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This article, based on a report presented at the Scientific Session of the Russian Academy of Sciences, highlights the history of the formation of space medicine, its theoretical foundations, and the role of scientists of the Academy of Sciences in the preparation and implementation of the first manned flight into space. The achievements of domestic specialists in space physiology, biology, and medicine promoting the development of manned cosmonautics are considered. Examples are given of the implementation of the results of space research, as well as instruments and devices for medical support of space crews, into practical health care. The problems of medical support of future interplanetary flights and the ways of their solution are analyzed., (© Pleiades Publishing, Ltd. 2021, ISSN 1019-3316, Herald of the Russian Academy of Sciences, 2021, Vol. 91, No. 6, pp. 626–629. © Pleiades Publishing, Ltd., 2021.Russian Text © The Author(s), 2021, published in Vestnik Rossiiskoi Akademii Nauk, 2021, Vol. 91, No. 11, pp. 1036–1040.)

Eighty outbred CD-I male and female mice (initial body mass of 31-34 g) and 40 male Wistar rats (initial body mass of 280-360 g) were randomly distributed into the experimental and control groups by sex and body mass. According to the results of experiments, consumption of rectified light-isotope water over 30 days immediately after irradiation by gamma-quanta 60Co at 5 Gy and 6.5 Gy can increase survivability rate significantly, accelerate hemopoiesis recovery and prevent body mass loss in irradiated animals. Therefore, light-isotope water can be considered as an effective agent for treatment of the bone marrow syndrome.

Studies results of gravity unloading influence on spinal control system of muscle structure and functions are summarized. It was shown that demyelization of axons due to reduction of genes expression responsible for myelin proteins synthesis, decrease in one of the key enzymes of cholinergic system--cholineacetyltransferase activity, alteration of normal kinetics of quantal and non-quantal neurotransmitter secretion, impaired autoregulation of acetylcholine secretion from motor nerve endings through presynaptic cholinergic receptors, slowing of axonal transport of substances in motor neurons that innervate postural muscles played the important role in the development of hypogravitational motor symptoms. At the same time, the evidences of neuroprotective mechanisms enclosing (increase in heat shock proteins Hsp25 and Hsp70 expression), that hinder apoptosis development in motor neurons and glial cells in the spinal cord under conditions of model hypogravity, were revealed.

In the review it was represented the modern ideas on the processes involved in the formation of the protein composition of the urine of healthy people. In the last decade the development of highly sensitive mass spectrometric methods for the detection of proteins has given impetus to the study of the protein composition of human body fluids, including urine. Modern methods of separation of complex protein mixtures and determination of the individual components of these mixtures that are used in proteomics, can detect in urine significant number of proteins and peptides of different origin. Little-known, but very important problem for biomedical research is a physiological variation of the protein composition of urine revealed by proteomics. Under physiological conditions, there are many factors that affect the filtration of plasma proteins in the glomeruli and reabsorption in the proximal tubules of the nephron. These include hypoxia, oxidative stress, changes in acid-base balance and blood pressure, the effects of parathyroid hormone, angiotensin-II and other regulators of water and electrolyte metabolism. It is shown that the close structural and functional relationship of processes of reabsorption in the proximal tubules of the nephron causes dependence modulation of sodium reabsorption, water, chloride, phosphate, bicarbonate, and changes in the various parts of the process of re-absorption of the protein.

The paper deals with the application of functional load tests to assess the renal function and water-salt metabolism in human subjects during spaceflight simulating experiments and in cosmonauts in orbit and in the course of postflight recovery. The tests gave insight into mechanisms of the osmotic and volumetric regulation systems and enabled the development upon this knowledge of countermeasures to correct shifts in water-salt homeostasis.

A concept of the radiation risk of the manned interplanetary flights is proposed and substantiated. Heavy charged particles that are a component of the galactic cosmic rays (GCR) have a high damaging effect on the biological structures as great amount of energy is deposited in heavy particle tracks. The high biological effectiveness of heavy ions is observed in their action on cell genetic structures and the whole organism, including the brain structures. The hippocampus is the part of the central nervous system that is the most sensitive to radiation--first of all, to heavy charged particles. Irradiation of animals with accelerated iron ions at doses corresponding to the real fluxes of GCR heavy nuclei, to which Mars mission crews can be exposed, leads to marked behavioral function disorders in the post-irradiation period. To evaluate the radiation risk for the interplanetary flight crews, the concept of successful mission accomplishment is introduced. In these conditions, the central nervous system structures can be the critical target of GCR heavy nuclei. Their damage can modify the higher integrative functions of the brain and cause disorders in the crew members' operator performances.

