[Metabolome profiling in the study of aging processes]. / Metabolomnoe profilirovanie v izuchenii protsessov stareniia.

Aging of a living organism is closely related to systemic metabolic changes. But due to the multilevel and network nature of metabolic pathways, it is difficult to understand these connections. Today, this problem is solved using one of the main approaches of metabolomics - untargeted metabolome profiling. The purpose of this publication is to systematize the results of metabolomic studies based on such profiling, both in animal models and in humans.

[Ten years of the Russian metabolomics: history of development and achievements]. / Desiat' let rossiiskoi metabolomike: istoriia razvitiia i osnovnye rezul'taty.

Metabolomics is one of the omics sciences, the technologies of which are widely used today in many life sciences. Its application influenced the discovery of new biomarkers of diseases, the description of biochemical processes occurring in many organisms, laid the basis for a new generation of clinical laboratory diagnostics. The purpose of this review is to show how metabolomics is represented in the studies of Russian scientists, to demonstrate the main directions and achievements of the Russian science in this field. The review also highlights the history of metabolomics, existing problems and the place of Russian metabolomics in their solution.

[Blood metabolome analysis for creating a digital image of a healthy person]. / Metabolomnyi analiz krovi dlia sozdaniia tsifrovogo obraza zdorovogo cheloveka.

In the frame of the work, data on the implementation of metabolomics tests in medicine have been systematized. Based on the obtained data, a set of protocols was proposed, the sequential realization of which makes it possible to conduct a blood metabolome analysis for medical purposes. Using this analysis and the number of blood samples from healthy volunteers, a prototype of a healthy person's metabolomic image has been developed; it allows visually and digitally to assess the compliance of the human blood metabolome with the norm. At the same time, 99% of the metabolic processes reflected in the blood plasma are estimated. If abnormalities are detected, the metabolomic image allows to get the value of these deviations of metabolic processes in digital terms.

Evaluation of various RNA-seq approaches for identification of gene outrons in the flatworm Opisthorchis felineus.

The parasitic flatworm Opisthorchis felineus is one of the causative agents of opisthorchiasis in humans. Recently, we assembled the O. felineus genome, but the correct genome annotation by means of standard methods was hampered by the presence of spliced leader trans-splicing (SLTS). As a result of SLTS, the original 5'-end (outron) of the transcripts is replaced by a short spliced leader sequence donated from a specialized SL RNA. SLTS is involved in the RNA processing of more than half of O. felineus genes, making it hard to determine the structure of outrons and bona fide transcription start sites of the corresponding genes and operons, being based solely on mRNA-seq data. In the current study, we tested various experimental approaches for identifying the sequences of outrons in O. felineus using massive parallel sequencing. Two of them were developed by us for targeted sequencing of already processed branched outrons. One was based on sequence-specific reverse transcription from the SL intron toward the 5'-end of the Y-branched outron. The other used outron hybridization with an immobilized single-stranded DNA probe complementary to the SL intron. Additionally, two approaches to the sequencing of rRNA-depleted total RNA were used, allowing the identification of a wider range of transcripts compared to mRNAseq. One is based on the enzymatic elimination of overrepresented cDNAs, the other utilizes exonucleolytic degradation of uncapped RNA by Terminator enzyme. By using the outron-targeting methods, we were not able to obtain the enrichment of RNA preparations by processed outrons, which is most likely indicative of a rapid turnover of these trans-splicing intermediate products. Of the two rRNA depletion methods, a method based on the enzymatic normalization of cDNA (Zymo-Seq RiboFree) showed high efficiency. Compared to mRNA-seq, it provides an approximately twofold increase in the fraction of reads originating from outrons and introns. The results suggest that unprocessed nascent transcripts are the main source of outron sequences in the RNA pool of O. felineus.

Migration of primordial germline cells is negatively regulated by surrounding somatic cells during early embryogenesis in Drosophila melanogaster.

