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Here in, we have designed two new unfused non-fullerene small molecules based on asymmetric benzo[1,2-b:3.4-b', 6,5-b"]trithiophene (BTT) central donor core and different terminal units, i.e. 2-(3-oxo-2,3-dihydro-1H-inden-1-ylidene)malononitrile (NFA-4) and 1,3-diethyl-2-thioxodi hydropyrimidine-4,6(1H,5H)-dione (NFA-5) and their optical and electrochemical properties were investigated. Employing a wide band-gap copolymer D18, the binary D18: NFA-4 and D18:NFA-5 bulk heterojunction-based organic solar cells realized an overall power conversion efficiency of about 17.07% and 11.27 %, respectively. The higher value of power conversion efficiency for the NFA-4-based organic solar cells, as compared to the NFA-5 counterpart, is attributed to the enhanced values of short circuit current, open circuit voltage, and fill factor. After the incorporation of NFA-5 into the binary bulk heterojunction D18:NFA-4, the ternary organic solar cells attained a power conversion efficiency of 18.05 %, which is higher than that for the binary counterparts and attributed to the increased values of short circuit current, fill factor, and open circuit voltage. The increased value of short circuit current is associated with the effective utilization of excitons through the energy transfer from the NFA-5 to NFA-4 as the NFA-4 exhibits a more significant dipole moment than the NFA-5 and is effectively dissociated into a free charge carrier., (© 2024 Wiley‐VCH GmbH.)

Malaria-causing protozoa of the genus Plasmodium have exerted one of the strongest selective pressures on the human genome, and resistance alleles provide biomolecular footprints that outline the historical reach of these species 1 . Nevertheless, debate persists over when and how malaria parasites emerged as human pathogens and spread around the globe 1,2 . To address these questions, we generated high-coverage ancient mitochondrial and nuclear genome-wide data from P. falciparum, P. vivax and P. malariae from 16 countries spanning around 5,500 years of human history. We identified P. vivax and P. falciparum across geographically disparate regions of Eurasia from as early as the fourth and first millennia BCE, respectively; for P. vivax, this evidence pre-dates textual references by several millennia 3 . Genomic analysis supports distinct disease histories for P. falciparum and P. vivax in the Americas: similarities between now-eliminated European and peri-contact South American strains indicate that European colonizers were the source of American P. vivax, whereas the trans-Atlantic slave trade probably introduced P. falciparum into the Americas. Our data underscore the role of cross-cultural contacts in the dissemination of malaria, laying the biomolecular foundation for future palaeo-epidemiological research into the impact of Plasmodium parasites on human history. Finally, our unexpected discovery of P. falciparum in the high-altitude Himalayas provides a rare case study in which individual mobility can be inferred from infection status, adding to our knowledge of cross-cultural connectivity in the region nearly three millennia ago., (© 2024. The Author(s).)

GP40141 is a romiplostim biosimilar. A Phase 1 clinical trial was previously conducted in healthy volunteers to evaluate the pharmacodynamics (PD), pharmacokinetics (PK), and safety of GP40141 compared to the reference romiplostim (NCT05652595). Using noncompartmental analysis, the biosimilarity of PD end points was determined according to the classical criterion (0.8-1.25). PK end points were also in good agreement between GP40141 and the reference romiplostim; however, the confidence interval for the area under concentration-time curve from time 0 to the time of last measurement was slightly out of the bioequivalence range (0.91-1.29). Population PK/PD was used in the present study to characterize the individual PK and PD data of 56 healthy subjects in 2 cross-over periods of the Phase 1 clinical trial. Body weight and neutralizing antibodies to romiplostim were found to be important predictors of apparent volume of distribution and linear elimination constant, respectively. Within the framework of the conducted modeling, population estimates of PK/PD parameters were obtained, which were in agreement with literature data for the reference romiplostim. Additionally, values of intersubject variability, previously unreported for romiplostim in a healthy subject population, were derived. Covariate analysis, conducted during model development, as well as visual diagnostics and model-based simulations, demonstrated the absence of significant differences in PK and PD between GP40141 and romiplostim-ref., (© 2024, The American College of Clinical Pharmacology.)

Objective: Aim: To assess, analyze and present early postoperative results of transcatheter aortic valve implantation in patients with aortic stenosis., Patients and Methods: Materials and Methods: During the period from 2017 to 2023, we examined in total 77 patients with severe aortic stenosis and high risk of surgery who were eligible for the TAVI procedure at the "Heart Institute Ministry of Health of Ukraine"., Results: Results: Before implantation, the mean and maximum aortic valve gradients were 53.7±19.1 mm Hg and 90.1±28.8 mm Hg, respectively. The mean and maximum aortic valve gradients after implantation were 9.67±3.18 and 18.7±6.41, respectively (p<0.001). The calculated left ventricular ejection fraction was 57.5±8.22% before surgery and 58.8±7.91% after surgery (p=0.412). After the procedure, moderate (2) degree of paravalvular aortic regurgitation was observed in 2 patients and light degree - in 21 patients. Before surgery, mitral regurgitation of 2-3 degrees was observed in 15 patients, and only in two patients after TAVI The survival rate of our patients was 96.4% after 180 days of supervision. In-hospital and 30-day mortality was 1.8%, while 180-day mortality was 3.6%. No deterioration was observed in patients with moderate aortic regurgitation during echocardiographic studies performed at 1, 3 and 6 months after TAVI., Conclusion: Conclusions: TAVI is rapidly emerging as a life-saving alternative for patients who are inoperable or at high risk of surgery due to comorbidities. The selection of patients for TAVI is important to optimize procedural and long-term outcomes. It is important for cardiologists in our country to refer patients with severe aortic stenosis after diagnosis to centers that perform TAVI.

Objective: . Aim: The choice of aortic valve stenosis correction method is determined by a number of clinical and technical parameters. The task was to compare early postoperative outcomes in patients after correction of aortic valve stenosis using TAVI and surgical aortic valve replacement with a biological prosthesis., Patients and Methods: Materials and Methods: This retrospective study analyzed the medical records of adult patients (18 years of age and older) who had transcatheter aortic valve implantation or surgical aortic valve replacement with a biological prosthesis at the State Institution "Heart Institute of the Ministry of Health" in the period from 2018 to 2022., Results: Results: In 47 (47.5%) cases, TAVI was performed and in 52 (52.5%) cases, SAVR with a biological prosthesis was performed. Patients who underwent TAVI were significantly older (p=0.002) and had a higher EuroSCORE II operative risk score (p<0.001). In patients with TAVI, larger diameter aortic valve prostheses were significantly more often used compared with the SAVR group with biological prosthesis (27.5±2.74 vs. 22.5±1.84, p<0.001). The early postoperative period in patients with TAVI was characterized by an 11.4% (p=0.046) and 15.4% (p=0.006). The length of stay in the ICU (p=0.024), as well as the duration of hospitalization in general (p=0.005), was also significantly lower in patients with TAVI compared with patients with biological prosthesis SAVR., Conclusion: Conclusions: Despite the higher surgical risk of surgery according to EuroSCORE II, TAVI was characterized by a lower incidence of postoperative complications, with shorter duration of stay in ICU and hospitalization in general in comparison with patients undergoing SAVR with a biological prosthesis.

