Effect of a helium and oxygen mixture on physiological parameters of rats with cerebral arterial air embolism.

Introduction: Cerebral arterial air embolism (CAE) is a serious and potentially dangerous condition that can interrupt the blood supply to the brain and cause stroke. One of the promising gas mixtures for emergency treatment of air embolism is an oxygen-helium mixture. Methods: We modeled CAE in awake rats by injecting air into the common carotid artery. Immediately after CAE, animals were either untreated or underwent hyperbaria, oxygen inhalation, heated air inhalation, or helium-oxygen mixture inhalation. Body temperature, locomotor activity, respiratory and cardiovascular parameters were monitored in the animals before CAE modeling, and 3 and 24 h after CAE modeling. Results: After 3 hours of CAE modeling in awake rats, depression of the nervous, cardiovascular and respiratory systems, as well as decreased body temperature were observed. 24 h after CAE modeling multifocal cerebral ischemia was observed. Normobaric helium-oxygen mixture inhalation, on par with hyperbaric treatment, restored body temperature, locomotor activity, respiratory volume, respiratory rate, and blood pressure 3 hours after CAE, and prevented the formation of ischemic brain damage lesions 24 h after CAE. Discussion: Thus, inhalation of a heated oxygen-helium gas mixture (O2 30% and He 70%) immediately after CAE improves the physiological condition of the animals and prevents the foci of ischemic brain damage formation.

Measurement of the Positive Muon Anomalous Magnetic Moment to 0.20 ppm.

We present a new measurement of the positive muon magnetic anomaly, a_{µ}≡(g_{µ}-2)/2, from the Fermilab Muon g-2 Experiment using data collected in 2019 and 2020. We have analyzed more than 4 times the number of positrons from muon decay than in our previous result from 2018 data. The systematic error is reduced by more than a factor of 2 due to better running conditions, a more stable beam, and improved knowledge of the magnetic field weighted by the muon distribution, ω[over ˜]_{p}^{'}, and of the anomalous precession frequency corrected for beam dynamics effects, ω_{a}. From the ratio ω_{a}/ω[over ˜]_{p}^{'}, together with precisely determined external parameters, we determine a_{µ}=116 592 057(25)×10^{-11} (0.21 ppm). Combining this result with our previous result from the 2018 data, we obtain a_{µ}(FNAL)=116 592 055(24)×10^{-11} (0.20 ppm). The new experimental world average is a_{µ}(exp)=116 592 059(22)×10^{-11} (0.19 ppm), which represents a factor of 2 improvement in precision.

Identification of specific gene methylation patterns during motor neuron differentiation from spinal muscular atrophy patient-derived iPSC.

Spinal muscular atrophy is a progressive motor neuron disorder caused by deletions or point mutations in the SMN1 gene. It is not known why motor neurons are particularly sensitive to a decrease in SMN protein levels and what factors besides SMN2 underlie the high clinical heterogeneity of the disease. Here we studied the methylation patterns of genes on sequential stages of motor neuron differentiation from induced pluripotent stem cells derived from the patients with SMA type I and II. The genes involved in the regulation of pluripotency, neural differentiation as well as those associated with spinal muscular atrophy development were included. The results show that the PAX6, HB9, CHAT, ARHGAP22, and SMN2 genes are differently methylated in cells derived from SMA patients compared to the cells of healthy individuals. This study clarifies the specificities of the disease pathogenesis and extends the knowledge of pathways involved in the SMA progression.

Genetic Risk Factors for the Development of COVID-19 Coronavirus Infection.

The COVID-19 coronavirus pandemic has spread to 215 countries around the world and caused tens of millions of infections and more than a million deaths worldwide. In the midst of COVID-19 infection, it is extremely important to identify new protein and gene targets that may be highly sensitive diagnostic and prognostic markers of the severity and outcome of the disease for combating this pandemic. Identification of individual genetic predisposition allows personalizing programs of medical rehabilitation and therapy. It has now been shown that the transmissibility and severity of COVID-19 infection can be affected by gene variants in both the human body (ACE2, HLA-B*4601, FcγRIIA, MBL, TMPRSS2, TNFA, IL6, blood group A antigen, etc.) and the virus itself (ORF8 in RNA polymerase, ORF6 in RNA primase, S, N, E proteins). The presence of mutations in the proteins of the virus can change the affinity and specificity for the binding of targeted drugs to them, being the molecular basis of individual differences in the response of the human body to antiviral drugs and/or vaccines. The review summarizes the data on the variants of the genomes of the coronavirus and humans associated with an individual predisposition to an increased or decreased risk of transmission, severity, and outcome of COVID-19 infection. Targeted drugs and vaccines being developed for the therapy of COVID-19 infection are briefly reviewed.

