[Kalmann syndrome in monozygous twins as an isolated manifestation of the SOX10 gene defect].

More than 30 genes are known to take part in hypothalamic-pituitary-gonadal axis development at the date and role of more than 10 other genes is studied. Despite it about 50% of isolated hypogonadotropic hypogonadism cases still have no molecular genetic explanation.A number of specific associations between iHH and different not-reproductive manifestations called syndromic forms are distinguished in general group of iHH. For example, the combination of Kalmann syndrome with sensorineural hearing loss is known as manifestation for defects of some genes encoding factors of neuronal migration; in patients with this phenotype CHD7, SOX10 genes defects are most frequent. However, defects in the genes of neuronal migration factors are characterized by a wide variability of phenotype, which is explained by the epigenetic mechanisms influence. Carriers of the mutation within the same family may lack some non-reproductive manifestations as well as hypogonadism.Here we present a case of Kalmann syndrome in monozygous twins, caused by a previously not described heterozygous mutation c.462C> G: p.I154M in the SOX10 gene in the absence of sensorineural hearing loss. The mutation was inherited from a father who has only isolated anosmia in the phenotype. This mutation was identified during full exome sequencing. This unique observation for Russia shows on the one hand expediency to check SOX10 sequence in addition to the other factors of neuronal migration and differentiation and, on the other hand, the prospect of full exome sequencing in a group of patients with undifferentiated iHH.

[Clinical and molecular genetic features of cases of isolated hypogonadotropic hypogonadism, associated with defects in GNRHR genes].

Congenital hypogonadotropic hypogonadism (CHH) is a rare disorder characterised by lack of pubertal development and infertility, due to deficient production, secretion or action of gonadotropin-releasing hormone (GnRH). Clinically, there are variants of CHH with hypo-/anosmia (Kalman syndrome) and normosmic hypogonadotropic hypogonadism. Given a  growing list of gene mutations accounting for CHH, the application of next generation sequencing (NGS) comprises an excellent molecular diagnostic approach because it enables the simultaneous evaluation of many genes. Biallelic mutations in GNRHR gene lead to the development of hypogonadotropic hypogonadism with normosmia. In this paper, we describe 16 patients with proven GnRH resistance and estimate the frequency of pathogenic variants in the GNRHR gene in the Russian population.

[Hereditary Cushing's syndrome caused by primary bilateral macronodular adrenal hyperplasia due to ARMC5 mutation with concomitant primary hyperparathyroidism: the first known case in Russia].

Primary bilateral macronodular adrenal hyperplasia (PBMAH), a genetically heterogeneous disease, is a rare cause of Cushing's syndrome. Until recently, few cases were attributed to mutations in known genes. However, in 2013, ARMC5, a newly discovered tumor suppressor gene, was identified. Further studies have shown that mutations in the ARMC5 gene are found in 25-55% of all PBMAH cases. This article describes a clinical case of hereditary Cushing's syndrome caused by PBMAH in a 37-year old patient. The patient's family history is remarkable for the presence of Cushing's syndrome and PBMAH in the patient's mother. Bilateral adrenalectomy was performed as the treatment of choice. Genetic analysis using whole-exome sequencing confirmed the hereditary cause of the disease, revealing a germline heterozygous mutation in the ARMC5 gene. The patient also had concomitant mild primary hyperparathyroidism, which had not been observed before in genetic carriers with the ARMC5 mutation.

[CDC73 mutations in young patients with primary hyperparathyroidism: A description of two clinical cases]. / Mutatsii v gene CDC73 u molodykh patsientok s pervichnym giperparatireozom (opisanie dvukh klinicheskikh sluchaev).

The article describes two clinical cases of severe primary hyperparathyroidism (PHPT) caused by parathyroid carcinoma in young female patients who underwent molecular genetic testing to rule out the hereditary forms of PHPT. In both patients, heterozygous germline nonsense mutations of tumor suppressor gene CDC73 encoding parafibromin (p.R91X and p.Q166X) were identified using next-generation sequencing with Ion Torrent Personal Genome Machine (Thermo Fisher Scientific - Life Technologies, USA). It is the first description of CDC73 mutations in Russia, one of the mutations is described for the first time in the world. Identification of germline mutations in the CDC73 gene in patients with PHPT necessitates regular lifelong screening for other manifestations of hyperparathyroidism-jaw tumor syndrome (HPT-JT), PHPT recurrence due to parathyroid carcinoma as well, and identification of mutation carriers among first-degree relatives.