Polymer microgels, micrometer-sized cross-linked polymer particles, are considered to be a promising type of advanced materials for a wide range of applications. To enhance the microgels' applicability, it is essential to incorporate various functional groups into a microparticle polymer network. Yet, the availability of functional groups for the interaction with surroundings depends strongly on the properties of the polymer network and has a great impact on further effective usage. In this theoretical study, we address this question and, with the help of coarse-grained molecular dynamics computer simulations, assess the segmental mobility and accessibility of functional groups bound to polymer network depending on microgel architecture and solvent quality. Additionally, we evaluate the minimum number of functional groups needed to facilitate the hopping mechanism between the functional groups (i.e., charge transfer). As an example of practical implementation of the obtained results, we estimate the optimal network topology for redox-active microgels to provide the maximum charge capacity for the dispersion electrolyte in redox-flow batteries.

Aims: The pharmacodynamic (PD) similarity between GP40141, a proposed romiplostim biosimilar, and reference romiplostim was evaluated. Pharmacokinetics and safety were also assessed., Methods: In this phase 1, randomized, double-blind, single-dose, crossover comparative study with an adaptive design, 56 healthy male volunteers were randomized 1:1 to receive a 3 ug × kg -1 subcutaneous dose of GP40141 and reference romiplostim. The PD similarity between GP40141 and the reference romiplostim was determined using the standard equivalence criteria (80%-125%) for the area under the platelet count-time curve from time 0 to the time of the last sampling for PD (AUC plt ) and the maximum observed platelet count (P max )., Results: GP40141 and the reference romiplostim exhibited similar PD profiles. 90% CI for the geometric mean ratios for the primary PD parameters (AUC plt, P max ) for GP40141 (T) and the reference romiplostim (R) were fully contained within the predefined equivalence limits of 80%-125%: 98.13%-102.42% for AUC plt and 97.56%-105.80% for P max . The pharmacokinetic profiles of GP40141 and the reference romiplostim were well described. No adverse events were observed during the clinical trial after the administration of GP40141 and the reference romiplostim., Conclusion: This study demonstrates the PD similarity of GP40141 to the reference romiplostim. Both treatments had comparable safety profiles (NCT05652595)., (© 2023 GEROPHARM. Pharmacology Research & Perspectives published by British Pharmacological Society and American Society for Pharmacology and Experimental Therapeutics and John Wiley & Sons Ltd.)

Phenol-soluble modulins (PSMs) are virulent peptides secreted by staphylococci that undergo self-assembly into amyloid fibrils. This study focuses on Staphylococcus aureus PSMα1 and PSMα3, which share homologous sequences but exhibit distinct amyloid fibril structures. Upon subjecting PSMα1 to an 80°C heat shock, it fibrillates into cross-β structures, resulting in the loss of cytotoxic activity. Conversely, PSMα3 cross-α fibrils undergo reversible disaggregation upon heat shock, leading to the recovery of cytotoxicity. The differential thermostability probably arises from the presence of hydrogen bonds along the β-strands within the β-sheets of the cross-β fibrils. We propose that the breakdown of PSMα3 fibrils into soluble species, potentially co-aggregating with membrane lipids, is crucial for its toxic process and enables the reversible modulation of its biological activity under stress conditions. In contrast, the formation of robust and irreversible cross-β fibrils by PSMα1 corresponds to its role in biofilm stability. These findings emphasize how the unique fibril morphologies and thermostability of PSMα1 and PSMα3 shape their functional roles in various environments of S. aureus ., Competing Interests: All authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Rayan, Barnea, Khokhlov, Upcher and Landau.)

Selective blocking of individual isoforms of carbonic anhydrase (CA) is now one of the main directions in the development of its inhibitors. The new 1,2,4-oxadiazole-containing sulfonamides B12 and B13 predominantly block CA II and CA IX. The study of acute toxicity of B12 and B13 showed their safety. Substance B13 caused a relatively short-term, but rapid (within 30 min) decrease in the intraocular pressure in rabbits, which indicates the promise of its use for the emergency decrease in the intraocular pressure in medical practice. Analysis of the effects of sulfonamides on the functions of CNS showed that compound B12 probably exhibit tranquilizing activity; B13 is promising for the creation of drugs that have an antidepressant effect and at the same time increase the mental and physical performance., (© 2023. Springer Science+Business Media, LLC, part of Springer Nature.)

Modern humans have populated Europe for more than 45,000 years 1,2 . Our knowledge of the genetic relatedness and structure of ancient hunter-gatherers is however limited, owing to the scarceness and poor molecular preservation of human remains from that period 3 . Here we analyse 356 ancient hunter-gatherer genomes, including new genomic data for 116 individuals from 14 countries in western and central Eurasia, spanning between 35,000 and 5,000 years ago. We identify a genetic ancestry profile in individuals associated with Upper Palaeolithic Gravettian assemblages from western Europe that is distinct from contemporaneous groups related to this archaeological culture in central and southern Europe 4 , but resembles that of preceding individuals associated with the Aurignacian culture. This ancestry profile survived during the Last Glacial Maximum (25,000 to 19,000 years ago) in human populations from southwestern Europe associated with the Solutrean culture, and with the following Magdalenian culture that re-expanded northeastward after the Last Glacial Maximum. Conversely, we reveal a genetic turnover in southern Europe suggesting a local replacement of human groups around the time of the Last Glacial Maximum, accompanied by a north-to-south dispersal of populations associated with the Epigravettian culture. From at least 14,000 years ago, an ancestry related to this culture spread from the south across the rest of Europe, largely replacing the Magdalenian-associated gene pool. After a period of limited admixture that spanned the beginning of the Mesolithic, we find genetic interactions between western and eastern European hunter-gatherers, who were also characterized by marked differences in phenotypically relevant variants., (© 2023. The Author(s).)

Objective: Evaluation of the bioequivalence of the tested Relonova, tablets, 10 mg and Maxalt, tablets, 10 mg drugs on an empty stomach in healthy volunteers., Material and Methods: The pharmacokinetic analysis population included 40 volunteers, the safety analysis population included 40 volunteers. The average age of randomized volunteers (men - 20, women - 20) was 29.3±8.9 years, height 1.71±0.09 m, body weight 70.86±11.66 kg, mean BMI 24.18±2.81 kg/m 2 . The method used high performance liquid chromatography with tandem mass spectrometric detection. Statistical analysis of the obtained data was performed based on the assumption of a log-normal distribution of the parameters AUC0-72 and Cmax., Results: The ratio of geometric means for the key pharmacokinetic parameters (AUC0-t, AUC0-inf and Cmax) of rizatriptan is close to 90%, CI is within the acceptable range for bioequivalent drugs (80-125%). The intrasubject variability (CVintra) for rizatriptan was 23.74% (Cmax), 10.94% (AUC0-t). The average profiles of the pharmacokinetic curves of rizatriptan when taking the test and reference drugs have similar shapes. Relonova and reference Maxalt are bioequivalent., Conclusion: The results of the study make it possible to recommend Relonova for further clinical study and wide practical application.

