Antibiotics from Extremophilic Micromycetes.

Extremophilic microorganisms, which are capable of functioning normally at extremely high or low temperatures, pressure, and in other environmental conditions, have been in the focus of microbiologists' attention for several decades due to the biotechnological potential of enzymes inherent in extremophiles. These enzymes (also called extremozymes) are used in the production of food and detergents and other industries. At the same time, the inhabitants of extreme econiches remained almost unexplored for a long time in terms of the chemistry of natural compounds. In recent years, the emergence of new antibiotic-resistant strains of pathogens, which affect humans and animals has become a global problem. The problem is compounded by a strong slowdown in the development of new antibiotics. In search of new active substances and scaffolds for medical chemistry, researchers turn to unexplored natural sources. In recent years, there has been a sharp increase in the number of studies on secondary metabolites produced by extremophiles. From the discovery of penicillin to the present day, micromycetes, along with actinobacteria, are one of the most productive sources of antibiotic compounds for medicine and agriculture. Many authors consider extremophilic micromycetes as a promising source of small molecules with an unusual mechanism of action or significant structural novelty. This review summarizes the latest (for 2018-2019) experimental data on antibiotic compounds, which are produced by extremophilic micromycetes with various types of adaptation. Active metabolites are classified by the type of structure and biosynthetic origin. The data on the biological activity of the isolated metabolites are summarized.

Genetic Specificity of the Siberian Forest Reindeer (Rangifer tarandus valentinae Flerov, 1932) of the Kuznetsk Alatau.

This is the first study to show the genetic identity of the Altai-Sayan population of the forest reindeer of the Kuznetsk Alatau (Rangifer tarandus valentinae). The population is characterized by the existence of unique mitochondrial lines, the absence of signs of introgression of domestic rein deer mtDNA, as well as a low level of genetic diversity. In the sample studied, only two nucleotide substitutions (both of them transitions) were revealed, the nucleotide diversity (0.0015 ± 0.00136) was almost ten times lower than in most populations of wild reindeer in Russia and was comparable only with that of some wild reindeer populations of Norway and Svalbard. The haplotype diversity (h) was also relatively low (0.615 ± 0.102).

[Epidemiological and clinical aspects of diagnosis, treatment and prophylaxis of imported malaria cases in Russian Federation].

Actually one of the main tasks of health workers in the field of the tropical diseases prevention (malaria) is early detection of malaria imported cases and efficacious treatment. In order to prevent the re-establishment of local malaria transmission by Anopheles mosquitoes from imported malaria cases, and fatal cases of disease there is develop and implement the Case Management Protocol of malaria diagnosis and treatment (2014, 2019) based on long-term experience of epidemiologists and clinicians, taking into account recommendations of WHO (2013, 2015). In this article the main principles of diagnosis and treatment of different malaria species Plasmodium falciparumand Plasmodium vivax-malaria, prophylaxis measures of autochthonous cases from imported cases of the word endemic region are discussed.

Effect of Type 2 Diabetes Mellitus on Five-Year Survival of Patients Hospitalized Because of Acute Decompensated Heart Failure.

OBJECTIVE: To assess the impact of type 2 diabetes mellitus (T2DM) on prognosis of patients hospitalized because of acute decompensated heart failure (ADHF). MATERIALS AND METHODS: We analyzed data of the hospital register of ADHF which comprised information on 735 patients (254 [35%] with T2DM) consecutively admitted in 2010-2011. Median follow-up was 1790 days. RESULTS: The presence of T2DM was associated with increased risk of death: during the index hospitalization due to ADHF (hazard ratio [HR] 1.7, 95% confidence interval [CI] 1.0-2.8), within 18 months (HR 1.4, 95% CI 1.0-1.8), and within 5 years (HR 1.3, 95% CI 1.0-1.5). CONCLUSIONS: T2DM is common among acute decompensated heart failure patients (up to 35% of cases). T2DM is an independent risk factor of death during the index hospitalization and over the next 18 months and 5 years.

Problems of clinical diagnosis and treatment of P. falciparum malaria in Russian Federation.

