The development of a hiPSC-based platform to identify tissue-dependencies of IDH1 R132H.

The application of patient-derived (PD) in vitro tumor models represents the classical strategy for clinical translational oncology research. Using these cellular heterogeneous cultures for the isolation of cancer stem cells (CSCs), suggested to be the main driver for disease malignancy, relies on the use of surrogate biomarkers or is based on CSC-enriching culture conditions. However, the ability of those strategies to exclusively and efficiently enrich for CSC pool has been questioned. Here we present an alternative in vitro CSC model based on the oncogenic transformation of single clone-derived human induced pluripotent stem cells (hiPSC). Hotspot mutations in the DNA encoding for the R132 codon of the enzyme isocitrate dehydrogenase 1 (IDH1) and codon R175 of p53 are commonly occurring molecular features of different tumors and were selected for our transformation strategy. By choosing p53 mutant glial tumors as our model disease, we show that in vitro therapy discovery tests on IDH1-engineered synthetic CSCs (sCSCs) can identify kinases-targeting chemotherapeutics that preferentially target tumor cells expressing corresponding genetic alteration. In contrast, neural stem cells (NSCs) derived from the IDH1R132H overexpressing hiPSCs increase their resistance to the tested interventions indicating glial-to-neural tissue-dependent differences of IDH1R132H. Taken together, we provide proof for the potential of our sCSC technology as a potent addition to biomarker-driven drug development projects or studies on tumor therapy resistance. Moreover, follow-up projects such as comparing in vitro drug sensitivity profiles of hiPSC-derived tissue progenitors of different lineages, might help to understand a variety of tissue-related functions of IDH1 mutations.

In Vitro Antiviral Activity of a New Indol-3-carboxylic Acid Derivative Against SARS-CoV-2.

The coronavirus disease (COVID-19) pandemic has brought into sharp relief the threat posed by coronaviruses and laid the foundation for a fundamental analysis of this viral family, as well as a search for effective anti-COVID drugs. Work is underway to update existent vaccines against COVID-19, and screening for low-molecular-weight anti-COVID drug candidates for outpatient medicine continues. The opportunities and ways to accelerate the development of antiviral drugs against other pathogens are being discussed in the context of preparing for the next pandemic. In 2012-2015, Tsyshkova et al. synthesized a group of water-soluble low-molecular-weight compounds exhibiting an antiviral activity, whose chemical structure was similar to that of arbidol. Among those, there were a number of water-soluble compounds based on 5-methoxyindole-3-carboxylic acid aminoalkyl esters. Only one member of this rather extensive group of compounds, dihydrochloride of 6-bromo-5-methoxy-1-methyl-2-(1-piperidinomethyl)-3-(2-diethylaminoethoxy) carbonylindole, exhibited a reliable antiviral effect against SARS-CoV-2 in vitro. At a concentration of 52.0 µM, this compound completely inhibited the replication of the SARS-CoV-2 virus with an infectious activity of 106 TCID50/mL. The concentration curves of the analyzed compound indicate the specificity of its action. Interferon-inducing activity, as well as suppression of syncytium formation induced by the spike protein (S-glycoprotein) of SARS-CoV-2 by 89%, were also revealed. In view of its synthetic accessibility - high activity (IC50 = 1.06 µg/mL) and high selectivity index (SI = 78.6) - this compound appears to meets the requirements for the development of antiviral drugs for COVID-19 prevention and treatment.

Water and Chlorine in the Martian Subsurface Along the Traverse of NASA's Curiosity Rover: 1. DAN Measurement Profiles Along the Traverse.

This paper presents estimates of the water and chlorine contents in the subsurface of Gale crater based on the measurements by the Dynamic Albedo of Neutrons (DAN) instrument onboard the NASA Curiosity rover. It is Part 1 of a two-paper series. Data derived both from DAN active and passive measurements are presented in discrete surface areas (pixels) assuming a homogeneous distribution of water within the DAN sensing depth (60 cm) along the traverse of the rover. It is shown that the content of hydrogen, reported as Water Equivalent Hydrogen, varies between almost zero and a maximum of (6.1 ± 0.7) wt.%. The content of absorption equivalent chlorine varies between almost zero and (2.6 ± 0.2) wt.%. Such variations are thought to be related to the different geological processes and environmental conditions present in the strata along the traverse during the evolutionary history of Gale crater. The second paper (Part 2) studies particular properties of water and abundances of neutron absorbing elements at distinct geological regions, that the rover crossed on its way.