Cell migration is an important morphogenetic process necessary at different stages of individual development and body functioning. The initiation and maintenance of the cell movement state requires the activation of many factors involved in the regulation of transcription, signal transduction, adhesive interactions, modulation of membranes and the cytoskeleton. However, cell movement depends on the status of both migrating and surrounding cells, interacting with each other during movement. The surrounding cells or cell matrix not only form a substrate for movement, but can also participate in the spatio-temporal regulation of the migration. At present, there is no exact understanding of the genetic mechanisms of this regulation. To determine the role of the cell environment in the regulation of individual cell migration, we studied the migration of primordial germline cells (PGC) during early embryogenesis in Drosophila melanogaster. Normally, PGC are formed at the 3rd stage of embryogenesis at the posterior pole of the embryo. During gastrulation (stages 6-7), PGC as a consolidated cell group passively transfers into the midgut primordium. Further, PGC are individualized, acquire an amoeboid form, and actively move through the midgut epithelium and migrate to the 5-6 abdominal segment of the embryo, where they form paired embryonic gonads. We screened for genes expressed in the epithelium surrounding PGC during early embryogenesis and affecting their migration. We identified the myc, Hph, stat92E, Tre-1, and hop genes, whose RNA interference leads to premature active PGC migration at stages 4-7 of embryogenesis. These genes can be divided into two groups: 1) modulators of JAK/STAT pathway activity inducing PGC migration (stat92E, Tre-1, hop), and 2) myc and Hph involved in epithelial morphogenesis and polarization, i. e. modifying the permeability of the epithelial barrier. Since a depletion of each of these gene products resulted in premature PGC migration, we can conclude that, normally, the somatic environment negatively regulates PGC migration during early Drosophila embryogenesis.

Parallel entangling operations on a universal ion-trap quantum computer.

The circuit model of a quantum computer consists of sequences of gate operations between quantum bits (qubits), drawn from a universal family of discrete operations1. The ability to execute parallel entangling quantum gates offers efficiency gains in numerous quantum circuits2-4, as well as for entire algorithms-such as Shor's factoring algorithm5-and quantum simulations6,7. In circuits such as full adders and multiple-control Toffoli gates, parallelism can provide an exponential improvement in overall execution time through the divide-and-conquer technique8. More importantly, quantum gate parallelism is essential for fault-tolerant error correction of qubits that suffer from idle errors9,10. However, the implementation of parallel quantum gates is complicated by potential crosstalk, especially between qubits that are fully connected by a common-mode bus, such as in Coulomb-coupled trapped atomic ions11,12 or cavity-coupled superconducting transmons13. Here we present experimental results for parallel two-qubit entangling gates in an array of fully connected trapped 171Yb+ ion qubits. We perform a one-bit full-addition operation on a quantum computer using a depth-four quantum circuit4,14,15, where circuit depth denotes the number of runtime steps required. Our method exploits the power of highly connected qubit systems using classical control techniques and will help to speed up quantum circuits and achieve fault tolerance in trapped-ion quantum computers.

[The history of sanitary epidemiological service of the Primorskiy Krai].

The article presents the history of development of sanitary business and state sanitary epidemiological service of the Primorskiy Krai related to general history of Russia in XIX-XX centuries. The study established input of physicians of Vladivostok into implementation of sanitary activities during first decades from city foundation: opening of the Pasteur station, struggle with epidemics of very dangerous infectious diseases, functioning of sanitary executive commission. The activities concerning support of sanitary epidemiological well-being of population during the Civil War in the Far East, years of socialism development and in post-Soviet period are considered.

Observation of chiral surface excitons in a topological insulator Bi2Se3.