This clinical case presents the results of using the Occlutech PLD occluder for transcatheter closure of a paravalvular leak (PVL) via a transapical approach in the remote period after mitral valve prosthetics. According to our results and to the literature, the procedure for closing the PVL of the mitral valve from a transapi¬cal approach using a special Occlutech PLD occluder is characterized by relative safety for patients, clinical effectiveness in terms of eliminating or reducing the degree of regurgitation and related symptoms.

Aortic valve stenosis occurs in about 3% of people over 65. It is the most important heart valve disease in developed countries. Pathogenesis includes processes similar to those in atherosclerosis, including lipid accumulation, inflammation and calcification., A Case Report: In this study, we describe the case transcatheter aortic valve implantation in a 73-year-old patient after mitral valve replacement and tricuspid valve repair 15 years ago., Conclusions: Transcatheter aortic valve implantation is an effective method of surgical treatment of elderly patients with aortic stenosis with a high risk of mortality in traditional surgical correction of defects. This type of treatment can be widely used in repeated interventions, where there is an adhesion process, technical complexity and a significant risk of complications. This method of treatment minimizes side effects and shortens the patient's rehabilitation period., (© 2022 MEDPRESS.)

COVID-19 has had a significant impact on health care systems, including drug use. The present study aimed to evaluate the patterns of community supply of antimicrobials from community pharmacies during the COVID-19 pandemic in five cities of Russia. In a cross-sectional study, a random sample of pharmacies reported all episodes of antimicrobials supply during a one-week period. Patterns of supply (age and gender of customer, drug name and formulation, prescription availability, indication, etc.) were analyzed. Altogether, 71 pharmacies took part in the study and 5270 encounters were recorded. In total, 4.2% of visits resulted in supply of more than one antimicrobial agent and 5.2% were for parenteral formulations. The rate of prescription-based purchase in participated cities varied from 40.5 to 99.1%. Systemic antibiotics and antivirals accounted for the majority of supplies (60.5 and 26.3%, respectively). Upper respiratory tract infections were reported as the indication for antimicrobials usage in 36.9% of cases, followed by skin and soft tissue infections (12.1%) and urinary tract infections (8.7%); COVID-19 accounted for 8.4% of all supplies. Amoxicillin with clavulanic acid, azithromycin and amoxicillin were indicated as the top three antimicrobials purchased for upper respiratory tract infections, and azithromycin, umifenovir and levofloxacin were the top three for COVID-19. In general, a high rate of drugs dispensing without prescription was revealed. Antibiotics for systemic use remained the most common antimicrobials, whereas presumably viral upper respiratory tract infections were the main reason for their purchase. COVID-19 infection itself was responsible for a small proportion of the supply of antimicrobial agents, but systemic antibiotics accounted for more than a half of supplies.

The study was carried out to assess the state of cardiologic care and to determine current vectors of its development in the region with low population density. The health care system of the Kostroma Oblast was determined as research base. The information and methodological foundation of the study was compiled according results of special studies of patients aged from 8 to 80 years (n=1,400). The combination of research methods was implemented. The main vectors of the modern development of the cardiology service are identified: regional automated monitoring of quality of cardiologic care with operational analysis of its potential by 25 conjugated factors; implementation of continuous quality management technology according proposed algorithm; implementation of the decision-making scheme with allocation of 10 alternatives of achieving effectiveness of medical care according 4 criteria (standard performance, clinical result achievement, patient satisfaction, resources saving);, implementation of personalized approach to patient management.

During the Early Bronze Age, populations of the western Eurasian steppe expanded across an immense area of northern Eurasia. Combined archaeological and genetic evidence supports widespread Early Bronze Age population movements out of the Pontic-Caspian steppe that resulted in gene flow across vast distances, linking populations of Yamnaya pastoralists in Scandinavia with pastoral populations (known as the Afanasievo) far to the east in the Altai Mountains 1,2 and Mongolia 3 . Although some models hold that this expansion was the outcome of a newly mobile pastoral economy characterized by horse traction, bulk wagon transport 4-6 and regular dietary dependence on meat and milk 5 , hard evidence for these economic features has not been found. Here we draw on proteomic analysis of dental calculus from individuals from the western Eurasian steppe to demonstrate a major transition in dairying at the start of the Bronze Age. The rapid onset of ubiquitous dairying at a point in time when steppe populations are known to have begun dispersing offers critical insight into a key catalyst of steppe mobility. The identification of horse milk proteins also indicates horse domestication by the Early Bronze Age, which provides support for its role in steppe dispersals. Our results point to a potential epicentre for horse domestication in the Pontic-Caspian steppe by the third millennium BC, and offer strong support for the notion that the novel exploitation of secondary animal products was a key driver of the expansions of Eurasian steppe pastoralists by the Early Bronze Age., (© 2021. The Author(s).)

Purpose: To investigate the possibilities of pharmacoeconomic and pharmacogenetic factors monitoring to assess the effectiveness of treatment of a cardiological profile patients as a part of the implementation of a personalized approach., Material and Methods: 200 patients with arterial hypertension and CHD were examined. Pharmacotherapy was analyzed. ABC/VEN and DDD analysis, pharmacoeconomic analysis were applied. Genetic analysis of the polymorphism of the genes CYP2D6*4 and CYP2D6*10 encoding the subfamily of the cytochrome isoenzyme Р-450 was carried out. An original monitoring method was used to assess the effect of pharmacoeconomic and pharmacogenetic factors on the performance of cardiac care., Results: When conducting a pharmacoeconomic analysis of cases of cardiac care, it was found that the costs of drug therapy are significant and take over 10% of the total costs. However, its effectiveness is insufficient in 58% of cases in inpatient and 37% in outpatient care. The analysis showed that there is an inverse mean correlation between gene polymorphism and clinical performance of cardiac care (r = -0.62) and a direct strong correlation between polypharmacy in pharmacotherapy, not accounting for interdrug interaction and clinical performance (r = 0.89).

The formation of heterogeneous nematic and smectic liquid crystals in the general case of an arbitrary geometry is investigated in the framework of molecular-statistical approach [Emelyanenko and Khokhlov, J. Chem. Phys. 142, 204905 (2015)JCPSA60021-960610.1063/1.4921684]. The molecular aspects of the orientational and translational orderings at the curved surfaces of small solid objects dispersed in liquid crystal are considered, and the differential equations for gradients of the order parameters in vicinities of the small objects are presented in the general form. The five elastic constants are obtained within the same approach, from which we were able to predict that a significant space variations of the order parameters can be observed within the 0.5-0.8μm area around any small object, almost independently of its own dimension. Therefore, the liquid crystals can be a simple tool for the optical visualization of nano-objects. It is also demonstrated that the kind of molecular self-organization (smectic, nematic or conventionally isotropic) at the surfaces of small solid objects can be different from that in the bulk of mesogenic material. Totally we predict eight various combinations of simple states at the surfaces and in the bulk depending on the solid objects' size and temperature. It is also shown that the surfaces of 10μm-size solid objects and larger act almost as flat surfaces, while the surfaces of 1μm-size solid objects and smaller act almost as point defects.