Amplitude and temporal responses of heart rate to stepwise increase or decrease of treadmill running intensity were investigated in rats. Heart rate amplitude response was shown to be connected mainly with the change of sympathetic nervous activity whereas heart rate temporal response was shown to be determined predominantly by parasympathetic cardiotrophic influences.

Changes of titin and myosin heavy chain isoform composition in skeletal muscles (m. soleus, m. gastrocnemius, m. tibialis anterior, m. psoas major) in Mongolian Gerbil (Meriones unguiculatus ) were investigated after 12-day spaceflight on board of Russian space vehicle "Foton-M3". In m. psoas and m. soleus in the gerbils from "Flight" group the expected increase in the content of fast myosin heavy chain isoforms (IIxd and IIa, respectively) were observed. No significant differences were found in the content of IIxd and IIa isoforms of myosin heavy chain in m. tibialis anterior in the gerbils from control group as compared to that in "Flight" group. An unexpected increase in the content of slow myosin heavy chain I isoform and a decrease in the content of fast IIx/d isoform in m. gastrocnemius of the gerbils from "Flight" group were observed. In skeletal muscles of the gerbils from "Flight" group the relative content of titin N2A-isoform was reduced (by 1,2-1,7 times), although the content of its NT-isoform, which was revealed in striated muscles of mammals in our experiments earlier, remained the same. When the content of titin N2A-isoform was decreased, no predictable abnormalities in sarcomeric structure and contractile ability of skeletal muscles in the gerbils from "Flight" group were found. An assumption on the leading role of titin NT-isoform in maintenance of structural and functional properties of striated muscles of mammals was made.

The significant progress in the clarification of cellular mechanisms governing tissue homeostasis and physiological remodeling was achieved in recent decades. Undifferentiated cells such as multipotent mesenchymal stromal (stem) cells (MMSCs) play an important role in these processes. MMSCs reside in virtually all postnatal organs and tissues occupying a specific tissue niche associated with the perivascular spaces. The most important property of MMSCs is, on the one hand, their ability to provide structural integrity of tissues and on the other - to respond on paracrine stimuli and migrate into the site of injury, promoting the tissue repair. The main feature of the MMSC physiological and regenerative milieu is a low oxygen tension, which can significantly modify the properties ofstromal cells. This review is concerned with analysis of the recent data on the MMSC tissue niches in terms of integration of these cells into the comprehensive physiological and reparative tissue remodeling and the role of the partial oxygen pressure in the realization of MMSCs.

Aim: Study microbicidal activity of low temperature argon plasma (LTP) that is a stream of partially ionized argon having macroscopic temperature of the environment against Chlamydia trachomatis obligate intracellular parasites. Study viability of host cells in parallel., Materials and Methods: McCoy line cells infected with C. trachomatis (Bu-434/L2 strain) were exposed to LTP obtained by using atmospheric pressure plasma SHF generator. Intracellular localization of chlamydiae was visualized by luminescent microscopy., Results: Exposure of infected McCoy line cells resulted in the destruction of chlamydia inclusions and practically complete elimination of intracellular bacteria. At the same time LTP exposure did not result in immediate death of host cells, an insignificant reduction of the number of cells was observed 24 hours after the exposure to LTP., Conclusion: The effect of LTP for elimination of intracellular chlamydia without significant changes in viability of eukaryotic host cells was demonstrated.

Systematically results and new analysis data on the investigation of human bone system in space flight, the orbital station Mir and International Space Station, are presented. The bone mineral density, bone mineral content, identified as bone mass and body composition using dual energy X-ray absorptiometry were measured. Theoretically, an expected bone mass loss in trabecular tissue of lower skeletal half may by described as a quickly developing but reversible osteopenia and considered as evidence of functional adaptation of bone tissue to the changing mechanical load. A hypothesis of main mechanisms of osteopenia in microgravity is presented. High individual variability of bone mass losses and stability of individual pattern of correlation between bone mass losses in different skeletal segments were found. It is not possible to identify the relationship between bone mass losses and duration of space missions. Therefore it is not a sufficient ground to calculate the probability of reaching the critical level of bone demineralization by prolonged space flight. The same relates to the probability of prognosis of bone quality changes. There is data about dual energy X-ray absorptiometry that is insufficient for this prognosis. The main direction of investigations is presented which might optimize the interplanetary mission from the point of view of skeletal mechanical functions preservation.