[Radiation lesion formation and character of repair processes in the hematopoietic system of primates exposed to continuous and fractionated gamma-irradiation by equally effective doses].

The article is dedicated to comparison of the biological effectiveness of continuous and fractionated gamma-irradiation of rhesus macaques by equally effective doses. These radiation conditions are broadly used in radiobiological experiments. Specifically, they are applied in modeling radiation effects on cosmonauts during extended exploration mission. A model of radiation damage and repair on the cell, tissue and organism levels, i.e., a model of effective residual dose responsible for change in mammals' resistance to irradiation of varying duration was used to calculate equally effective doses in the experiment with primates subject to continuous and fractionated exposure. The authors publish data related to formation of radiation lesion and rate of ensuing hemopoiesis reparation. Two groups of animals were compared in resistance modification followed after testing by acute irradiation. The test was to reproduce a radiation situation for cosmonauts in the event of a cannonade of powerful solar proton events resulting in an effective residual dose of 1 Sv total The experiment evidenced close resemblance of the hemopoietic effects in primates exposed to the compared radiation conditions.

[Problems of ensuring human radiation safety during interplanetary flights].

The work contains the analyses and discussion of the main sources of space radiation specified for interplanetary flights, the dosimetric functionals used for describing the processes of radiation lesions and reparation of the organism in the conditions of the complex radiation impact with a broad charge composition of cosmic rays and a peculiar spatial and temporal dose behavior. It represents the results of calculations of the radiation risks during the flight and the total lifelong radiation risk with taking into account all the delayed unfavorable biological consequences. The main uncertainties in the calculated values of radiation risk leading to its undervaluation are analyzed. In addition, also provided is the range of theoretical and experimental investigations necessary for the adjustment of coefficient values used in the algorithm of radiation risk calculations, as well as in the nomenclature of experiments for estimating the individual resistance of man to the extreme influence and investigations aimed at estimating and increasing the reliability of the operator activity of cosmonauts.

[Dose loads on and radiation risk values for cosmonauts on a mission to Mars estimated from actual Martian vehicle engineering development].

The current design philosophy of a Mars orbiting vehicle, takeoff and landing systems and the transport return vehicle was taken into consideration for calculating the equivalent doses imparted to cosmonaut's organs and tissues by galactic cosmic rays, solar rays and the Earth's radiation belts, values of the total radiation risk over the lifespan following the mission and over the whole career period, and possible shortening of life expectancy. There are a number of uncertainties that should be evaluated, and radiation limits specified before setting off to Mars.

[Space radiation doses in the anthropomorphous phantom in space experiment "Matryeshka-R" and spacesuit "Orlan-M" during extravehicular activity].

Russian space experiment "Matryeshka-R" was conducted in 2004-2005 to study dose distribution in the body of anthropomorphous phantom inserted in a spacesuit imitating container mounted on outer surface of the ISS Service module (experiment "Matryeshka"). The objective was to compare doses inside the phantom in the container to human body donned in spacesuit "Orlan-M" during extravehicular activity (EVA). The shielding function was calculated using the geometric model, specification of the phantom shielded by the container, "Orlan-M" description, and results of ground-based estimation of shielding effectiveness by gamma-raying. Doses were calculated from the dose attenuation curves obtained for galactic cosmic rays, and the AE-8/AP-8 models of electron and proton flows in Earth's radiation belt. Calculated ratios of equivalent doses in representative points of the body critical organs to analogous doses in phantom "Matryeshka" H(ORLAN-M)/H(Matryeshka) for identical radiation conditions vary with organs and solar activity in the range from 0.1 to 1.8 with organs and solar activity. These observations should be taken into account when applying Matryeshka data to the EVA conditions.

[Radiation safety provisions in a piloted mission to Mars based on calculated risks of overdose behind shielding].

The article deals with the prime sources of radiation hazard in a mission to Mars, compares the radiation risk values in flight and over the life span with consideration for various shielding thicknesses in habitable compartments and radiation shelter, and estimates possible life shortening. Given the stochastic nature of solar cosmic rays effects in a two-year mission and probability of powerful solar proton events, calculated were not only the mean tissue-equivalent doses behind various thickness of the shelter but also probability of their violation, risks of immediate and delayed radiation consequences and conceivable approaches to risk mitigation.