AIM: To study the causes of falciparum malaria deaths in Russian Federation and to optimize therapy for severe forms of the disease. MATERIALS AND METHODS: The analysis of falciparum malaria cases with deaths recorded in Russian Federation from 2013 to 2017 was conducted. The results of optimization of pathogenetic therapy of severe forms of falciparum malaria for the prevention of adverse outcomes in the intensive care unit of the Infectious Clinical Hospital №2 of Moscow in 44 patients with severe course are presented. Treatment, clinical laboratory and instrumental investigations were carried out in accordance with our intensive care protocol, which took into account the current WHO recommendations. RESULTS: From 2013 to 2017 there were nine deaths from falciparum malaria reported in patients from African countries (6) and India (3). In Russia, due to the lack of effective drugs of artemisinin group, quinine with tetracycline or doxycycline is used for etiotropic therapy of patients with complicated form of falciparum malaria. In the management of such patients, the basis for treatment was the prevention of ischemic, reperfusion injuries of organs and hemorrhagic complications. In the infectious clinical hospital №2 of Moscow, since 2007, the intensive care unit has developed and tested a protocol for intensive therapy in patients with severe and complicated forms of falciparum malaria, including preventive methods of extracorporeal hemocorrection with prolonged veno-venous hemodiafiltration therapy and plasmapheresis, as a result of which the mortality rate decreased from 84 to 6.8. CONCLUSION: The country's lack of anti-malarial drugs, the insufficient awareness of the population about the risk of infection and measures to prevent malaria, late referral of cases for medical care and errors of clinical diagnosis and treatment annually lead to fatal outcomes. In such situation, the experience of optimizing the treatment of severe falciparum malaria is particularly useful, allowing decreasing the mortality.

[Effect of Type 2 Diabetes Mellitus on Five­Year Survival of Patients Hospitalized Because of Acute Decompensated Heart Failure].

OBJECTIVE: To assess the impact of type 2 diabetes mellitus (T2DM) on prognosis of patients hospitalized because of acute decompensated heart failure (ADHF). MATERIALS AND METHODS: We analyzed data of the hospital register of ADHF which comprised information on 735 patients (254 [35%] with T2DM) consecutively admitted in 2010-2011. Median follow­up was 1790 days. RESULTS: The presence of T2DM was associated with increased risk of death: during the index hospitalization due to ADHF (hazard ratio [HR] 1.7, 95% confidence interval [CI] 1.0-2.8), within 18 months (HR 1.4, 95% CI 1.0-1.8), and within 5 years (HR 1.3, 95% CI 1.0-1.5). CONCLUSIONS: T2DM is common among acute decompensated heart failure patients (up to 35% of cases). T2DM is an independent risk factor of death during the index hospitalization and over the next 18 months and 5 years.

[(INDUCED MALARIA)].

Induced malaria continues to be one of the most pressing public health problems in malaria-endemic countries. Ma- laria parasites remain viable in stored blood at a temperature of 2-6°C for 3 weeks. The paper presents current problems associated with transfusion-induced malaria. In the USSR and then in the Russian Federation, sporadic cases of induced malaria (Plasniodium vivax, P.malariae, rarely P.falciparum) were notified (230 cases in 1958 to 1990 and only 5 in 1991 to 2016). Current (immunological and molecular) methods for the laboratory diagnosis of malaria do not provide a 100% detection rMfteor its pathogens; therefore, it is necessary to search for highly efficient, rapid, and low-cost diagnostic methods to ensure the biological safety of donation.

[(INTRODUCTION OF RESEARCH RESULTS INTO THE TRAINING OF PHYSICIANS IN THE SPECIALTY OF PARASITOLOGY)].

The paper presents the results of theoretical and practical studies into parasitology, which were conducted at the E.I.Martsinovsky Institute of Medical Parasitology, Tropical and Vector-Borne Diseases and then used for the training of specialists with higher medical education at the Department of Tropical Medicine and Parasitic Diseases, I.M.Sechenov First Moscow State Medical University. The need to develop professional skills is related to the increasing learning require- ments due to socioeconomic conditions and the epidemiological situation in the country.

[(THE IMPACT OF MIGRATION PROCESSES ON- BIOSAFETY AND HUMAN HEALTH)].

Infectious diseases are one of the serious threats to biosafety in modern society In recent years, there have been con- siderably increased international migrations: tourism and pilgrimage; labor migration flows; migration of refugees and settlers in times of armed conflicts, household migrations because of family ties and traditions. Since the number of Rus- sian tourists and migrants from endemic countries remains high, these contingents should receive special attention in the malaria epidemiological surveillance system. The paper discusses the risks of possible consequences of population migra- tions and prevention measures.