Observations of neutron radiation environment during Odyssey cruise to Mars.

In April 2001, Mars Odyssey spacecraft with the High Energy Neutron Detector (HEND) onboard was launched to Mars. HEND/Odyssey was switched on measurement mode for most of transit to Mars to monitor variations of spacecraft background and solar activity. Although HEND/Odyssey was originally designed to measure Martian neutron albedo and to search for Martian subsurface water/water ice, its measurements during cruise phase to Mars are applicable to evaluate spacecraft ambient radiation background. The biological impact of the neutron component of this radiation background should be understood, as it must be taken into account in planning future human missions to Mars. We have modeled the spacecraft neutron spectral density and compared it with HEND measurements to estimate neutron dose equivalent rates during Odyssey cruise phase, which occurred during the maximum period of solar cycle 23. We find that the Odyssey ambient neutron environment during May - September 2001 yields 10.6 ± 2.0 µSv per day in the energy range from 0 to 15 MeV, and about 29 µSv per day when extrapolated to the 0-1000 MeV energy range during solar quiet time (intervals without Solar Particle Events, SPEs). We have also extrapolated HEND/Odyssey measurements to different periods of solar cycle and find that during solar minimum (maximum of GCR flux), the neutron dose equivalent rate during cruise to Mars could be as high as 52 µSv per day with the same shielding. These values are in good agreement with results reported for a similar measurement made with an instrument aboard the Mars Science Laboratory during its cruise to Mars in 2011-2012.

A bright γ-ray flare interpreted as a giant magnetar flare in NGC 253.

Soft γ-ray repeaters exhibit bursting emission in hard X-rays and soft γ-rays. During the active phase, they emit random short (milliseconds to several seconds long), hard-X-ray bursts, with peak luminosities1 of 1036 to 1043 erg per second. Occasionally, a giant flare with an energy of around 1044 to 1046 erg is emitted2. These phenomena are thought to arise from neutron stars with extremely high magnetic fields (1014 to 1015 gauss), called magnetars1,3,4. A portion of the second-long initial pulse of a giant flare in some respects mimics short γ-ray bursts5,6, which have recently been identified as resulting from the merger of two neutron stars accompanied by gravitational-wave emission7. Two γ-ray bursts, GRB 051103 and GRB 070201, have been associated with giant flares2,8-11. Here we report observations of the γ-ray burst GRB 200415A, which we localized to a 20-square-arcmin region of the starburst galaxy NGC 253, located about 3.5 million parsecs away. The burst had a sharp, millisecond-scale hard spectrum in the initial pulse, which was followed by steady fading and softening over 0.2 seconds. The energy released (roughly 1.3 × 1046 erg) is similar to that of the superflare5,12,13 from the Galactic soft γ-ray repeater SGR 1806-20 (roughly 2.3 × 1046 erg). We argue that GRB 200415A is a giant flare from a magnetar in NGC 253.

Human Diploid Fibroblast Cell Lines - a Model System for Studying Immunodulatory Properties of Modern Immunobiological Drugs and Viruses.

The immunomodulatory properties of immunobiological drugs Glutoxim and Phosprenyl we well as vesicular stomatitis virus and inactivated tick-borne encephalitis vaccine virus were studied using human diploid fibroblast cell line from the collection of M. P. Chumakov Federal Research Center for Research and Development of Immunobiological Products. All tested preparations exhibited immunomodulatory activity in human diploid fibroblast cell line. Glutoxim in doses of 0.1 and 0.25 µg/ml stimulated production of IL-6 and IL-10 during 24-48 h of culturing, but did not stimulate production of IL-1ß. Phosprenyl, on the contrary, increased production of IL-1ß and the levels of IL-6 and IL-10. Vesicular stomatitis virus stimulated the production of IL-1ß, IL-6, and IL-10, while inactivated tick-borne encephalitis vaccine virus stimulated the production of cytokines IL-8 and IL-18. Immunomodulatory activity of inactivated tick-borne encephalitis vaccine virus was first demonstrated in the in vitro system.

Optical diagnostics of negative ion beam transport.