[Experimental studies of the relative biological effectiveness of accelerated charged particles varying in energy].

Experimental results and literary data were analyzed for the relative biological effectiveness of heavy charged particles in a broad range of energy and LET to cells of humans and other mammals in culture, whole body of laboratory animals, microorganisms, bacteriophages, and plants. Analyzed were data obtained with the use of a diversity of tests of acute and delayed lesions induced by ionizing radiation, cancers and cataracts, specifically. Non-parametric methods are applied in parallel to the classic method of calculating the coefficients of relative biological effectiveness by correlating the equal-effective doses of the standard and a given radiation. Consideration is given to factors that may modify RBE values estimated for different types of radiation.

[Radiation protective quality of spacesuit "Orlan-M" during extravehicular activities on the International Space Station].

Sampling irradiation of spacesuit "Orlan-M" allowed construction of a simulation model of the spacesuit shielding function for critical body organs. The critical organs self-shielding model is a Russian standard anthropomorphic phantom. Radiation protective quality of the spacesuit was assessed by calculating the dose attenuation rates for several critical body organs of an ISS crewmember implementing EVA. These calculations are intended for more accurate assessment of radiation risk to the ISS crews donning "Orlan-M" in near-Earth orbits.

[Medium-term forecast of solar cosmic rays radiation risk during a manned Mars mission].

Medium-term forecasting radiation hazard from solar cosmic rays will be vital in a manned Mars mission. Modern methods of space physics lack acceptable reliability in medium-term forecasting the SCR onset and parameters. The proposed estimation of average radiation risk from SCR during the manned Mars mission is made with the use of existing SCR fluence and spectrum models and correlation of solar particle event frequency with predicted Wolf number. Radiation risk is considered an additional death probability from acute radiation reactions (ergonomic component) or acute radial disease in flight. The algorithm for radiation risk calculation is described and resulted risk levels for various periods of the 23-th solar cycle are presented. Applicability of this method to advance forecasting and possible improvements are being investigated. Recommendations to the crew based on risk estimation are exemplified.

[Evaluation of the radiation risk of determinate effects from space radiation in a piloted mission to Mars]. / Otsenka radiatsionnogo riska determinirovannykh éffektov vozdeistviia kosmicheskoi radiatsii pri pilotiruemoi ékspeditsii na Mars.

Solar cosmic rays (SCR) are one of the sources of radiation risk specific to space flights. On Earth, occupational exposure has a regular character and radiation risk is an attribute of nothing else but stochasticity of radiobiological effects. In space flight, SCR impart stochasticity to the radiation environment and, therefore, probability to all, including determinate, radiobiological effects. The most dangerous effect is radiation disease the dosimetric functional of which is an equivalent dose to the blood-forming organs. In addition, this radiation pathology is modulated by reparative processes in the blood-forming tissue which must be also taken into account during radiation risk evaluation. Using the speculated mission to Mars as an example, it was shown that radiation risk of determinate effects defined as probability of death by radiation disease in consequence of exposure to SCR can be comparable in value to the risk from stochastic effects.

[Scientific substantiation of experimental determination of the radiation effective dose in an interplanetary flight]. / Nauchnoe obosnovanie éksperimental'nogo opredeleniia éffektivnoi dozy izlucheniia v mezhplanetnom polete.

The present-day method of effective dose determination with a simplified human body model (spherical phantom) lacks the parameter of vehicle shielding. Introduction of the parameter will increase only the effective depth of various critical organs in the spherical phantom which can be easily accounted for during preliminary calculations. In future these facts, as well as data about impacts of the angular distribution of galactic cosmic rays (GCR), will be integrated into the calculation procedure. Analysis of the GCR dose contribution will not be very intricate owing to the GCR spectrum stability and isotropy of the angular distribution. Thus, basic calculation and measurement procedures will be fully unaltered.

Diversity of structure and function of DNA polymerase (gp43) of T4-related bacteriophages.