The protected electron states at the boundaries or on the surfaces of topological insulators (TIs) have been the subject of intense theoretical and experimental investigations. Such states are enforced by very strong spin-orbit interaction in solids composed of heavy elements. Here, we study the composite particles-chiral excitons-formed by the Coulomb attraction between electrons and holes residing on the surface of an archetypical 3D TI, [Formula: see text] Photoluminescence (PL) emission arising due to recombination of excitons in conventional semiconductors is usually unpolarized because of scattering by phonons and other degrees of freedom during exciton thermalization. On the contrary, we observe almost perfectly polarization-preserving PL emission from chiral excitons. We demonstrate that the chiral excitons can be optically oriented with circularly polarized light in a broad range of excitation energies, even when the latter deviate from the (apparent) optical band gap by hundreds of millielectronvolts, and that the orientation remains preserved even at room temperature. Based on the dependences of the PL spectra on the energy and polarization of incident photons, we propose that chiral excitons are made from massive holes and massless (Dirac) electrons, both with chiral spin textures enforced by strong spin-orbit coupling. A theoretical model based on this proposal describes quantitatively the experimental observations. The optical orientation of composite particles, the chiral excitons, emerges as a general result of strong spin-orbit coupling in a 2D electron system. Our findings can potentially expand applications of TIs in photonics and optoelectronics.

Complete 3-Qubit Grover search on a programmable quantum computer.

The Grover quantum search algorithm is a hallmark application of a quantum computer with a well-known speedup over classical searches of an unsorted database. Here, we report results for a complete three-qubit Grover search algorithm using the scalable quantum computing technology of trapped atomic ions, with better-than-classical performance. Two methods of state marking are used for the oracles: a phase-flip method employed by other experimental demonstrations, and a Boolean method requiring an ancilla qubit that is directly equivalent to the state marking scheme required to perform a classical search. We also report the deterministic implementation of a Toffoli-4 gate, which is used along with Toffoli-3 gates to construct the algorithms; these gates have process fidelities of 70.5% and 89.6%, respectively.

[Pharmacometabonomics - the novel way to personalized drug therapy]. / Farmakometabonomika ­ novyi podkhod k personalizatsii lekarstvennoi terapii.

The review is devoted to pharmacometabonomics - a new branch of science focused on personalization of drug therapy through the comprehensive analysis of metabolites of patient's biological fluids. It considers the history of pharmacometabonomic, positioning to other "-omic" sciences, and system approach, realized by this science, in determination of individual therapeutic dose of the drugs and also a technical implementation of pharmacometabonomic based on direct mass spectrometry of blood plasma metabolites. Special attention is paid to a comparative analysis of pharmacometabonomics and other main approaches to personalized therapy in the clinic, such as pharmacogenetics and therapeutic drug monitoring. Finally, prospects of pharmacometabonomics applications in clinical practice were also discussed.

Chiral Spin Mode on the Surface of a Topological Insulator.

Using polarization-resolved resonant Raman spectroscopy, we explore collective spin excitations of the chiral surface states in a three dimensional topological insulator, Bi_{2}Se_{3}. We observe a sharp peak at 150 meV in the pseudovector A_{2} symmetry channel of the Raman spectra. By comparing the data with calculations, we identify this peak as the transverse collective spin mode of surface Dirac fermions. This mode, unlike a Dirac plasmon or a surface plasmon in the charge sector of excitations, is analogous to a spin wave in a partially polarized Fermi liquid, with spin-orbit coupling playing the role of an effective magnetic field.

The S1 ← S0 fluorescence excitation spectrum and structure of propanal in the S1 excited electronic state.