[(EXPERIENCE WITH GEOGRAPHIC INFORRMATION SYSTEMS USED IN EPIDEMIOLOGICAL STUDIES (AS AN EXAMPLE OF MALARIA AND DIROFILARIASIS)].

The effective application of GIS against parasitic diseases requires the patterns of spread of parasitic diseases in certain natural, climatic, and socioeconomic conditions of different regions where there are epidemically effective carriers. The epidemiological parameters defining a high risk of an epidemiological process after P.vivax importation into Russia were calculated using the developed HealthMapper controlled module with a database. Analysis of the average long-term air temperatures in the administrative territories of Russia over 78 years, namely July, the warmest month of the year when there are the largest numbers of all types of mosquito vectors and high levels of microfilaria in the peripheral blood of in- fected dogs (definitive hosts), has shown that the northern border of the maximum possible area of dirofilariasis in Russia is most fully described by the +14C July isotherm.

[The Mechanisms of Transgenerational Inheritance and Their Potential Contribution to Human Phenotypes].

As of today, classical genetics has already completed the majority of groundwork to describe the laws of inheritance, identify the causes of many human diseases, and dissect the mechanisms of transfer of genetic information from parents to offspring. However, recent studies indicate that inheritance of phenotypic traits may also occur through nongenetic factors, in particular, through epigenetic factors, that manifest their effects in a transgenerational fashion. This review discusses findings in the area of transgenerational inheritance that open a new era in modern genetics. We discuss the mechanisms of transgenerational inheritance, including DNA methylation, histone modifications, and noncoding RNA transfer, and give an overview of the approaches to detect transgenerational effects in humans.

[MALARIA IMPORTATION BY RUSSIA'S CITIZENS AND FOREIGNERS, INTO THE CITIES AND TOWNS OF THE RUSSIAN FEDERATION].

A total of 436 malaria cases, including 12 from the CIS countries and 424 from far foreign countries (of Africa and Central and South-East Asia), were imported into the Russian Federation in 2010-2014. Most (96.6%) cases were notified in the urban areas of 52 administrative subjects of Russia. The largest number of the imported cases were seasonal workers (39.2%), tourists (31.3%), students and foreign postgraduate students (19.5%), and ship or aircraft crews (10%). During a short malaria transmission season (June to August), there were 150 cases of different types, out of them there were only 63 cases of tertian malaria (its pathogen is Plasmodium vivax, to which malaria mosquitoes of Russia's fauna are susceptible). The relatively small number of infection sources in the short transmission (June to August) season of malaria, its importation into low-susceptibility large towns, and a small proportion of imported vivax malaria cases substantially reduce the risk of malaria in the highrisk areas of the country.

SCIENTIFIC AND PRACTICAL STUDIES OF MALARIA IN THE CIS COUNTRIES AND GEORGIA.

The paper presents the scientific studies of malaria pathogens and vectors, which have been specially conducted in the endemic areas of the CIS countries and Georgia for use in an epidemiological surveillance system. The main ones investigate the structure of malaria foci and the level of G-6-PD deficiency among residents, determine the malariogenic potential. of the territory and the risk of infection in the population, and specify the taxonomy, systematics, and spread of major malaria vectors in .the countries ofWHO European Region. In addition, the time and magnitude of manifestations of long-term post-incubation tertian malaria were established; th6 susceptibility of P.vivax to antimalarials and the levels of resistance and irritability of malaria vectors to insecticides were studied. The experience in using a geographic information system for the epidemiological surveillance of malaria is given.

[Antimicrobial Activity of Substances Produced by Trichoderma citrinoviride Strain VKPM F-1228: Optimization of Cultivation and Assessment of Spectrum of Individual Peptaibols].

The Trichoderma citrinoviride VKPM F-1228 strain produces a complex of peptide-based antibiotics with antibacterial and antimycotic action. Synthesis of peptaibols is closely related to the conidiogenesis in the culture. The optimal procedure of the strain cultivation for production of peptaibols is stationary growing for 14 days at a temperature of 28 degrees C and pH 7.5 followed by formation of a dense mycelium film on the modified Saburo medium containing 30 gr/l of glucose and 12.5 gr/l of peptone. Eight individual peptaibols were extracted. The spectrum of their activity was estimated with the use of opportunistic bacteria and micromycetes as well as pathogenic clinical aspergilli. Compounds 9, 13, 14, 15 and 16 were shown active against opportunistic fungi and bacteria including methicillin resistant S. aureus, whereas compounds 9, 13 and 14 in addition showed antimycotic activity against clinical aspergilli.