Introduction: Tuberculosis (TB) is one of the top ten causes of death worldwide. Improvement of the treatment options via development of new drugs and treatment regimens that would be more convenient for patients is one of key options of improving the effecacy of the TB prevention and careis. Since the creation of new treatment regimens by minimizing the number of the drugs used and reducing the duration of treatment is the most promising and correct direction, macozinone, a new candidate of the benzothiazinone series, can become the basis for development of new chemotherapy regimens for drug-resistant forms of TB including the combination of macozinone with the most effective modern anti-TB drugs., Aim: Comparative evaluation of the pharmacokinetic properties of macozinone capsules 80 mg and the new dosage form a dispersible tablet for preparation of oral solution., Materials and Methods: Solubility of the substance macozinone in biorelevant media in vitro, permeability of macozinone in the test Caco-2 in vitro, as well as pharmacokinetics of macozinone in dogs in vivo were evaluated., Results: The solubility assessment in biorelevant media showed that the average limit of macozinone substance dissolution in the pH 5.0 acetate buffer solution was from 6 to 9 mg/l, in FaSSIF medium (fasted) from 2.5 to 4 mg/l, and in FeSSIF medium (after meals) from 16.8 to 29 mg/l. It is established that the cell permeability of the pharmaceutical substance macozinone in the CACO-2 test system is on average 2.510-6cm/s in the forward direction from the apical to basolateral cell membrane, and 1.510-6cm/s in the reverse direction, which corresponds to low permeability. The main pharmacokinetic parameters of macozinone dispersable tablets 160 mg, after dosing with food and on an empty stomach, as well as capsules 80 mg, when administered on an empty stomach in vivo studies in dogs are presented., Discussion: The specific physicochemical properties of macozinone, the problems of developing the new dosage form, as well as ways of solving some of them are presented., Conclusion: In the process of new dosage forms development, the existing chemical properties of the macozinone substance should be considered. One of the promising ways of increasing bioavailability and, consiquently, efficacy is development a fundamentally new drug form with modified release within the absorption window.

Tuberculosis is a chronic infectious disease, usually localized in the respiratory system and representing one of the most important global social and biomedical health problems associated with the spread of therapy-resistant forms (multidrug-resistant and extensively drug-resistant tuberculosis). One of the most promising targets for the development of antimycobacterial drugs is the enzyme DprE1, which is involved in the synthesis of the cell wall of mycobacteria. In the series of DprE1 inhibitor drugs, the most advanced drug is PBTZ169 (INN maсozinone). Clinical trials (CT) of the efficacy and safety of macozinone are conducted by the pharmaceutical company LLC NEARMEDIC PLUS in the Russian Federation, and in other countries (Sponsors: Innovative Medicines for Tuberculosis Foundation, cole polytechnique fdrale de Lausanne and Bill and Melinda Gates Foundation). The publication describes results of completed I, IIa and Ib phases CT, conducted in the Russian Federation., Aim: The goal of phase I CT was to assess the safety, tolerability and pharmacokinetics (PK) of PBTZ169, 40 mg capsule, after single and multiple administration under fasting conditions in increasing doses in healthy volunteers. The goal of phase IIa CT was to study the efficacy (in terms of early bactericidal activity EBA), safety and PK of the drug PBTZ169, 80 mg capsules, in various doses, when used as monotherapy in patients with newly diagnosed respiratory tuberculosis with bacterial excretion and retained sensitivity to isoniazid and rifampicin. The purpose of phase Ib CT was to evaluate the safety, tolerability, PK of PBTZ169, 80 mg capsule, after single, double and multiple administration under fasting conditions in increasing doses, as well as the effect of food on its bioavailability in healthy volunteers., Materials and Methods: The data of 100 healthy volunteers and 15 patients with newly diagnosed pulmonary tuberculosis, who received the study medication PBTZ169, capsules 40 mg and 80 mg, in the dose range 40 mg 1280 mg of PBTZ169, obtained during phase I, IIa and Ib CTs were analyzed. During I phases CTs, safety, tolerability, and PK of the drug after a single and multiple administration under fasting condition and after meals at rising doses were evaluated. The safety assessment included evaluation of AE/SAE, vital signs, ECG results, and laboratory tests results in the safety population. In the course of phase IIa CT, in addition to safety, tolerance, and PK evaluation, the efficacy of the drug (in terms of EBA) using sputum culture on agar with CFU/ml counting (main method) and quantitative PCR method (auxiliary method) was evaluated., Results: During all CTs, a high safety and tolerability profile was shown, the main PK parameters of the drug and the efficacy were described. PBTZ169 demonstrated linear PK in the dosage range up to 640 mg after single and multiple administration, a statistically significant of EBA of the drug after monotherapy at the dose of 640 mg/day was demonstrate, and it was concluded that the preferred regimen of the drug PBTZ169 intake is administration after meals. Good tolerability and a favorable safety profile of the drug in the studied doses range were demonstrate during all the CTs., Conclusion: One of the most promising and currently studied drugs-inhibitors of DprE1, a new target for the cell wall of mycobacteria, is PBTZ169 or macozinone, which is being develop by the Russian pharmaceutical company NEARMEDIC PLUS ltd.

It has been hypothesized that the Neolithic transition towards an agricultural and pastoralist economy facilitated the emergence of human-adapted pathogens. Here, we recovered eight Salmonella enterica subsp. enterica genomes from human skeletons of transitional foragers, pastoralists and agropastoralists in western Eurasia that were up to 6,500 yr old. Despite the high genetic diversity of S. enterica, all ancient bacterial genomes clustered in a single previously uncharacterized branch that contains S. enterica adapted to multiple mammalian species. All ancient bacterial genomes from prehistoric (agro-)pastoralists fall within a part of this branch that also includes the human-specific S. enterica Paratyphi C, illustrating the evolution of a human pathogen over a period of 5,000 yr. Bacterial genomic comparisons suggest that the earlier ancient strains were not host specific, differed in pathogenic potential and experienced convergent pseudogenization that accompanied their downstream host adaptation. These observations support the concept that the emergence of human-adapted S. enterica is linked to human cultural transformations.

Thermoresponsivity of chitosan induced by β-glycerophosphate (GP) in diluted aqueous solutions has been first studied by high-sensitivity differential scanning calorimetry. It has been found that the GP solutions of chitosan undergo a first-order phase transition upon heating. The onset of this transition coincides with the cloud point of the system. This allows one to identify the thermoresponsivity of chitosan as a macroscopic demonstration of the phase separation transition. The transition temperature, enthalpy, heat capacity increment, and width were determined as functions of GP and chitosan concentrations, and the dielectric constant of the solvent. Based on this data, we suggested that GP binds cooperatively to the chitosan matrix at low temperatures. The standard free energy of GP binding (Δ b g int = -6 ± 1 kJ mol -1 ) was estimated from the DSC data. It was shown that the Okada-Tanaka model of cooperative hydration of polymers adequately describes the thermogram of the GP induced phase transition of chitosan., (Copyright © 2019 Elsevier Ltd. All rights reserved.)