We have obtained and analyzed the S1 ← S0 fluorescence excitation spectra of jet-cooled propanal-h1 (CH3CH2CHO) and -d1 (CH3CH2CDO). Using the results of theoretical studies of the structure of propanal molecule in the S1 lowest excited singlet electronic state, we have assigned the bands of both spectra to the vibronic transitions of the cis conformer (in the S0 ground electronic state) to the 1 and 3 conformers (in the S1 state) differed by the angle of the C2H5 ethyl group rotation around the central C-C bond. The origins of the 1 ← cis and 3 ← cis electronic transitions have been observed at 29 997 and 30 075 cm(-1) for propanal-h1 and at 30 040 and 30 115 cm(-1) for propanal-d1, respectively. The high activity of torsional (C2H5 ethyl groups) and inversional (CCHO/CCDO carbonyl fragments) vibrations and the intensity distribution of the bands in torsional sequences (passing through maximum) are in agreement with the theoretical prediction that the S1 ← S0 electronic excitation of the cis conformer causes (after geometrical relaxation) the pyramidalization of carbonyl fragments and the rotation of ethyl groups around the central C-C bond. A number of energy levels have been found for torsional and inversional vibrations, and also fundamentals of ν10 (CCO bend) and ν13 (CCC bend) for the both 1 and 3 conformers of propanal-h1 and -d1 have been found. Then the "experimental" potential functions of inversion for the pair of the 1 and 3 conformers have been determined. The heights of potential barriers to inversion and the angle values corresponding to the minima of potential functions of inversion are 900 cm(-1) and 35° for propanal-h1 and 820 cm(-1) and 34° for propanal-d1, respectively.

Isolation and complete genome sequencing of rabies virus strain isolated from a brown bear (Ursus arctos) that attacked a human in Primorsky krai (November, 2014).

An attack of a brown bear (Ursus arctos) on human was detected in November, 2014 in the Barabash village (Khasan region of the Primorski krai) located in close proximity to the national park Land of the Leopard. The bear was shot. The deviant behavior of the bear indicated the possibility of rabies. The diagnosis was confirmed by means of laboratory methods. The strain RABV/Ursus arctos/Russia/Primorye/PO 01/2014 (further PO 01) was isolated from the brain of the bear. PO 01 is the first completely sequenced Far Eastern strain of RABV. It can be considered as topotypic. PO 01 considerably differs from the vaccine strain RV 97 (GenBank EF542830) that is the basis of attenuated vaccine applied in the Land of the Leopard. At the same time, the immunodominant sites in PO 01 and RV 97 proteins differ slightly. It can be recommended to continue application of the vaccine. The analysis of the PO 01 genome (GenBank KP997032) revealed its belonging to the Eurasian genetic subgroup of the genotype 1 (street rage). Thus, this genetic subgroup stretches to the East. Expansion of the cross-border protected territories of Russia and China in the Far East demands the correct statistics of circulation of the lyssaviruses to be kept.

Draft Genome Sequences of Two Pyrazinamide-Resistant Clinical Isolates, Mycobacterium tuberculosis 13-4152 and 13-2459.

We report draft genome sequences of two pyrazinamide (PZA)-resistant isolates, Mycobacterium tuberculosis 13-4152 and 13-2459. Isolate 13-4152 is PZA resistant, though it lacks mutations in known genes of PZA resistance. The comparative analysis of these genomes with those stored in GenBank revealed unique mutations, which may elucidate new mechanisms of PZA resistance.

Draft Genome Sequence of Mycobacterium tuberculosis Strain E186hv of Beijing B0/W Lineage with Reduced Virulence.

We report a draft genome sequence of Mycobacterium tuberculosis strain E186hv, belonging to the Beijing B0/W lineage and isolated from a patient from Kurgan, Russia. This clinical isolate showed a reduced virulence phenotype unusual for this lineage and resistance to isoniazid, rifampin, ethambutol, pyrazinamide, and ofloxacin. We analyzed single nucleotide polymorphisms (SNPs) associated with virulence.

[Mass spectrometry analysis of blood plasma lipidome as method of disease diagnostics, evuation of effectiveness and optimization of drug therapy].