A diagnostic complex for monitoring the position, propagation direction, and angular distribution dispersion of a particle beam planned for application in the Boron Neutron Capture Therapy facility is described in this paper. For the beam position and direction, the precision is, respectively, 0.1 mm and 1 mrad at 10 mA CW H- beam with energy of about 35 keV and a diameter of the order of 10 mm. The energy spread and angular divergence were measured within the accuracy of about 100 eV and 3 mrad, respectively. The acceptable precision of about 1 mm for the beam position is obtained at a relatively short exposure to 10 ms. To increase the radiation intensity of the beam, the addition of various gases was studied. The addition of gas decreases the beam width and increases the negative ions stripping.

Selection of Domestic Cell Lines for the Creation of Diagnostic and Preventive Preparations against Enterovirus 71.

We studied the sensitivity of domestic proprietary human and animal cell lines from the collection of M. P. Chumakov Federal Scientific Center for Research and Development of Immuneand-Biological Products to infection with different enterovirus 71 strains. A cell system based on domestic proprietary permanent cell line 4647 was for the first time used for reproduction of four enterovirus 71 strains (BrCr, 42266, 42934, and 43374). It was shown that strain 4647 is the optimal cell substrate for enterovirus 71 reproduction. The titers of enterovirus 71 for all four strains considerably (by 2 lgTCID50/ml and more) increased during sequential passages in permanent cell line 4647. The prospects of using permanent cell line 4647 for creation of diagnostic and preventive preparations against 71 was demonstrated.

Study of continuous wave 33 keV H- beam transport through the low energy beam transport section.

The transport of a continuous wave 33 keV negative ion beam through the low energy beam transport section, designed for beam injection into the tandem accelerator, was studied. The continuous wave H- beam, produced by the Penning surface-plasma source with hollow cathodes and cesium addition, was separated and focused by the 90° bending magnet and then transported through the 0.8 m long transport tube, equipped with beam electrical and optical diagnostics. The beam current was measured by a water-cooled Faraday cup at the transport tube exit. Beam sizes and profiles were measured by CCD cameras looking into the beam from the back and sides. The additions of hydrogen, argon, and xenon to the transport tube and to the bending magnet chamber in the pressure range of 10-6 to 10-4 Torr were tested. The influence of gas addition on the beam space charge compensation and beam transport was studied. A mechanism for the H- beam focusing due to space charge overcompensation and beam compression by the positive charge, produced with positive ion accumulation in the beam, is discussed.

Development of continuous wave high voltage negative ion beam injector for tandem accelerator.

A vacuum-insulated tandem accelerator, delivering the continuous wave 8 mA, 2 MeV proton beam, is operated regularly at the Budker Institute of Nuclear Physics, where a 10 mA, 25 keV negative ion injector is used. Recently, a new injector with an upgraded negative ion source and beam preacceleration has been developed to increase the tandem accelerated current. The transport line of the new injector is composed of a bending magnet with 90° ion beam turn, an acceleration tube for negative ion acceleration to the energy up to 150 keV, and a 0.6 m long transport section. The H- ion beam production, its acceleration, and transport were studied at a test stand, which is equipped with electrical and optical diagnostics. The data on 14 mA, 133 keV continuous wave negative ion beam production and transport are presented. The undesirable coacceleration of secondary electrons, produced in the acceleration tube, was recorded as well. The coaccelerated electrons' current contributed up to 2% of the total accelerated beam at the operational vacuum in the low energy beam transport. The coaccelerated electrons were removed from the beam with a magnetic filter. The numerical modeling of the beam transport was carried out. A reasonable agreement between the modeled and experimental data was obtained.

Polyprenyl Phosphates Induce a High Humoral and Cellular Response to Immunization with Recombinant Proteins of the Replicative Complex of the Hepatitis C Virus.

The search for new adjuvants remains the critical task for the creation of hepatitis C vaccines due to the weak immunogenicity of biotechnological products. When immunizing mice with the recombinant proteins NS3 and NS5B of the hepatitis C virus (HCV), the adjuvant activity of three immunomodulators was compared. Phosprenyl® on the basis of polyprenyl phosphate (PPP), chemically synthesized analogue of the bacterial cell wall glucosaminyl muramyl dipeptide (GMDP), and IFN-α recombinant protein were tested. GMDP increased the activity of IgG1 antibodies 4-6 times but did not stimulate the production of IFN-γ; IFN-α has not shown any adjuvant properties. The introduction of recombinant HCV proteins together with PPP in low doses increased the activity of IgG2a isotype antibodies 4-7 times and increased IFN-γ secretion 3 times. Thus, it was first shown that PPP polarizes the immune response to Th1-type and is a promising adjuvant for the development of a vaccine against hepatitis C.