The point of view of the author of this article, who participates in the work of several scientific journals, on the current situation with publishing articles by scientists of various specialties is presented. Two approaches to this problem are considered: "informal" (focused only on the quality of published manuscripts) and "formal" (taking into account mainly the scientometric indicators of both authors and journals). The continuous commercialization of this process, associated with the emergence of a huge number of publications that require significant article processing charges from scientists to publish the results of their research, is noted. At the same time, the financial interests of publishers promote reducing the requirements for reviewing and editing articles submitted to the editorial board. It is emphasized the need for the appropriate formal scientometric indicators for researchers applying for grants as well as for the corresponding positions and titles, which has arisen at the present stage. According to the author, excessive attention to such formal rankings does not improve the effectiveness of scientific publications, negatively affecting, in particular, the process of blind peer reviewing, grammar and style of manuscripts, statistical processing of data given in articles, design of illustrations, as well as the quality of reference lists., Competing Interests: COMPLIANCE WITH ETHICAL STANDARDSThe author declares that he has no conflicts of interest., (© Allerton Press, Inc. 2020, ISSN 0096-3925, Moscow University Biological Sciences Bulletin, 2020, Vol. 75, No. 4, pp. 159–163. © Allerton Press, Inc., 2020.Russian Text © The Author(s), 2020, published in Vestnik Moskovskogo Universiteta, Seriya 16: Biologiya, 2020, Vol. 75, No. 4, pp. 195–199.)

By sequencing 523 ancient humans, we show that the primary source of ancestry in modern South Asians is a prehistoric genetic gradient between people related to early hunter-gatherers of Iran and Southeast Asia. After the Indus Valley Civilization's decline, its people mixed with individuals in the southeast to form one of the two main ancestral populations of South Asia, whose direct descendants live in southern India. Simultaneously, they mixed with descendants of Steppe pastoralists who, starting around 4000 years ago, spread via Central Asia to form the other main ancestral population. The Steppe ancestry in South Asia has the same profile as that in Bronze Age Eastern Europe, tracking a movement of people that affected both regions and that likely spread the distinctive features shared between Indo-Iranian and Balto-Slavic languages., (Copyright © 2019 The Authors, some rights reserved; exclusive licensee American Association for the Advancement of Science. No claim to original U.S. Government Works.)

The origin of Yersinia pestis and the early stages of its evolution are fundamental subjects of investigation given its high virulence and mortality that resulted from past pandemics. Although the earliest evidence of Y. pestis infections in humans has been identified in Late Neolithic/Bronze Age Eurasia (LNBA 5000-3500y BP), these strains lack key genetic components required for flea adaptation, thus making their mode of transmission and disease presentation in humans unclear. Here, we reconstruct ancient Y. pestis genomes from individuals associated with the Late Bronze Age period (~3800 BP) in the Samara region of modern-day Russia. We show clear distinctions between our new strains and the LNBA lineage, and suggest that the full ability for flea-mediated transmission causing bubonic plague evolved more than 1000 years earlier than previously suggested. Finally, we propose that several Y. pestis lineages were established during the Bronze Age, some of which persist to the present day.

A biaxial surface potential Φ&#95;{s} of smectic-C^{*} surface-stabilized ferroelectric liquid crystals (SSFLCs) is introduced in this paper to explain the experimentally observed electric-field dependence of polarization P[over ̃]&#95;{cell}(E), in particular the shape of the static hysteresis loops. Our potential consists of three independent parts. The first nonpolar part Φ&#95;{n} describes the deviation of the prime director n (which is the most probable orientation of the long molecular axes) from the easy alignment axis R, which is located in the boundary surface plane. It is introduced in the same manner as the uniaxial Rapini potential. The second part Φ&#95;{p} of the potential is a polar term associated with the presence of the polar axis in a FLC. The third part Φ&#95;{m} relates to the inherent FLC biaxiality, which has not been taken into consideration previously. The Φ&#95;{m} part takes into account the deviations of the secondary director m (which is the most probable orientation of the short molecular axes) from the normal to the boundary surface. The overall surface potential Φ&#95;{s}, which is a sum of Φ&#95;{n},Φ&#95;{p}, and Φ&#95;{m}, allows one to model the conditions when either one, two, or three minima of the SSFLC cell free energy are realized depending on the biaxiality extent. A monodomain or polydomain structure, as well as the bistability or monostability of SSFLC cells, depends on the number of free-energy minima, as confirmed experimentally. In this paper, we analyze the biaxiality impact on the FLC alignment. We also answer the question of whether the bistable or monostable structure can be formed in an SSFLC cell. Our approach is essentially based on a consideration of the biaxial surface potential, while the uniaxial surface potential cannot adequately describe the experimental observations in the FLC.

By means of computer modelling, the self-organization of dense planar brushes of macromolecules with amphiphilic monomer units was addressed and their state diagram was constructed. The diagram of states includes the following regions: disordered position of monomer units with respect to each other, strands composed of a few polymer chains and lamellae with different domain spacing. The transformation of lamellae structures with different domain spacing occurred within the intermediate region and could proceed through the formation of so-called parking garage structures. The parking garage structure joins the lamellae with large (on the top of the brushes) and small (close to the grafted surface) domain spacing, which appears like a system of inclined locally parallel layers connected with each other by bridges. The parking garage structures were observed for incompatible A and B groups in selective solvents, which result in aggregation of the side B groups and dense packing of amphiphilic macromolecules in the restricted volume of the planar brushes.

It is well known that the number of dividing cells in an organism decreases with age. The average rate of cell division in tissues and organs of a mature organism sharply decreases, which is probably a trigger for accumulation of damage leading to disturbance of genome integrity. This can be a cause for the development of many age-related diseases and appearance of phenotypic and physiological signs of aging. In this connection, the protein poly(ADP-ribosyl)ation system, which is activated in response to appearance of various DNA damage, attracts great interest. This review summarizes and analyzes data on changes in the poly(ADP-ribosyl)ation system during development and aging in vivo and in vitro, and due to restriction of cell proliferation. Special attention is given to methodological aspects of determination of activity of poly(ADP-ribose) polymerases (PARPs). Analysis of relevant publications and our own data has led us to the conclusion that PARP activity upon the addition of free DNA ends (in this review referred to as stimulated PARP activity) is steadily decreasing with age. However, the dynamics of PARP activity measured without additional activation of the enzyme (in this review referred to as unstimulated activity) does not have such a clear trend: in many studies, the presented differences are statistically non-significant, although it is well known that the number of unrepaired DNA lesions steadily increases with aging. Apparently, the cell has additional regulatory systems that limit its own capability of reacting to DNA damage. Special attention is given to the influence of the cell proliferative status on PARP activity. We have systematized and analyzed data on changes in PARP activity during development and aging of an organism, as well as data on differences in the dynamics of this activity in the presence/absence of additional stimulation and on cellular processes that are associated with activation of these enzymes. Moreover, data obtained in different models of cellular aging are compared.