This article analyzes the physiological data using the principle of invariant relationships, to reveal the mechanisms of adaptive variability. It was used physical-chemical, biochemical, and hormonal blood parameters of cosmonauts who have committed short-term and long space flights. These results suggest that application of the methods of fractal geometry to quantitative estimates of homeostasis allows to allocate the processes depending on the increase/decrease of adaptive variability and fix the state of stability or instability of certain physiological regulatory subsystems, due to mobility and to reduce the level of stability which remains stable internal structure of relationships throughout the body.

Increasing distance between practical public health services and collecting of theoretical information in the field of biomedical researches reflects the necessity of professional contact between clinicians and scientists in many areas associated with medicine for active carrying over ("translation") of the modern basic researches in which mechanisms of basic metabolic processes and possibilities of their correction are detected, to effective medical help to individual patient, i.e., personified medicine. Such approach was called transmitting medicine. Examples of the personified medicine in which biomedical researches together with the anamnesis morbi of individual patient that are responsible for treatment strategy including doses and regimens are discussed.

The first human flight to space made by Yu. A. Gagarin on April 12, 1961 was a crucial event in the history of cosmonautics that had a tremendous effect on further progress of the human civilization. Gagarin's flight had been prefaced by long and purposeful biomedical researches with the use of diverse bio-objects flown aboard rockets and artificial satellites. Data of these researches drove to the conclusion on the possibility in principle for humans to fly to space. After a series of early flights and improvements in the medical support system space missions to the Salyut and Mir station gradually extended to record durations. The foundations of this extension were laid by systemic researches in the fields of space biomedicine and allied sciences. The current ISS system of crew medical care has been successful in maintaining health and performance of cosmonauts as well as in providing the conditions for implementation of flight duties and operations with a broad variety of payloads. The ISS abounds in opportunities of realistic trial of concepts and technologies in preparation for crewed exploration missions. At the same, ground-based simulation of a mission to Mars is a venue for realization of scientific and technological experiments in space biomedicine.

Results of application of LTP at atmospheric pressure as an antibacterial agent during the last decade are considered with reference to physicochemical mechanisms of its bactericidal action. The principles of designing modern LTP sources are described in conjunction with the results of LTP application against pathogenic bacteria in vitro and in biofilms. The possibility to destroy biofilm matrix by LTP is estimated along with the results of its testing for the treatment of acute and chronic wound surfaces. Prospects for the development of "plasma medicine" in this country and abroad are discussed with special emphasis on its advantages, such as the absence of long-acting toxic compounds, small probability of spontaneous mutations accounting for resistance to LTP, relatively low cost of LTP sources, independence of LTP effect of the surface relief, painless application.

This report is a detailed review of the current data on the mechanic and gravitational sensitivity of osteoblasts and osteogenic precursor cells in vitro. It summarizes the numerous responses of cells with an osteoblastic phenotype and osteogenic precursor cells and especially their responses to the alteration of their mechanic or gravitational surroundings. The review also discusses the osteogenic cell's pathways of signal transduction and the mechanisms of gravitational sensitivity. It was shown that the earliest multipotent stromal precursor cells of an adult organism's bone marrow can sense changes of intensity in a gravitational or mechanic field in model conditions, which may play a certain role in the development of osteopenia in microgravity.

Immediate early gene (IEG) expression is the important part of adaptive reactions caused by short-term high-intensity physical activities. IEG leads to activation of transcription, protein neo-synthesis and form-specific stress response. We were looking for human body physical exercise adaptation leukocytes IEG expression markers. Gene expression profiles were measured using microarray technology and validated by real time PCR. In this study, we describe several cell stress adaptation regulators groups: stress response, splicing and cell signaling.

In long-lasting stay in state of weightlessness the astronaut develops a moderate hypophydratation of the organism accompanied by increase production of vasopressin. Most changes of the water-salt balance and kidney function will be fast enough normalised. The synthetic agonist of vasopressin V2-receptors proved to be able to control human hydratation status. The data obtained indicate a certain efficacy of Desmopressin thus opening prospects for development of a simple pharmacological means of prophylactics of the weightlessness effect.