The ADRON-RM Instrument Onboard the ExoMars Rover.

This overview presents the physical principles, design, measurement capabilities, and summary of planned operations of the autonomous detector of radiation of neutrons onboard rover at Mars (ADRON-RM) on the surface of Mars. ADRON-RM is a Russian project selected for the joint European Space Agency-Roscosmos ExoMars 2020 landing mission. A compact passive neutron spectrometer, ADRON-RM, was designed to study the abundance and distribution of water and neutron absorption elements (such as Cl, Fe, and others) in the martian subsurface along the path of the ExoMars rover. Key Words: Mars exploration-Surface-Neutron Spectroscopy-Water. Astrobiology 17, 585-594.

[Antiviral activity of phosprenyl and gamapren against infection caused by influenza a (H5N1) virus in cell culture].

The antiviral activity of Phosprenyl and Gamapren in vitro against highly pathogenic strain of avian influenza H5N1 virus was studied. Inoculation of the virus to the susceptible cell culture led to development of the cytopathogenic effect. Preliminary introduction of Phosprenyl and Gamapren an hour prior to infecting the cells with virus 10.0 TCID50 dose completely inhibited the cytopathogenic activity of the virus. At higher doses of virus (100.0 TCID50) significant inhibition of the infectious activity of the virus was observed: 70% of infected cells survived under the action of Phosprenyl, and 90% under the action of Gamapren. With the introduction of the preparations simultaneously with the infection of cells with virus at a dose of 10.0 TCID50 virtually 100% of infected cells survived, while in control cultures death of 100% of the cells occurred. After infection with the virus at a dose of 100.0 TCID50 Phosprenyl and Gamapren caused 50% protection of the cells. The antiviral effect of the drugs Phosprenyl and Gamapren may be associated not only with their virulicidal, but with anti-viral activity as well.

A comparative study of LaBr3(Ce(3+)) and CeBr3 based gamma-ray spectrometers for planetary remote sensing applications.

The recent availability of large volume cerium bromide crystals raises the possibility of substantially improving gamma-ray spectrometer limiting flux sensitivities over current systems based on the lanthanum tri-halides, e.g., lanthanum bromide and lanthanum chloride, especially for remote sensing, low-level counting applications or any type of measurement characterized by poor signal to noise ratios. The Russian Space Research Institute has developed and manufactured a highly sensitive gamma-ray spectrometer for remote sensing observations of the planet Mercury from the Mercury Polar Orbiter (MPO), which forms part of ESA's BepiColombo mission. The Flight Model (FM) gamma-ray spectrometer is based on a 3-in. single crystal of LaBr3(Ce(3+)) produced in a separate crystal development programme specifically for this mission. During the spectrometers development, manufacturing, and qualification phases, large crystals of CeBr3 became available in a subsequent phase of the same crystal development programme. Consequently, the Flight Spare Model (FSM) gamma-ray spectrometer was retrofitted with a 3-in. CeBr3 crystal and qualified for space. Except for the crystals, the two systems are essentially identical. In this paper, we report on a comparative assessment of the two systems, in terms of their respective spectral properties, as well as their suitability for use in planetary mission with respect to radiation tolerance and their propensity for activation. We also contrast their performance with a Ge detector representative of that flown on MESSENGER and show that: (a) both LaBr3(Ce(3+)) and CeBr3 provide superior detection systems over HPGe in the context of minimally resourced spacecraft and (b) CeBr3 is a more attractive system than LaBr3(Ce(3+)) in terms of sensitivities at lower gamma fluxes. Based on the tests, the FM has now been replaced by the FSM on the BepiColombo spacecraft. Thus, CeBr3 now forms the central gamma-ray detection element on the MPO spacecraft.

Effect of plasma grid bias on extracted currents in the RF driven surface-plasma negative ion source.