Polymer-dispersed liquid crystal composites have been a focus of study for a long time for their unique electro-optical properties and manufacturing by "bottom-up" techniques at large scales. In this paper, nematic liquid crystal oblate droplets with conical boundary conditions (CBCs) under the action of electric field were studied by computer simulations and polarized optical microscopy. Droplets with CBCs were shown to prefer an axial-bipolar structure, which combines a pair of boojums and circular disclinations on a surface. In contrast to droplets with degenerate planar boundary conditions (PBCs), hybridization of the two structure types in droplets with CBCs leads to a two-minima energy profile, resulting in an abrupt structure transition and bistable behavior of the system. The nature of the low-energy barrier in droplets with CBCs makes it highly sensitive to external stimuli, such as electric or magnetic fields, temperature, and light. In particular, the value of the electric field of the structure reorientation in droplets with CBCs was found to be a few times smaller than the one for droplets with PBCs, and the droplet state remained stable after switching off the voltage.

Parkinson's disease (PD) is a movement disorder, mainly affecting population consisting of the aged. PD occurs chiefly due to progressive loss of dopaminergic neurons in nigrostriatal pathway. Largely, PD patients suffer from non-motor symptoms, such as depression, anxiety, fatigue, and sleep disorders, that needs further investigation and addressing during PD research. Depression in PD is a predominant and complex symptom, and its pathology exists extrinsic to the nigrostriatal system. This disease can  ultimately be managed by a combination of regular physiotherapy and proper medication. Taking together the present scenario of PD, including the nature of disease, characteristics, treatment, diagnosis of the patients with PD, these outcomes were reviewed to be explored along with many speech-based solutions to PD in this study. This neurodegenerative disorder needs advancement in  research and development which  can help patients with PD to lead a normal life.

During the 1 st millennium before the Common Era (BCE), nomadic tribes associated with the Iron Age Scythian culture spread over the Eurasian Steppe, covering a territory of more than 3,500 km in breadth. To understand the demographic processes behind the spread of the Scythian culture, we analysed genomic data from eight individuals and a mitochondrial dataset of 96 individuals originating in eastern and western parts of the Eurasian Steppe. Genomic inference reveals that Scythians in the east and the west of the steppe zone can best be described as a mixture of Yamnaya-related ancestry and an East Asian component. Demographic modelling suggests independent origins for eastern and western groups with ongoing gene-flow between them, plausibly explaining the striking uniformity of their material culture. We also find evidence that significant gene-flow from east to west Eurasia must have occurred early during the Iron Age.

Purpose: The article aims to provide the history, organization, and approaches to clinical pharmacology in the Russian Federation., Methods: This article is based on major international and Russian documents, along with groundbreaking historical facts and scientific articles related to the development of modern clinical pharmacology the Russian Federation., Findings: Improving the quality of drug therapy is the main goal of clinical pharmacology in the Russian Federation. Decisions of the World Health Organization, scientific achievements, and the work of well-known scientists among the world community and in the Russian Federation have strongly influenced the development of clinical pharmacology the Russian Federation. Clinical pharmacology in the Russian Federation addresses a wide range of problems; it actively engages in modern scientific research, education; and clinical practice. Clinical pharmacologists participate in studies of new drugs and often have a specific area of expertise., Implications: The future development of clinical pharmacology in the Russian Federation will be related to improvements in training, refinement of the framework that regulates clinical pharmacologists, and the creation of clinical pharmacology laboratories with modern equipment., (Copyright © 2016 Elsevier HS Journals, Inc. All rights reserved.)

Ancient DNA makes it possible to observe natural selection directly by analysing samples from populations before, during and after adaptation events. Here we report a genome-wide scan for selection using ancient DNA, capitalizing on the largest ancient DNA data set yet assembled: 230 West Eurasians who lived between 6500 and 300 bc, including 163 with newly reported data. The new samples include, to our knowledge, the first genome-wide ancient DNA from Anatolian Neolithic farmers, whose genetic material we obtained by extracting from petrous bones, and who we show were members of the population that was the source of Europe's first farmers. We also report a transect of the steppe region in Samara between 5600 and 300 bc, which allows us to identify admixture into the steppe from at least two external sources. We detect selection at loci associated with diet, pigmentation and immunity, and two independent episodes of selection on height.

The Bronze Age of Eurasia (around 3000-1000 BC) was a period of major cultural changes. However, there is debate about whether these changes resulted from the circulation of ideas or from human migrations, potentially also facilitating the spread of languages and certain phenotypic traits. We investigated this by using new, improved methods to sequence low-coverage genomes from 101 ancient humans from across Eurasia. We show that the Bronze Age was a highly dynamic period involving large-scale population migrations and replacements, responsible for shaping major parts of present-day demographic structure in both Europe and Asia. Our findings are consistent with the hypothesized spread of Indo-European languages during the Early Bronze Age. We also demonstrate that light skin pigmentation in Europeans was already present at high frequency in the Bronze Age, but not lactose tolerance, indicating a more recent onset of positive selection on lactose tolerance than previously thought.

We generated genome-wide data from 69 Europeans who lived between 8,000-3,000 years ago by enriching ancient DNA libraries for a target set of almost 400,000 polymorphisms. Enrichment of these positions decreases the sequencing required for genome-wide ancient DNA analysis by a median of around 250-fold, allowing us to study an order of magnitude more individuals than previous studies and to obtain new insights about the past. We show that the populations of Western and Far Eastern Europe followed opposite trajectories between 8,000-5,000 years ago. At the beginning of the Neolithic period in Europe, ∼8,000-7,000 years ago, closely related groups of early farmers appeared in Germany, Hungary and Spain, different from indigenous hunter-gatherers, whereas Russia was inhabited by a distinctive population of hunter-gatherers with high affinity to a ∼24,000-year-old Siberian. By ∼6,000-5,000 years ago, farmers throughout much of Europe had more hunter-gatherer ancestry than their predecessors, but in Russia, the Yamnaya steppe herders of this time were descended not only from the preceding eastern European hunter-gatherers, but also from a population of Near Eastern ancestry. Western and Eastern Europe came into contact ∼4,500 years ago, as the Late Neolithic Corded Ware people from Germany traced ∼75% of their ancestry to the Yamnaya, documenting a massive migration into the heartland of Europe from its eastern periphery. This steppe ancestry persisted in all sampled central Europeans until at least ∼3,000 years ago, and is ubiquitous in present-day Europeans. These results provide support for a steppe origin of at least some of the Indo-European languages of Europe.