Measurement of the Positive Muon Anomalous Magnetic Moment to 0.46 ppm.

We present the first results of the Fermilab National Accelerator Laboratory (FNAL) Muon g-2 Experiment for the positive muon magnetic anomaly a_{µ}≡(g_{µ}-2)/2. The anomaly is determined from the precision measurements of two angular frequencies. Intensity variation of high-energy positrons from muon decays directly encodes the difference frequency ω_{a} between the spin-precession and cyclotron frequencies for polarized muons in a magnetic storage ring. The storage ring magnetic field is measured using nuclear magnetic resonance probes calibrated in terms of the equivalent proton spin precession frequency ω[over ˜]_{p}^{'} in a spherical water sample at 34.7 °C. The ratio ω_{a}/ω[over ˜]_{p}^{'}, together with known fundamental constants, determines a_{µ}(FNAL)=116 592 040(54)×10^{-11} (0.46 ppm). The result is 3.3 standard deviations greater than the standard model prediction and is in excellent agreement with the previous Brookhaven National Laboratory (BNL) E821 measurement. After combination with previous measurements of both µ^{+} and µ^{-}, the new experimental average of a_{µ}(Exp)=116 592 061(41)×10^{-11} (0.35 ppm) increases the tension between experiment and theory to 4.2 standard deviations.

Space Medicine: Scientific Foundations, Achievements, and Challenges.

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.

Generation of a spinal muscular atrophy type III patient-specific induced pluripotent stem cell line ICGi003-A.

Spinal muscular atrophy (SMA) is a genetic disease, which characterized by the degeneration of motor neurons in the spinal cord and further striated muscle atrophy. The research of the processes in diseased neurons is complicated due to the impossibility of obtaining them safely from patients. Thus, we generated SMA type III induced pluripotent stem cell lines via using non-integrated episomal plasmid vectors. The resulting cell line expresses the major pluripotency markers and can differentiate in vitro into derivatives of three germ layers. The iPSC line can be used for further studies by providing in vitro the relevant cell types.

Generation of three Duchenne muscular dystrophy patient-derived induced pluripotent stem cell (iPSC) lines ICGi002-A, ICGi002-B and ICGi002-C.

Duchenne muscular dystrophy (DMD) is a severe and rapidly progressive hereditary muscular disease with X-linked recessive inheritance, occurring mainly in males. A complete loss of dystrophin resulted from out-of-frame deletion mutations in the DMD gene leads to Duchenne muscular dystrophy. DMD induced pluripotent stem cells (iPSCs) are a suitable cell model to study muscle development and disease mechanisms underlying muscular dystrophy and to screen novel compounds with potential therapeutic effects. We generated iPSCs from a DMD patient using non-integrating episomal plasmid vectors. The obtained iPSC lines showed ESC-like morphology, expression pluripotency markers, displayed a normal karyotype and possessed trilineage differentiation potential.

[Cys-Flanked Cationic Peptides For Cell Delivery of the Herpes Simplex Virus Thymidine Kinase Gene for Suicide Gene Therapy of Uterine Leiomyoma].