Extraction of negative ions from the large inductively driven surface-plasma negative ion source was studied. The dependencies of the extracted currents vs plasma grid (PG) bias potential were measured for two modifications of radio-frequency driver with and without Faraday screen, for different hydrogen feeds and for different levels of cesium conditioning. The maximal PG current was independent of driver modification and it was lower in the case of inhibited cesium. The maximal extracted negative ion current depends on the potential difference between the near-PG plasma and the PG bias potentials, while the absolute value of plasma potential in the driver and in the PG area is less important for the negative ion production. The last conclusion confirms the main mechanism of negative ion production through the surface conversion of fast atoms.

High voltage holding in the negative ion sources with cesium deposition.

High voltage holding of the large surface-plasma negative ion source with cesium deposition was studied. It was found that heating of ion-optical system electrodes to temperature >100 °C facilitates the source conditioning by high voltage pulses in vacuum and by beam shots. The procedure of electrode conditioning and the data on high-voltage holding in the negative ion source with small cesium seed are described. The mechanism of high voltage holding improvement by depletion of cesium coverage is discussed.

Efficient cesiation in RF driven surface plasma negative ion source.

Experiments on hydrogen negative ions production in the large radio-frequency negative ion source with cesium seed are described. The system of directed cesium deposition to the plasma grid periphery was used. The small cesium seed (∼0.5 G) provides an enhanced H(-) production during a 2 month long experimental cycle. The gradual increase of negative ion yield during the long-term source runs was observed after cesium addition to the source. The degraded H(-) production was recorded after air filling to the source or after the cesium washing away from the driver and plasma chamber walls. The following source conditioning by beam shots produces the gradual recovery of H(-) yield to the high value. The effect of H(-) yield recovery after cesium coverage passivation by air fill was studied. The concept of cesium coverage replenishment and of H(-) yield recovery due to sputtering of cesium from the deteriorated layers is discussed.

Inductively driven surface-plasma negative ion source for N-NBI use (invited).

The long-pulse surface-plasma source prototype is developed at Budker Institute of Nuclear Physics for negative-ion based neutral beam injector use. The essential source features are (1) an active temperature control of the ion-optical system electrodes by circulation of hot thermal fluid through the channels, drilled in the electrode bodies, (2) the concaved transverse magnetic field in the extraction and acceleration gaps, preventing the electrons trapping and avalanching, and (3) the directed cesium deposition via distribution tubes adjacent to the plasma grid periphery. The long term effect of cesium was obtained just with the single cesium deposition. The high voltage strength of ion-optical system electrodes was improved with actively heated electrodes. A stable H(-) beam with a current ∼1 A and energy 90 keV was routinely extracted and accelerated.

[Efficacy of polyprenyl phosphates in the experimental genital herpes model].

An experimental model of the primary genital herpes (herpes simplex type 2, HSV-2) in the female guinea pigs was suggested to study the infectious process activity of polyprenyl phosphates (PPP) and PPP+acyclovir (AC) complex treatment. The morphofunctional features of the guinea pig ovaries were studied in the control and experimental groups (the latter were inoculated with PPP and/or AC as a primary infection treatment) at the stage of the recurrent genital herpes aggravation. It was shown that in the case of combined PPP +AC use significant changes in the disease symptoms were observed, as well as a decrease in the infectious process activity and duration, and positive remote effect on the ovarian morphophysiology.

Two-dimensional wave-number spectral analysis techniques for phase contrast imaging turbulence imaging data on large helical device.

An analysis method for unfolding the spatially resolved wave-number spectrum and phase velocity from the 2D CO2 laser phase contrast imaging system on the large helical device is described. This is based on the magnetic shear technique which identifies propagation direction from 2D spatial Fourier analysis of images detected by a 6 × 8 detector array. Because the strongest modes have wave-number at the lower end of the instrumental k range, high resolution spectral techniques are necessary to clearly resolve the propagation direction and hence the spatial distribution of fluctuations along the probing laser beam. Multiple-spatial point cross-correlation averaging is applied before calculating the spatial power spectrum. Different methods are compared, and it is found that the maximum entropy method (MEM) gives best results. The possible generation of artifacts from the over-narrowing of spectra are investigated and found not to be a significant problem. The spatial resolution Δρ (normalized radius) around the peak wave-number, for conventional Fourier analysis, is ∼0.5, making physical interpretation difficult, while for MEM, Δρ ∼ 0.1.