The transitions between smectic, nematic, and isotropic phases are investigated in the framework of a unified molecular-statistical approach. The new translational order parameter is different from the one introduced in K. Kobayashi [Phys. Lett. A 31, 125 (1970)] and W. L. McMillan [Phys. Rev. A 4, 1238 (1971)]. The variance of the square sine of intermolecular shift angle along the director is introduced to take self-consistently into account the most probable location of the molecules with respect to each other, which is unique for every liquid crystal (LC) material and is mainly responsible for the order parameters and phase sequences. The mean molecular field was treated in terms of only two parameters specific to any intermolecular potential of elongated molecules: (1) its global minimum position with respect to the shift of two interacting molecules along the director and (2) its inhomogeneity/anisotropy ratio. A simple molecular model is also introduced, where the global minimum position is determined by the linking groups elongation Δ/d, while the inhomogeneity/anisotropy ratio Gβ/Gγ is determined by the ratio of electrostatic and dispersion contributions. All possible phase sequences, including abrupt/continuous transformation between the smectic and nematic states and the direct smectic-isotropic phase transition, are predicted. The theoretical prediction is in a good agreement with experimental data for some simple materials correlating with our molecular model, but it is expected to be valid for any LC material.

It was found first that macromolecules made of amphiphilic monomer units could form spontaneously an ultra-thin layer on the surface which the macromolecules are grafted to. The width of such layer is about double size of monomer unit consisting of hydrophilic A (repulsive) and hydrophobic (attractive) B beads. The hydrophilic A beads are connected in a polymer chain while hydrophobic B beads are attached to A beads of the backbone as side groups. Three characteristic regimes are distinguished. At low grafting density, the macromolecules form ultra-thin micelles of the shape changing with decrease of distance d between grafting points as following: circular micelles-prolonged micelles-inverse micelles-homogeneous bilayer. Those micelles have approximately constant height and specific top-down A-BB-A structure. At higher grafting density, the micelles start to appear above the single bilayer of amphiphilic macromolecules. The thickness of grafted layer in these cases is different in different regions of grafting surface. Only at rather high density of grafting, the height of macromolecular layer becomes uniform over the whole grafting surface. The study was performed by computer modeling experiments and confirmed in framework of analytical theory.

In this paper the three new narrow bandgap D–A conjugated copolymers P1, P2 and P3 based on different weak donor fused thiophene-imidazole containing derivatives and the same benzothiadiazole acceptor unit were synthesized by Stille cross-coupling polymerization and characterized by 1H NMR, elemental analysis, GPC, TGA, DSC. These copolymers exhibit intensive absorbance in the range 350–900 nm and the optical bandgap lies in the range of 1.50–1.61 eV, which corresponds to the maximum photon flux of the solar spectrum. The electrochemical bandgap derived from cyclic voltammetry varies within the limits 1.47–1.65 eV and is approximately very close to the optical bandgap. The highest occupied molecular orbital (HOMO) energy level of all copolymers is deep lying (−5.24 eV and −5.37 eV and −5.25 eV for P1, P2 and P2, respectively) which shows that copolymers have good stability in the air and assured a higher open circuit voltage (Voc) for polymer BHJ solar cells. These copolymers were used as donors along with PC71BM and the BHJ polymer solar cells based on P1:PC71BM, P2:PC71BM and P3:PC71BM processed from chloroform (CF) solvent with 3 v% DIO as an additive showed an overall PCE of 4.55%, 6.76% and 5.16%, respectively.

Achalasia is a progressive oesophageal motility disorder of unstudied aetiology involving the smooth muscle layer of the oesophagus. Insufficient knowledge of the pathogenesis of achalasia and the lack of clear treatment approaches has led to an increase of advanced disease forms. Common clinical manifestations of the disease are: incomplete LES relaxation, non-specific initial manifestations and as a result late medical seeking. Occurrence of achalasia cardiae is significantly low, therefore it is important to analyse the available clinical data. The article presents an experience of treatment of 30 patients over the last 16 years of observation. The average age of patients was 50, 5 years; insignificant male predominance is noted. III or IV disease state was diagnosed in 86.7% of patients; this diagnosis was confirmed by esophagogastroduodenoscopy. In the group of 24 patients who underwent attempted endoscopic dilatation of the cardiae, most of the included patients with stage II and III disease. Immediate good and satisfactory results of endoscopic treatment were obtained in 20 patients (83.3%), in 4 cases (16.7%) developed recurrent disease.

An algorithm involving classical molecular dynamics simulations with mapping and reverse mapping procedure is here suggested to simulate the crosslinking of the polystyrene dissolved in dichloroethane by monochlorodimethyl ether. The algorithm comprises consecutive stages: molecular dynamics atomistic simulation of a polystyrene solution, the mapping of atomistic structure onto coarse-grained model, the crosslink formation, the reverse mapping, and finally relaxation of the structure dissolved in dichloroethane and in dry state. The calculated values of the specific volume and the elastic modulus are in reasonable quantitative correspondence with experimental data.

In general, bio-macromolecules are composed of hydrophilic and hydrophobic moieties and are confined within small cavities, such as cell membranes and intracellular organelles. Here, we studied the self-organization of macromolecules having groups with different affinities to solvents under spherical nano-scale confinement by means of computer modeling. It is shown that depending on the interaction parameters of monomer units composed of side- and main-chain monomer groups along a single linear macromolecule and on cavity size, such amphiphilic polymers undergo the conformational transitions between hollow nanospheres, rod-like and folded cylindrical structures, and a necklace conformation with and without a particular ordering of beads. The diagram of the conformations in the variables the incompatibility parameter of monomer units and the cavity radius is constructed.

There is a viewpoint that suppression of the proliferative capacity of cells and impairment of the regeneration of tissues and organs in aging are a consequence of specially arisen during evolution mechanisms that reduce the risk of malignant transformation and, thus, protect against cancer. We believe that the restriction of cell proliferation in an aging multicellular organism is not a consequence of implementing a special program of aging. Apparently, such a program does not exist at all and aging is only a "byproduct" of the program of development, implementation of which in higher organisms suggests the need for the emergence of cell populations with very low or even zero proliferative activity, which determines the limited capacity of relevant organs and tissues to regenerate. At the same time, it is the presence of highly differentiated cell populations, barely able or completely unable to reproduce (neurons, cardiomyocytes, hepatocytes), that ensures the normal functioning of the higher animals and humans. Apparently, the impairment of regulatory processes, realized at the neurohumoral level, still plays the main role in the mechanisms of aging of multicellular organisms, not just the accumulation of macromolecular defects in individual cells. It seems that the quality of the cells themselves does not worsen with age as much as reliability of the organism control over cells, organs and tissues, which leads to an increase in the probability of death.