Uterine leiomyoma (UL) is the most common benign tumor in women of reproductive age. Gene therapy using suicidal genes appears to be a promising approach for UL treatment. One of key factors for success of gene therapy is the right choice of genetic construct carrier. A promising group of non-viral carriers for cell delivery of expression vectors is cationic Cys-flanked peptides which form tight complexes with DNA due to electrostatic interactions and the presence of interpeptide disulfide bonds. The paper reports a comparative study of the physico-chemical, toxic, and transfectional properties of the DNA-peptide complexes obtained by matrix polymerization or oxidative polycondensation of Cys-flanked peptides using the chain growth terminator 2-amino ethanethiol. We have demonstrated the therapeutic effect of the delivery of the pPTK-1 plasmid carrying the herpes simplex virus type 1 (HSV-1) thymidine kinase gene into PANC-1, and HEK-293T cell culture as well as into primary UL cells. It has been shown that the carriers obtained by oxidative polycondensation transform primary UL cells more efficiently than those produced by matrix polymerization. Treatment with ganciclovir resulted in the death of up to 40% of UL cells transfected with the pPTK-1 plasmid. The perspectives of use of the polyR6 carrier produced by oxidative polycondensation as a tool for the development of modular peptide carriers for the purposes of UL gene therapy were discussed.

Effect of Peptide AEDG on Telomere Length and Mitotic Index of PHA-Stimulated Human Blood Lymphocytes.

We studied the effect of peptide AEDG on telomere length and mitotic index of PHA-stimulated blood lymphocytes from young (18-22 years, N=5) and middle-aged (49-54 years, N=6) men. In the younger age group, no significant changes in the mitotic index were detected, while in the middle-aged group, a decrease in this parameter was found in one case. The relative length of telomeric regions of metaphase chromosomes was evaluated by in situ fluorescence hybridization with DNA probes specific to telomeres. After incubation with peptide AEDG, significant changes in the relative telomere length were found in 7 of 11 individuals (3 cases in the younger age group and 4 cases in the middle age group). Significant increase in telomere length after exposure to peptide AEDG was revealed in 5 cases, including two individuals of the younger age group (by 41 and 55%) and three individuals of the middle age group (by 156, 18, and 76%). In one individual of the younger age group and in one of the middle-age group, a significant decrease in telomere length (by 37 and 15%, respectively) was found. A tendency to normalization of telomere lengths was noted: this parameter increased in individuals with initially lower telomere length relative to the group mean value and decreased in individuals with initially longer telomeres compared to the mean length in the group.

Generation of two spinal muscular atrophy (SMA) type I patient-derived induced pluripotent stem cell (iPSC) lines and two SMA type II patient-derived iPSC lines.

Spinal muscular atrophy (SMA) is a neuromuscular disease caused by deletion or mutation in SMN1 gene. SMA human induced pluripotent stem cells (iPSCs) represent a useful and valid model for the study of the disorder, as they provide in vitro the target cells. We generated iPSCs from a SMA type I patient and SMA type II patient by using non-integrating episomal plasmid vectors. The resulting iPSCs are episomal-free, express pluripotency markers, display a normal karyotype, retain the mutation (homozygous deletion of SMN1) and are able to differentiate into the three germ layers.

Differential DNA Hydroxymethylation in Human Uterine Leiomyoma Cells Depending on the Phase of Menstrual Cycle and Presence of MED12 Gene Mutations.

Using immunofluorescence with specific antibodies, we analyzed DNA hydroxymethylation in uncultured cells from 25 human uterine leiomyomas considering the menstrual cycle phase during surgery and the presence of MED12 gene mutations. It was found that each tumor node had specific DNA hydroxymethylation level that did not depend on the presence of mutations in MED12 gene, but depended on the phase of menstrual cycle. The degree of DNA hydroxymethylation was significantly lower in cells of leiomyomas excised during the luteal phase compared to the follicular phase (p=0.0431). Hormonal status changing at various phases of menstrual cycle is a factor affecting DNA hydroxymethylation in leiomyoma cells.

Effect of Simulated Microgravity and Lunar Gravity on Human Inspiratory Muscle Function: 'Selena-T' 2015 Study.