[CHANGES IN LIFESTYLE FACTORS AFFECT THE LEVELS OF NEUROPEPTIDES, INVOLVED IN THE CONTROL OF EATING BEHAVIOR, INSULIN RESISTANCE AND LEVEL OF CHRONIC SYSTEMIC INFLAMMATION IN YOUNG OVERWEIGHT PERSONS].

The continuous rise of overweight and obesity is a major concern for present and future healthcare management. The aim of our study was to evaluate the influence of lifestyle changes on central regulatory mechanisms of maintaining energy homeostasis, insulin resistance and chronic systemic inflammation in 18-25 year old overweight patients. The anthropometric measurements were done for each patient, including body weight, height, waist circumference (WC), hip circumference (HC), waist to hip ratio, and body mass index (BMI). Patients were divided into two groups according to their BMI. 20 males and 21 females with BMI > 25 kg/m2 were included in the first, study, group. The second, control, group consisted of 16 males and 11 females with BMI - 18.5 - 24.9 kg/m 2. Lipid profile, fasting glucose and insulin levels, HOMA-IR, TNF-α, ceruloplasmin, neuropeptides Agouti-related protein - AgRP and kokain- and amphetamine-mediated transcript - CART were examined at the beginning of the study (Day 1) and after 10 week treatment period (Day 70). During the 10 week treatment period, people in the study group underwent physical exercise programs of 40-60 minute duration three times per week, and brisk walking during the remaining days. The mean calorie expenditure during the exercise was 500 kcal/day. Each patient in the study group was given balanced, healthy diet with 20% calorie restriction from baseline diet. Our study reveled that negative energy balance caused a statistically significant decrease in AgRP, reduction of visceral fat stores, increase of HDL, reduction of TNF-α and dissolution of insulin resistance signs. Significant but not statistically significant reduction of CART level was observed after increased physical activity program and calorie restriction diet, which might play an important role in the mechanism of decreasing weight. However, further investigations are required in order to determine its place in body weight regulation.

[COMPLEX LABORATORY DIAGNOSIS OF MALARIA PATHOGENS IN THE PRE ELIMINATION PERIOD].

An immunological survey of 8,000 dwellers from 4 districts of Tajikistan failed to detect malaria pathogens by CareStartMalariaHPR2/PLDH (P. falciparum/P. vivax) COMBOGO161 AccessBio tests and showed the possibility of their further use under the Republic's conditions, particularly in the mountain villages and the human settlements bordering on Afghanistan. The results of examining 750 blood samples from the dwellers of sanitized foci in Tajikistan's areas, by applying molecular diagnosis via polymerase chain reaction, indicated no signs of parasites. A set ofthree methods, such as microscopic, immunological, and molecular diagnostic ones, was used to prove the absence of reliable malaria infection and local transmission sources.

[Spread of tropical malaria in the Republic of Tajikistan (1994-2008)].

Tropical malaria occurred in the Republic of Tajikistan in 1994 after 40-year absence and spread in 28 regions of Tajikistan and in 3 cities (Dushanbe, Kulyab, and Kurgan-Tyube), peaking in 2000 (831 cases). A total of 3585 cases of tropical malaria were notified in 602 foci during a 15-year period. Migrants imported the pathogenic agent by the route of Pakistan-Afghanistan-Tajikistan during armed conflicts and in trading activities continually.The emergence of Asian Plasmodium falciparum phenotypes was accompanied by the clinical complications of the disease: the high percentage of moderate and severe forms of the disease was observed in preschool children in the absence of fatal outcomes. The rising incidence of malaria was associated with not only with the intensive import of the infection and the flight of infected malaria mosquitoes, but also with the active examination of the population during homestead rounds and with the timely laboratory diagnosis of malaria pathogens. The long-term goal antimalarial measures in the Republic of Tajikistan in 2009 resulted in the pause in the local transmission of tropical malaria, which meant its elimination in the country.