A new method for the analysis of blood lipid based on direct mass spectrometry of lipophilic low molecular weight fraction of blood plasma has been considered. Such technique allows quantification of hundreds of various types of lipids and this changes existing concepts on diagnostics of lipid disorders and related diseases. The versatility and quickness of the method significantly simplify its wide use. This method is applicable for diagnostics of atherosclerosis, diabetes, cancer and other diseases. Detalization of plasma lipid composition at the molecular level by means of mass spectrometry allows to assess the effectiveness of therapy and to optimize the drug treatment of cardiovascular diseases by phospholipid preparations.

Pressure tuning the Fermi level through the Dirac point of giant Rashba semiconductor BiTeI.

We report measurements of Shubnikov-de Haas oscillations in the giant Rashba semiconductor BiTeI under applied pressures up to ∼2 GPa. We observe one high frequency oscillation at all pressures and one low frequency oscillation that emerges between ∼0.3-0.7 GPa indicating the appearance of a second small Fermi surface. BiTeI has a conduction band bottom that is split into two sub-bands due to the strong Rashba coupling, resulting in a 'Dirac point'. Our results suggest that the chemical potential starts below the Dirac point in the conduction band at ambient pressure and moves upward, crossing it as pressure is increased. The presence of the chemical potential above this Dirac point results in two Fermi surfaces. We present a simple model that captures this effect and can be used to understand the pressure dependence of our sample parameters. These extracted parameters are in quantitative agreement with first-principles calculations and other experiments. The parameters extracted via our model support the notion that pressure brings the system closer to the predicted topological quantum phase transition.

[Mass spectrometry of blood low-molecular fraction as a method for unification of therapeutic drug monitoring].

The article describes a new therapeutic drug monitoring (TDM) method based on direct infusion of low-molecular fraction of blood into electrospray ionization source of mass spectrometer. This technique allows performing TDM of almost all drugs used in clinic. In article, the universality and high-throughput of the method, that significantly simplifies its wide application, have been shown. Moreover, the possibility of method application in most cases of drug therapy has been argued as a tool of control of drug doses, rationality of drug therapy, and the quality of the drugs themselves. In conclusion, the prospects for application of the method as primary means of improving the quality and personalization of drug therapy have been discussed.

[Chemical composition of breast milk in females with preterm deliveries in the Primorsky Krai].

In the article there are presented data on the chemical composition of breast milk in females with preterm labor in the Primorye Territory, who were in the Department of newborns for premature babies of the Municipal Institution of Health "Children's city clinical hospital" in Vladivostok during 2010-2011 to care for their newborn infants. Laboratory studies were performed in the Federal State Institution of Health "Center of Hygiene and Epidemiology in the Primorye Territory."

Identification of phosphorylation sites in aminoglycoside phosphotransferase VIII from Streptomyces rimosus.

We demonstrate for the first time the role of phosphorylation in the regulation of activities of enzymes responsible for inactivation of aminoglycoside antibiotics. The aminoglycoside phosphotransferase VIII (APHVIII) from the actinobacterial strain Streptomyces rimosus ATCC 10970 is an enzyme regulated by protein kinases. Two serine residues in APHVIII are shown to be phosphorylated by protein kinases from extracts of the kanamycin-resistant strain S. rimosus 683 (a derivative of strain ATCC 10970). Using site-directed mutagenesis and molecular modeling, we have identified the Ser146 residue in the activation loop of the enzyme as the key site for Ca2+-dependent phosphorylation of APHVIII. Comparison of the kanamycin kinase activities of the unphosphorylated and phosphorylated forms of the initial and mutant APHVIII shows that the Ser146 modification leads to a 6-7-fold increase in the kanamycin kinase activity of APHVIII. Thus, Ser146 in the activation loop of APHVIII is crucial for the enzyme activity. The resistance of bacterial cells to kanamycin increases proportionally. From the practical viewpoint, our results increase prospects for creation of highly effective test systems for selecting inhibitors of human and bacterial serine/threonine protein kinases based on APHVIII constructs and corresponding human and bacterial serine/threonine protein kinases.