As a part of the multi-disciplinary "SELENA-T"-2015 Bed Rest Study, we investigated the pattern of inspiratory muscles fatigue in 22 healthy male subjects during incremental exercise test to exhaustion before and after 21 days of hypokinesia evoked by bed rest. Hypokinesia consisted of head-down bed rest (HDBR) at a minus 6° angle, simulating microgravity present on orbiting spacecraft, in 10 subjects. The remaining 12 subjects spent the first 5 days of hypokinesia in HDBR position and the subsequent 16 days in head-up bed rest (HUBR) at a plus 9.6° angle, as a presumed analog of lunar gravity that is six times less than Earth's gravity. Maximal inspiratory pressure (MIP) and electromyograms (EMG) of the diaphragm (D), parasternal (PS), sternocleidomastoid (SCM), and scalene (S) muscles served as indices of inspiratory muscle function. Before both HDBR and HUBR, exercise decreased MIP and centroid frequency (fc) of EMG (D, PS, SCM, and S) power spectrum (p < 0.05). After 3 weeks of HDBR, but not HUBR, inspiratory muscles fatigue was more expressed compared with control (p < 0.05). We conclude that HDBR lowers inspiratory muscles resistance to fatigue during high-intensity exercise while HUBR has no such effect. These changes may limit maximal ventilation and may contribute to exercise intolerance observed after prolonged simulated microgravity. The physiological mechanisms of respiratory muscle dysfunction after HDBR consist primarily of postural effects, and are not due only to hypokinesia.

A Method of Ground Simulation of Physiological Effects of Hypogravity on Humans.

A novel method of ground simulation in humans of physiological effects induced by the stay on the surface of celestial bodies with hypogravity was developed and successfully tested. This method is based on the change of gravity force angle, which decreases the gravitational component of the blood hydrostatic pressure characteristic of human vertical posture on the Earth and the load-weight onto the locomotor apparatus to the lower values expected at celestial bodies with hypogravity. The methodological requirements for ground simulation of the physiological effects of lunar gravity on human body are specified and substantiated by theoretical calculations. The experimental study revealed redistribution of liquid media in the human organism, functional changes in the cardiorespiratory system, and a decrease in the load-weight applied to the locomotor apparatus.

Detection of human genome mutations associated with pregnancy complications using 3-D microarray based on macroporous polymer monoliths.

Analysis of variations in DNA structure using a low-density microarray technology for routine diagnostic in evidence-based medicine is still relevant. In this work the applicability of 3-D macroporous monolithic methacrylate-based platforms for detection of different pathogenic genomic substitutions was studied. The detection of nucleotide replacements in F5 (Leiden G/A, rs6025), MTHFR (C/T, rs1801133) and ITGB3 (T/C, rs5918), involved in coagulation, and COMT (C/G, rs4818), TPH2 (T/A, rs11178997), PON1 (T/A rs854560), AGTR2 (C/A, rs11091046) and SERPINE1 (5G/4G, rs1799889), associated with pregnancy complications, was performed. The effect of such parameters as amount and type of oligonucleotide probe, amount of PCR product on signal-to-noise ratio, as well as mismatch discrimination was analyzed. Sensitivity and specificity of mutation detections were coincided and equal to 98.6%. The analysis of SERPINE1 and MTHFR genotypes by both NGS and developed microarray was performed and compared.

[The influence of fermented dairy whey on morphofunctional indices and physical training of sportsmen].

The aim of the study was to examine anthropometry, physical fitness, metabolism at the level of the microcirculation and adaptive processes of the organism as a whole under the inclusion of enzyme-hydrolyzed whey in the diet of 27 weightlifters 17-23 (21.7±2.7) years old, with the level of sports skills of 1 category of up to masters of sports. The body composition was determined by bioimpedance method, functioning of microcirculation system and oxygen transport were determined using the multifunction laser diagnostic complex. For analysis of heart rate variability we used complex "Varicard 2.51", physical fitness was assessed by generally accepted pedagogical tests. The products inclusion in the diet in the increasing dose of 0.5 to 1.5 g/kg of body weight within 21 days increases physical fitness. The growth of physical efficiency provided change of body composition with slight increase in muscle mass by 2% and decrease in fat component by 3.6% (p <0.05). Increasing muscle mass is the functional stimulus for the revitalization of the microcirculation system for the exchange of nutrients and energy. Under the consumption of serum the intensity of microcirculation increased by 131%, elevating dominance of active mechanisms of modulation of the flow over passive. As a result of intensive diffusion of oxygen from the blood into tissues, the saturation rate of mixed blood reduced by 7.7% and consumption of oxygen by cells of work tissues increased by 23.6%. Assimilation of nutrients and energy, adequate to physical exercises, improved functional capacity of the organism in general and extended its adaptive capacity, as evidenced by the increase of the balance of vegetative regulation of cardiac rhythm.