Trigger factor assists the refolding of heterodimeric but not monomeric luciferases.

The refolding of thermally inactivated protein by ATP-independent trigger factor (TF) and ATP-dependent DnaKJE chaperones was comparatively analyzed. Heterodimeric (αß) bacterial luciferases of Aliivibrio fischeri, Photobacterium leiognathi, and Vibrio harveyi as well as monomeric luciferases of Vibrio harveyi and Luciola mingrelica (firefly) were used as substrates. In the presence of TF, thermally inactivated heterodimeric bacterial luciferases refold, while monomeric luciferases do not refold. These observations were made both in vivo (Escherichia coli ΔdnaKJ containing plasmids with tig gene) and in vitro (purified TF). Unlike TF, the DnaKJE chaperone system refolds both monomeric and heterodimeric luciferases with equal efficiency.

[RANDTRAN: random transcriptome sequence generator that accounts for partition specific features in eukaryotic mRNA datasets].

The generation of true random and pseudorandom control sequences is an important problem of computational biology. Available random sequence generators differ in underlying probabilistic models that often remain undisclosed to users. Random sequences produced by differing probabilistic models substantially differ in their outputs commonly used as baselines for evaluations of the motif frequencies. Moreover, modern bioinformatics studies often require generation of matching control transcriptome with emulated partitions into ORFs, 5'- and 3'-UTRs as well as the proportion of non-coding RNAs within model transcriptome rather than relatively simple continuous control sequences. Here we describe novel random sequence generating tool RANDTRAN that accounts for the length distribution of 5' and 3' non-translated regions in given transcriptome and the partition-specific di- and trinucleotide compositions in translated and non-translated regions. RANDRAN presents matching control transcriptomes in ready-to-use UCSC genome browser-compatible input files. These features may be useful for generating of control sequence sets for common types of computational analysis of various sequence motifs within various sets of RNA. RANDTRAN is available for free download at http://www.genereseairch.ru/images/Randtran.rar.

[Follicular cell (papillary and follicular) thyroid carcinoma, genetic inheritance, and molecular diagnostic markers].

OBJECTIVE: To determine the genetic forms of follicular cell thyroid carcinoma (FCTC) (papillary and follicular thyroid carcinoma (PTC and FTC)), to identify criteria to individually predict the development of the same disease for relatives, and to assess the role of molecular markers in the diagnosis, prognosis, and treatment of this disease. SUBJECTS AND METHODS: One hundred and ninety adult patients aged 20 to 84 years with histologically verified PTC and FTC and 20 children (12 patients with PTC and 8 with benign thyroid tumors) aged 2 to 16 years were examined. To assess the role of the BRAF gene as a molecular marker for thyroid carcinoma, DNA was isolated from the thyroid tumor tissue of 29 patients, which had been obtained by fine-needle aspiration biopsy (FNAB) and scraping and swabbing the cytological specimen previously showing an area containing tumor cells. A BRAF c.1799T>A (p.V600E) mutation in the FNAB specimens was tested by allele-specific ligation, followed by PCR amplification. RESULTS: The examinees' families were found to have a segregation of benign thyroid tumor and nontumor diseases (13.6%). Neoplasias of different sites were observed in 15% of the patients' relatives. Multiple primary tumors were detected in 6.1% of the patients and in 25% of the examined children (3/12). PTC was ascertained to accumulate as two clinical forms in the families. One form belongs to familial PTC (FPTC) in which two or three generations of relatives in the family are afflicted by only PTC and have a more severe phenotype of the disease. The other includes an association of FPTC with papillary kidney cancer. Furthermore, FPTC and PTC may be a component of multitumor syndromes, such as multiple endocrine neoplasia type 1, Cowden syndrome, and familial adenomatous polyposis. The familial hereditary forms of FCTC were generally revealed in 4.2% of the patients. BRAF v600E mutations were found in only 3 patients with Stages II and III PTC and were not in all the 12 children with PTC. CONCLUSION: The found clinical manifestation of the hereditary forms of FCTC permits the identification of people at high risk for this disease. No correlation between somatic BRAF mutations with a less favorable course in PTC can be noticed because there are few observations. Analysis of published data on the role of molecular markers in FCTC has shown that the existing specific somatic changes complement information in the differential cytological diagnosis when examining FNAB specimens.