The replication DNA polymerase (gp43) of the bacteriophage T4 is a member of the pol B family of DNA polymerases, which are found in all divisions of life in the biosphere. The enzyme is a modularly organized protein that has several activities in one polypeptide chain (approximately 900 amino acid residues). These include two catalytic functions, POL (polymerase) and EXO (3 -exonuclease), and specific binding activities to DNA, the mRNA for gp43, deoxyribonucleotides (dNTPs), and other T4 replication proteins. The gene for this multifunctional enzyme (gene 43) has been preserved in evolution of the diverse group of T4-like phages in nature, but has diverged in sequence, organization, and specificity of the binding functions of the gene product. We describe here examples of T4-like phages where DNA rearrangements have created split forms of gene 43 consisting of two cistrons instead of one. These gene 43 variants specify separate gp43A (N-terminal) and gp43B (C-terminal) subunits of a split form of gp43. Compared to the monocistronic form, the interruption in contiguity of the gene 43 reading frame maps in a highly diverged sequence separating the code for essential components of two major modules of this pol B enzyme, the FINGERS and PALM domains, which contain the dNTP binding pocket and POL catalytic residues of the enzyme. We discuss the biological implications of these gp43 splits and compare them to other types of pol B splits in nature. Our studies suggest that DNA mobile elements may allow genetic information for pol B modules to be exchanged between organisms.

Solar cosmic rays as a specific source of radiation risk during piloted space flight.

Solar cosmic rays present one of several radiation sources that are unique to space flight. Under ground conditions the exposure to individuals has a controlled form and radiation risk occurs as stochastic radiobiological effects. Existence of solar cosmic rays in space leads to a stochastic mode of radiation environment as a result of which any radiobiological consequences of exposure to solar cosmic rays during the flight will be probabilistic values. In this case, the hazard of deterministic effects should also be expressed in radiation risk values. The main deterministic effect under space conditions is radiation sickness. The best dosimetric functional for its analysis is the blood forming organs dose equivalent but not an effective dose. In addition, the repair processes in red bone marrow affect strongly on the manifestation of this pathology and they must be taken into account for radiation risk assessment. A method for taking into account the mentioned above peculiarities for the solar cosmic rays radiation risk assessment during the interplanetary flights is given in the report. It is shown that radiation risk of deterministic effects defined, as the death probability caused by radiation sickness due to acute solar cosmic rays exposure, can be comparable to risk of stochastic effects. Its value decreases strongly because of the fractional mode of exposure during the orbital movement of the spacecraft. On the contrary, during the interplanetary flight, radiation risk of deterministic effects increases significantly because of the residual component of the blood forming organs dose from previous solar proton events. The noted quality of radiation responses must be taken into account for estimating radiation hazard in space.

Problems and conception of ensuring radiation safety during Mars missions.

The Mars mission differs from near-Earth manned space flights by radiation environment and duration. The importance of effective using the weight of the spacecraft increases greatly because all the necessary things for the mission must be included in its starting weight. For this reason the development of optimal systems of radiation safety ensuring (RSES) acquires especial importance. It is the result of sharp change of radiation environment in the interplanetary space as compared to the one in the near-Earth orbits and significant increase of the interplanetary flight duration. The demand of a harder limitation of unfavorable factors effects should lead to radiation safety (RS) standards hardening. The main principles of ensuring the RS of the Mars mission (optimizing, radiation risk, ALARA) and the conception of RSES, developed on the basis of the described approach and the experience obtained during orbital flights are presented in the report. The problems that can impede the ensuring of the crew members' RS are also given here.

Radiation environment monitoring for manned missions to Mars.

In this paper a radiation monitoring system for manned Mars missions is described, based on the most recent requirements on crew radiation safety. A comparison is shown between the radiation monitoring systems for Earth-orbiting and interplanetary spacecraft, with similarities and differences pointed out and discussed. An operational and technological sketch of the chosen problem solving approach is also given.

[Problems of radiation safety of a Martian expedition crew]. / Problemy radiatsionnoi bezopasnosti ékipazha marsianskoi ékspeditsii.

Analysis of the radiation conditions during a piloted expedition to Mars made it evident that the radiation safety system will be one of the most critical components of life support aboard the future Martian vehicle. The concept and main functions of the system have been considered. The authors give their vision of the radiation monitoring system based on the present-day radiation safety postulates, comparison and contrasting methods and equipment applied for the purpose in current orbital and projected interplanetary flights.