The paper is devoted to the role of Academician L. A. Orbeli and his school in foundation and development of extreme physiology. The works of L. A. Orbeli, his pupils and collaborators contributed to the advancement of key theoretical and applied aspects of hyperbaric physiology, flights in stratosphere, aviation physiology and medicine, space physiology and radiobiology.

Harsh environment and extreme factors related to the supposed exploration missions to Mars are considered as well as concomitant human organism reactions. Further investigations are required to get insight into the effects of gravity ranging from microgravity to hypogravity to hypergravity the crew will be exposed to during this voyage. A special emphasis should be placed on the studies of artificial gravity as an alternative to the existing in-flight countermeasures. Other issues to be attended include transitory states of human organism as a response to changes in gravity, effects of ionizing radiation and synergy of the variety of flight factors, and mechanisms of the hypomagnetic effects.

Bio-impedancemetiy was used to study dynamics of the human hydration status and body composition aboard the International space station (ISS). Body liquids in 12 Russian crewmembers were found reduced in different periods of space flight: the total, intra- and extracellular liquid volumes became less by 5.2 to 10.4% on the group average as compared with baseline values. In-flight changes in body composition also displayed a consistent pattern. While the lean mass loss was insignificant averaging 1.9-4.0%, the fatty mass gain averaged 4.6 to 8.2% in the initial three months on flight. We conclude that the human body hydration status falls along with the muscular mass reduction and fatty mass gain during long-duration space flight.

Purpose of the experiment was to define the hypothesized margins of phenotype adaptation and genotype modifications of bacteria-fungi associations that form the typical microbiota on space vehicle materials. The fundamental questions to answer were whether the selected test-cultures would remain vital after extended (comparable to the Mars mission duration) exposure in open space as part of microbesstructural material model systems, and how the space factors would affect microorganisms in the context of eco-safety of space vehicles and planetary quarantine precautions. The first extended (1.5 years) exposure of the model systems outside of the International space station proved survivability of bacterial and microfungal spores in open space. Ultrastructures of eukaryotic and prokaryotic organisms were found altered, and so were their biological properties.

The review deals with the analysis of osteodensitometry data from the cosmonauts flown on Russian space station MIR and the International space station and suppositions about involvement of different levels of metabolism regulation in bone loss triggered by insufficient mechanic loading in microgravity attendant by redistribution of body liquids. It is surmised that the initial reactions are associated with the biomechanical factor and recruitment of local mechanisms, i.e. osteocyte osteolysis and inhibition of osteoblast histogenesis. Regulation on the level of tissues and organs is responsible for destabilization of calcium homeostasis (low calcium absorption in the intestine and readsorption in the kidney). Changes in the hierarchy of ion and volume regulation may provoke osteoclast resorption which further increases osteopenia.

Fractionation of hydrogen stable isotopes was studied in 9 human subjects in a chamber with normal air pressure imitating a space cabin. Mass-spectrometry of isotopes in blood, urine, saliva, and potable water evidenced increases in the contents of heavy H isotope (deuterium) in the body liquids as compared with water. These results support one of the theories according to which the human organism eliminates heavy stable isotopes of biogenous chemical elements.

Experiments with tail-suspended female rats demonstrated that injection of sinestrol (synthesized estradiol) and myocalcic (sermon calcitonin) on a background of graded weight bearing (suspension interruption for 2 hrs. a day) prevented osteopenia in the spongy metaphyses of the shin-bone deprived of loading.

A study of water-electrolyte exchange, the condition of water milieu of the organism, and the volume- and electrolyte homeostasis regulation in space flights, and also in postflight period has shown the important role of the water-salt homeostasis in adaptation of the human and animal organism to weightlessness. Obviously, downturn of food consumption, renal excretion and the intestine output seem to be caused by suppression of activity of mechanisms of ion deposition. The most intensive changes of the liquid milieu volumes occur in the first days of weightlessness or in its ground simulation. And, with prolonged duration, the changes of extracellular liquid volume and the volume of plasma do not extend. After termination of long space flights, activation of renin-aldosterone systems occurs as well as a decrease in efficiency of antidiuretic hormone, misbalance of pressor/unpressor prostanoids. In the period of re-adaptation after space flights, development of desensitization of kidneys to endogenous ADH occurs. This is the basis for researches directed to improvement of the existing scheme of correction of the hydrogenous status of the astronaut organism in the closing stage of flight.