There is a viewpoint that suppression of the proliferative capacity of cells and impairment of the regeneration of tissues and organs in aging are a consequence of specially arisen during evolution mechanisms that reduce the risk of malignant transformation and, thus, protect against cancer. At the same time, senescent cells of the body begin to accumulate a variety of macromolecular defects, which, conversely, increase the likelihood of their transformation into cancer cells. Thus, according to the point, the restriction of cell proliferation is a double-edged sword, which, on the one hand, reduces the likelihood of developing cancer at an early age, but on the other hand--limits life span due to the accumulation of "damaged" cells in old age. However, it remains unclear why normal human cells in vitro, with none of the mentioned "anticancer" barriers functioning at the organismal level only, NEVER undergo spontaneous malignant transformation. In addition, it is also unclear how the freshwater hydra which, under certain conditions, has really no postmitotic and senescent cells, escapes both aging and cancer and, at such conditions (excluding the need for sexual reproduction), can live almost indefinitely, having a great regenerative potential (new organism can arise even from a 1/100 of the old one). I believe that the restriction of cell proliferation in an aging multicellular organism is not a consequence of implementing a special program. Apparently, there is no special program of aging. It is only a "byproduct" of the program of development, implementation of which in higher organisms suggests the need for the emergence of cell populations with very low or even zero proliferative activity, which determines the limited capacity of relevant organs and tissues to regenerate. At the same time, it is the presence of highly differentiated cell populations, barely able or completely unable to reproduce (neurons, cardiomyocytes, hepatocytes), that ensures the normal functioning of the higher animals and humans. Even the regeneration of these organs with the help of stem cells could lead to a breach of the necessary interactions in complex systems. Reductionism in experimental-gerontological research ("everything is determined by deleterious changes in single cells") that has become widespread in recent decades, stimulated the emergence of a number of model systems for studying mechanisms of aging in isolated cells (Hayflick phenomenon, the model of "stationary phase aging", the cell-kinetic model for testing geroprotectors and geropromoters, etc.). However, at present it seems that the data obtained in such models cannot be automatically applied to the situation in the whole organism. Apparently, the impairment of regulatory processes, realized at the neurohumoral level, still plays the main role in the mechanisms of aging of multicellular organisms, not just the accumulation of macromolecular defects in individual cells. It is possible that it is the deterioration of such regulation that may be the cause of the observed abnormal INCREASE of the intensity of proliferation of some cell populations in old age, resulting in senile acromegaly and age-related rise of numerous benign tumors. It seems that the quality of the cells themselves does not worsen with age as much as reliability of the organism CONTROL over cells, organs and tissues, which leads to an increase in the probability of death.

In order to study the effect of microgravity on the proliferation of mammalian osteosarcoma cells and osteoblasts, the changes in cell proliferation, spindle structure, expression of MAD2 or BUB1, and effect of MAD2 or BUB1 on the inhibition of cell proliferation is investigated by keeping mammalian osteosarcoma cells and osteoblasts under simulated microgravity in a rotating wall vessel (2D-RWVS) bioreactor. Experimental results indicate that the effect of microgravity on proliferation inhibition, incidence of multipolar spindles, and expression of MAD2 or BUB1 increases with the extension of treatment time. And multipolar cells enter mitosis after MAD2 or BUB1 is knocked down, which leads to the decrease in DNA content, and decrease the accumulation of cells within multipolar spindles. It can therefore be concluded that simulated microgravity can alter the structure of spindle microtubules, and stimulate the formation of multipolar spindles together with multicentrosomes, which causes the overexpression of SAC proteins to block the abnormal cells in metaphase, thereby inhibiting cell proliferation. By clarifying the relationship between cell proliferation inhibition, spindle structure and SAC changes under simulated microgravity, the molecular mechanism and morphology basis of proliferation inhibition induced by microgravity is revealed, which will give experiment and theoretical evidence for the mechanism of space bone loss and some other space medicine problems.

The processes that lead to violation of genome integrity are known to increase with age. This phenomenon is caused both by increased production of reactive oxygen species and a decline in the efficiency of antioxidant defense system as well as systems maintaining genome stability. Accumulation of different unrepairable genome damage with age may be the cause of many age-related diseases and the development of phenotypic and physiological signs of aging. It is also clear that there is a close connection between the mechanisms of the maintenance of genome stability, on one hand, and the processes of spontaneous tumor formation and lifespan, on the other. In this regard, the system of protein poly(ADP-ribosyl)ation activated in response to a variety of DNA damage seems to be of particular interest. Data accumulated to date suggest it to be a kind of focal point of cellular processes, guiding the path of cell survival or death depending on the degree of DNA damage. This review summarizes and analyzes data on the involvement of poly(ADP-ribosyl)ation in various mechanisms of DNA repair, its interaction with progeria proteins, and the possible role in the development of spontaneous tumors and lifespan determination. Special attention is given to the relationship between various polymorphisms of the human poly(ADP-ribose) polymerase-1 gene and longevity.

Currently, gerontologists, evaluating the effectiveness of various impacts on the aging process, as a rule, use a variety of molecular cell biomarkers of aging. This provides much more rapid results than in the case of the survival curve obtaining. However, in many cases the usefulness of these biomarkers of aging is grounded in works devoted to what is called cellular/cell senescence. Unfortunately, the evolution of the term in recent years has led to the loss, to a large extent, of its original meaning, that is the changes of the cells during their replicative senescence ("on Hayflick's grounds"), similar to the changes of cells in the aging organism. At present, most of the work in this area is related to the induction of the relevant changes in the cells (usually transformed) by various DNA damaging factors. Such an approach, although is very important to define a strategy to fight cancer, but, yet again, takes us away from the study of the real mechanisms of organismal aging. In addition, there are reasons to believe that the biomarkers of aging, proposed by these studies (and in particular, the most popular of them--the activity of senescence-associated beta-galactosidase), are related, as a rule, to the proliferative status of the cells, which in the whole body is generally determined by proper implementing the program of development and differentiation, leading to the emergence of tissues and organs composed of postmitotic or very slowly proliferating cells. Therefore, the possible disabling the aging program, apparently, will not lead to any changes in the age dynamics of those biomarkers of aging. This conclusion brings us back to the need for obtaining the survival curves of experimental animals or humans as the only true (although the most time- and money-consuming) approach to evaluating the effectiveness of the modification of the aging process.

We selected all case histories of patients living in the area served by the Syktyvkar policlinic #3 and treated in Republican Cardiological Dispensary in 2003-2009 with diagnosis of myocardial infarction (MI). Data on survival of patients after MI (mean duration of follow-up 4.6 years) was derived from information on date and cause of death of patients obtained from statistical office of the policlinic. Overall we analyzed data on 778 patients (46.3% women, mean age 63.7 years). For detection of independent factors related to lethal outcome we used binary logistic regression, for assessment of survival we used Kaplan-Meier method and Cox regression model of proportional hazards. From positions of gender differences we assessed pharmacoepidemiology of MI, efficacy of thrombolytic therapy, determined factors of hospital and long term mortality. No increase of risk of hospital or long term mortality associated with female sex was revealed by multifactorial analysis. Greatest prognostic significance in relation to unfavorable outcome irrespective of patients sex was established for the following factors: age, severity of MI course, severity of renal dysfunction. In acute period of MI in addition to these factors we revealed unfavorable influence of hyperglycemia and protective role of preceding hypertensive disease.

Postmastectomy syndrome often follows the radical surgery oа the breast cancer. The intersection of the branches of the intercostal nerve is an infrequent cause of the postmastectomy syndrome development. We studied the long-term follow up results in 30 patients after radical mastectomy by Madden with preservation of the branches of the intercostal nerve on the level of Th1-Th3. The method demonstrated the decrease of the postmastectomy syndrome and the improvement of quality of life.