coli from CD patients were closely related.

Results: We performed the shotgun genome sequencing of 28 E. coli isolates from ten CD patients and compared genomes from these isolates with already published genomes of CD strains and other pathogenic and non-pathogenic strains. CDEC was shown to belong to A, B1, B2 and D phylogenetic groups. The plasmid and several operons from the reference CD-associated E. coli strain LF82 were demonstrated to be more often present in CDEC genomes belonging to different phylogenetic groups than in genomes of commensal strains. The operons include carbon-source induced invasion GimA island, prophage I, iron uptake operons I and II, capsular assembly pathogenetic island IV and propanediol and galactitol utilization operons.

Conclusions: Our findings suggest that CDEC are phylogenetically diverse. However, some strains isolated from independent sources possess highly similar chromosome or plasmids. Though no CD-specific genes or functional domains were present in all CD-associated strains, some genes and operons are more often found in the genomes of CDEC than in commensal E. coli. They are principally linked to gut colonization and utilization of propanediol and other sugar alcohols.
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http://dx.doi.org/10.1186/s12864-017-3917-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5517970PMC
July 2017

Outer membrane vesicles secreted by pathogenic and nonpathogenic Bacteroides fragilis represent different metabolic activities.

Sci Rep 2017 07 10;7(1):5008. Epub 2017 Jul 10.

Federal Research and Clinical Centre of Physical-Chemical Medicine Federal Medical Biological Agency, Malaya Pirogovskaya str., 1a, Moscow, 119435, Russian Federation.

Numerous studies are devoted to the intestinal microbiota and intercellular communication maintaining homeostasis. In this regard, vesicles secreted by bacteria represent one of the most popular topics for research. For example, the outer membrane vesicles (OMVs) of Bacteroides fragilis play an important nutritional role with respect to other microorganisms and promote anti-inflammatory effects on immune cells. However, toxigenic B. fragilis (ETBF) contributes to bowel disease, even causing colon cancer. If nontoxigenic B. fragilis (NTBF) vesicles exert a beneficial effect on the intestine, it is likely that ETBF vesicles can be utilized for potential pathogenic implementation. To confirm this possibility, we performed comparative proteomic HPLC-MS/MS analysis of vesicles isolated from ETBF and NTBF. Furthermore, we performed, for the first time, HPLC-MS/MS and GS-MS comparative metabolomic analysis for the vesicles isolated from both strains with subsequent reconstruction of the vesicle metabolic pathways. We utilized fluxomic experiments to validate the reconstructed biochemical reaction activities and finally observed considerable difference in the vesicle proteome and metabolome profiles. Compared with NTBF OMVs, metabolic activity of ETBF OMVs provides their similarity to micro reactors that are likely to be used for long-term persistence and implementing pathogenic potential in the host.
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http://dx.doi.org/10.1038/s41598-017-05264-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5503946PMC
July 2017

Interaction of Toxin with Outer Membrane Vesicles Reveals New Mechanism of Its Secretion and Delivery.

Front Cell Infect Microbiol 2017 17;7. Epub 2017 Jan 17.

Federal Research and Clinical Centre of Physical-Chemical Medicine Federal Medical Biological AgencyMoscow, Russia; Lab of Systems Biology, Moscow Institute of Physics and TechnologyDolgoprudny, Russia; Department of Proteomics, Shemyakin-Ovchinnikov Institute of Bioorganic Chemistry of the Russian Academy of SciencesMoscow, Russia.

The only recognized virulence factor of enterotoxigenic (ETBF) that accompanies bloodstream infections is the zinc-dependent non-lethal metalloprotease toxin (BFT). The isolated toxin stimulates intestinal secretion, resulting in epithelial damage and necrosis. Numerous publications have focused on the interrelation of BFT with intestinal inflammation and colorectal neoplasia, but nothing is known about the mechanism of its secretion and delivery to host cells. However, recent studies of gram-negative bacteria have shown that outer membrane vesicles (OMVs) could be an essential mechanism for the spread of a large number of virulence factors. Here, we show for the first time that BFT is not a freely secreted protease but is associated with OMVs. Our findings indicate that only outer surface-exposed BFT causes epithelial cell contact disruption. According to our models confirmed by Trp quenching assay and NMR, BFT has special interactions with outer membrane components such as phospholipids and is secreted during vesicle formation. Moreover, the strong cooperation of BFT with polysaccharides is similar to the behavior of lectins. Understanding the molecular mechanisms of BFT secretion provides new perspectives for investigating intestinal inflammation pathogenesis and its prevention.
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http://dx.doi.org/10.3389/fcimb.2017.00002DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5240029PMC
September 2017

Binding site of restriction-modification system controller protein in Mollicutes.

BMC Microbiol 2017 Jan 31;17(1):26. Epub 2017 Jan 31.

Federal Research and Clinical Centre of Physical-Chemical Medicine, Malaya Pirogovskaya 1a, Moscow, 119992, Russia.

Background: Bacteria of the class Mollicutes underwent extreme reduction of genomes and gene expression control systems. Only a few regulators are known to date. In this work, we describe a novel group of transcriptional regulators that are distributed within different Mollicutes and control the expression of restriction-modification systems (RM-systems).

Results: We performed cross-species search of putative regulators of RM-systems (C-proteins) and respective binding sites in Mollicutes. We identified a set of novel putative C-protein binding motifs distributed within Mollicutes. We studied the most frequent motif and respective C-protein on the model of Mycoplasma gallisepticum S6. We confirmed our prediction and identified key nucleotides important for C-protein binding. Further we identified novel target promoters of C-protein in M. gallisepticum.

Conclusions: We found that C-protein of M. gallisepticum binds predicted conserved direct repeats of the (GTGTTAN) motif. Apart from its own operon promoter, HsdC can bind to the promoters of the clpB chaperone gene and a tRNA cluster.
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http://dx.doi.org/10.1186/s12866-017-0935-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5282649PMC
January 2017

Data on gut metagenomes of the patients with alcoholic dependence syndrome and alcoholic liver cirrhosis.

Data Brief 2017 Apr 17;11:98-102. Epub 2017 Jan 17.

Moscow Institute of Physics and Technology, Institutskiy per. 9, Dolgoprudny, Moscow Region 141700, Russia.

Alcoholism is associated with significant changes in gut microbiota composition. Metagenomic sequencing allows to assess the altered abundance levels of bacterial taxa and genes in a culture-independent way. We collected 99 stool samples from the patients with alcoholic dependence syndrome (=72) and alcoholic liver cirrhosis (=27). Each of the samples was surveyed using "shotgun" (whole-genome) sequencing on SOLiD platform. The reads are deposited in the ENA (project ID: PRJEB18041).
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http://dx.doi.org/10.1016/j.dib.2017.01.008DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5257029PMC
April 2017