Results of isotope investigations of atmospheric condensate and potable water supplied from Earth confirmed the fractionating of hydrogen and oxygen stable isotopes in the organism of ISS crewmembers. Samples of ISS atmospheric condensate were characterized by altered concentrations of 18O2 and deuterium. Atmospheric deuterium quantities varied in the interval of -67 to 79 +/- 3 ppm, whereas water deuterium made up -85 +/- 3 ppm as compared with SMOW. Atmospheric condensate consists of water vapor transpired and perspired by humans. In addition, cells of crews' red blood were also found to contain increased concentrations of deuterium as compared with the deuterium content of potable water. Results of isotopes measurements in urine, blood, saliva and potable water in a chamber experiment also evidenced in favour of the body fractionating of the stable isotopes of hydrogen and oxygen.

The telemedicine concept for a mission to Mars is presented including the basic operational units and subsystems, and problems of elaboration and creation of the telemedicine system with the use of multilevel structure functional modeling.

Such models of transplantable tumors as Lewis sarcoma, uterine sarcoma-322 and uterine carcinoma-5 were used to study possible inhibitory effect by low-deuterium water. Such water was given to experimental animals (20 mice in each group). Controls (30 in each group) received tap water with standard deuterium concentrations. Low-deuterium water treatment resulted in significant inhibitory effect on volume of all tumor patterns concerned: it delayed nodule formation at transplantation site. However, no increase in survival time was obtained.

The influence of oral insulin upon carbohydrate exchange in healthy volunteers was evaluated. One of the two forms of insulin used in the study was insulin, immobilized in a volume of polyacrylamide gel, modified by ovomucoid (proteolytic enzyme inhibitor), isolated from duck eggs; the other form was enteric-coated tablets bases on hydrogel substance. The oral administration of the hydrogel substance or the tablets resulted in the fall of blood glucose concentration by 34.9 +/- 4.4% and 28.6 +/- 6.9%, respectively. The maximal effect of the hydrogel substance and the tablets was observed at the 90th and the 180th minutes.

Results of experimental studies are reviewed that point out to the leading role of the support afferents in control of structural-functional properties of the tonic muscle system. It is shown that the support afferents play a role of the trigger in the postural system, the trigger enhancing (when the support is present) or inhibiting (when the support is withdrawn) the activity of tonic motor units (MU's). Under the absence of support condition, recorded in extensors are: an obvious decline of the muscle stiffness and the maximal voluntary force; a significant decrease of the absolute force of the isometric contraction of single skin muscle fibers evoked by Ca++; a prominent decline of the tonic muscle fibers transversal size; and the transformation of the myosin phenotype from slow to fast one. Mechanical stimulation of the support zones of soles in the regimes of locomotion (slow and fast stepping) under the absence of support condition eliminates all the above effects.

Water in amount of 5 ml/100 g body weight was administered through a gastric probe into the stomach in alert rats; subjects-volunteers drank 20 ml of water per 1 kg of body weight. This resulted in diuresis at the peak of which the excreted water fraction reached 23% in rats and 12.4% in human subjects, whereas excretion of the osmotically free water amounted to 0.103 +/- 0.018 ml/min/100 g body weight and 10.0 +/- 1.8 ml/min/1.73 m2 of the body surface, respectively. These data indicate a practically complete inhibition of the arginine vasopressin secretion. On intragastric administration of 10 micrograms of arginine vasopressin or 0.2 microgram of desmopressin, with water in rats, a prolonged and quite obvious antidiuretic response occurred, with a marked increase of reabsorption of the osmotically free water in kidneys. A direct correlation has been found between the dose of the intragastrically administered vasopressin in the dose range from 0.1 to 10 micrograms/100 g body weight and a decrease of clearance of the osmotically free water. In subjects volunteers, an antidiuretic reaction to administration of 0.2 mg of desmopressin with water, was found. The data obtained provide a direct proof of intestinal absorption of nanopeptides without loss of their physiological activity. Significance of the data obtained for physiology of digestion and for clinical medicine, is discussed.