Functional Features of Microcirculation System and its Possibilities of Oxygen Transport in Children and Youths of Bryansk Region in Conditions of Radioecological Pressure.

The questions of influence of low radiation doses on microcirculation of blood in ontogeny of males from 7 to 27 years are presented in the article. Using the method of laser Doppler ultrasounds, optical oximetry and laser fluorescent diagnostics, we studied the blood perfusion level in the microcirculation system of 315 schoolchildren and students, considered the regulation mechanisms of microcirculation, the level of oxygen saturation of hemoglobin both in the circulation system and mixed blood, the index of oxygen utilization in tissues and the value of fluorescent use of oxygen. We received the information about the changes in the frequency of occurrence of different microcirculation types associated with the age and region of residence. In the case of higher radiation levels we marked a significant increase of individuals with the "extreme" microcirculation type (hypoemic and hyperemic) against the background of the decreased mesoemic type. A special feature of the metabolism process in children, teenagers, and youths is a decrease of the microcirculation density with an increase of the myogenic tone of metaarterioles and precapillary sphincters. The tone of arterioles grows with age. As a result of the limited blood volume, oxygen. is pulled compensatory from blood in larger amounts; it is shown from a significant decrease of the level of oxygen saturation in mixed blood. The strongest differences are shown for the hypoemic and hyperemic microcirculation type. Dwelling on the areas with radio-ecological pressure is accompanied by an increase in the fluorescent index of oxygen use. The level of the total oxygen use in these individuals is higher than in those living in radiation favorable areas.

[Murine peritoneal neutrophil activation upon tungsten nanoparticles exposure in vivo].

Two examples of tungsten carbide nanoparticles (d = 15 nm, 50 nm) and tungsten carbide nanoparticles with 8% cobalt (d = 50 nm) have been found to induce the neutrophil activation 3 h and 36 h after intraperitoneal administration in the doses 0.005; 0.025; 0.05; 0.25; 0.5; 1; 2.5 and 5 microgram per 1 gram body weight to FVB mice. Neutrophil activation was calculated based on the CD11b and S100 antigen expression. Effect of nanoparticles is bimodal for all tested examples.

[Genetic and epigenetic news in gerontology].

The overview represents the recent most conspicuous findings in aging studies. It includes new data on the whole genome association studies (GWAS) in big cohort of centenaries, recently found mutation protecting from Alzheimer disease, discovery of hypothalamus as a command center of human aging, very important data on the negative effect of common antioxidants in the treatment of lung cancer as well as new data concerning antiaging and anticancer effects of common drugs such as rapamycine and metformin. Substantial part of the review is devoted to the epigenetic problems of senescence and feasible impact of basic epigenetic mechanisms (methylation of DNA and histone proteins, DNA heterochromatization) in regulation of gene expression, long-term genome reprogramming during early childhood, and transgeneration transmission of epigenetic traits. The necessity of transition from molecular studies of dormant human genome (anatomy of human genome) to genome in action (dynamic genome) and thus with special emphasis to epigenetic medicine is stressed.

[Structural-functional characteristics of cervical vessels in hypertensive patients under changed atmospheric pressure].

The ultrasonic location technique was used to measure intima-media thickness (IMT), as well as internal systolic diameter of and linear blood velocity in the cervical arteries in people with initial hypertension. Correlation analysis elicited a temporal contingency between these parameters and daily average values of atmospheric pressure. Thus, common carotid artery IMT tended to increase on high-pressure days. Besides, diameters of the common and internal carotid arteries, and vertebral artery were narrowed and, consequently, linear blood velocity in these vessels increased. This relationship is more evident in men than women and in elderly subjects than young. These results are suggestive of a vasoconstrictive action of high atmospheric pressure on these arteries. The relationship is not universal, as it is nonlinear for diameter of the internal carotid artery and inverse for the external one. This implies different sensitivity of arteries to the factor under study and possible blood redistribution in the arterial basin depending on external pressure. The relationship was observed equally on the day of investigation and previous days, which points to its temporal stability.