Molecular genetics of idiopathic pulmonary fibrosis

Idiopathic pulmonary fibrosis (IPF) is a severe progressive interstitial lung disease with a prevalence of 2 to 29 per 100,000 of the world’s population. Aging is a significant risk factor for IPF, and the mechanisms of aging (telomere depletion, genomic instability, mitochondrial dysfunction, loss of proteostasis) are involved in the pathogenesis of IPF. The pathogenesis of IPF consists of TGF-β activation, epithelial-mesenchymal transition, and SIRT7 expression decrease. Genetic studies have shown a role of mutations and polymorphisms in mucin genes (MUC5B), in the genes responsible for the integrity of telomeres (TERC, TERC, TINF2, DKC1, RTEL1, PARN), in surfactant-related genes (SFTPC, SFTPCA, SFTPA2, ABCA3, SP-A2), immune system genes (IL1RN, TOLLIP), and haplotypes of HLA genes (DRB1*15:01, DQB1*06:02) in IPF pathogenesis. The investigation of the influence of reversible epigenetic factors on the development of the disease, which can be corrected by targeted therapy, shows promise. Among them, an association of a number of specific microRNAs and long noncoding RNAs was revealed with IPF. Therefore, dysregulation of transposons, which serve as key sources of noncoding RNA and affect mechanisms of aging, may serve as a driver for IPF development. This is due to the fact that pathological activation of transposons leads to violation of the regulation of genes, in the epigenetic control of which microRNA originating from these transposons are involved (due to the complementarity of nucleotide sequences). Analysis of the MDTE database (miRNAs derived from Transposable Elements) allowed the detection of 12 different miRNAs derived in evolution from transposons and associated with IPF (miR-31, miR-302, miR-326, miR-335, miR-340, miR-374, miR-487, miR-493, miR-495, miR-630, miR-708, miR-1343). We described the relationship of transposons with TGF-β, sirtuins and telomeres, dysfunction of which is involved in the pathogenesis of IPF. New data on IPF epigenetic mechanisms can become the basis for improving results of targeted therapy of the disease using noncoding RNAs

Production of Ferroalloys and Recycling in the Continuous Oxygen Reactor

A new technology for the production of ferronickel in a new type of unit – a continuous oxygen reactor (COR). The heat source of the process is heat from the afterburning of the exhaust gases. High recovery rate is achieved by carrying out the recovery process in the ore-coal briquettes. Briquettes are located on a carbon substrate. The products are metal and slag granules. The process is characterized by satisfactory performance and low cost of ferronickel. Keywords: ferroalloy industry, continuous oxygen reactor, briquettes, ferronicke

Monitoring of illegal placement of solid waste with the use of space technology

© 2016, International Journal of Pharmacy and Technology. All rights reserved.This article is devoted to development and use of the space and geoinformational technologies allowing the state and municipal operating controls to carry out continuous monitoring of city and suburban territories regarding identification of unauthorized garbage dumps, to carry out control of their elimination. The purpose of the conducted research is definition of optimum ways with minimum expenses of labor and life capabilities to carry out searching of unauthorized garbage dumps and to provide monitoring for clear and rather in settlements. Object of a research is the modern territory of Kazan and its vicinities, with a total area more than 600 sq.km, numbering inhabitants more than 1,2 million human. In work traditional geographical methods were used: cartographical, based on methodological bases of thematic and complex mapping, on achievements in the field of geoinformational technologies, comparative and descriptive, a method of the space analysis, statistical. As a result of the conducted research the technique of probability assessment of placement of municipal solid waste with use of space and geoinformational technologies which will allow to make well-timed administrative decisions is developed and introduction of expressly developed hardware and software system on monitoring and holding the actions directed to elimination of unauthorized locations of municipal solid waste is offered

Probable Mechanisms of COVID-19 Pathogenesis

This review paper focuses on the search for innovative directions in the study of COVID­19 viral infection with the purpose of improving the methods of its treatment and vaccination. Thus far, comprehensive data have been obtained on the ability of nonretroviral RNA viruses, including those replicated in the cytoplasm, to integrate fragments of their genomes into the host DNA. This mechanism provided by the reverse  transcriptase and integrase of endogenous retroelements leads to the persistence of nonretroviral RNA viruses  through the expression of viral proteins by the host genome, which may serve as a prerequisite for the survival of such viruses. DNA integration events play a role in the development of both the immunological response and protective antiviral responses through the RNA interference system. These mechanisms may depend on the phylogenetically ancient fossils of nonretroviral RNA sequences in animal genomes. The discovery of SARS-CoV-2 fragments in COVID­19 recovered patients suggests that the pathogenesis of this disease may be associated with the integration of SARS-CoV-2 genome fragments in the human genome by means of proteins of endogenous retroviral elements. This assumption can be confirmed by the data about the development in older patients of predominantly severe forms of COVID­19 with “hyperactive” immune reactions, which normally weaken with ageing. This may be attributed to age­related abnormal activation of  retrocells, which contribute to reverse transcription and integration of exogenous viruses. This assumption is supported by the presence of coronavirus components in the nuclei of infected cells and the change in the expression of LINE­1 in the lung tissue cells of SARS patients. Due to the probable role of retrocells in the COVID­19 pathogenesis, LINE­1 reverse transcriptase inhibitors and targeted therapy using microRNAs may be offered as promising treatments for COVID­19

Application of GIS in interpretation of the results of multistage hydraulic fracturing monitoring by surface microseismic method

Currently, the problem of interpretation of microseismic monitoring data is a critical task. Along with the improvement of field survey technologies and data processing, as well as with the development of realtime hydraulic fracturing monitoring by microseismic methods there are several problems to solve, such as objectivity of geological data, the data reference with the local and regional stress-strain state of the rock massif. The aim of this work is the post-processing of surface microseismic monitoring results with the use of geographic information systems. An analytical basis of data processing is spatial statistics set of tools of ArcGIS ESRI software, which is traditionally used to identify the patterns in the spatial distribution of any point events containing georeference component. The paper shows an approach to process an interpretation in complex situations, such as fracking pump failure, when the cloud of microseismic events shows a random distribution. Main attention in the work was paid for geological interpretation of the results obtained and their relation with the results of regional stress-strain state investigation. Significant convergence is detected for the orientation of natural fractures defined by surface seismic surveys, microseismic monitoring of hydraulic fracture propagation and regional lineament analysis basing on satellite images

Assessment of regional investment attractiveness with the use of gis technologies

This article discusses problems of development and application of special geographic information systems (GIS) which promote performing objective assessment of investment attractiveness of territories for potential investors. This GIS class helps carry out analysis and forecast various businesses development on the territory of certain region, city, and areas with optimal business climate. Relevance of the matter is connected with absence of real investment attraction instruments which help to increase economic competitiveness of Russian regions. The purpose of the conducted research is to determine territorial difference in investment potentials of municipal and city districts of the Republic of Tatarstan and mechanisms of their increase. An object of the research is territory of the Republic of Tatarstan with its unique physiographic characteristics and economic and social situation. Traditional geographical methods which were used in research included cartographical (based on methodological framework of thematic and complex mapping and on achievements in geoinformation technologies area), comparative and descriptive, spatial analysis, statistical methods. The technique of integrated assessment of investment attractiveness of rural and urban districts of the Republic of Tatarstan with the use of geoinformation technologies is the main result of undertaken research. Creation of specialized geographic information system "The Investment Portal of the Republic of Tatarstan" which helps to make effective presentation of regional investment potential to investors is also the research effect

INTERRELATION OF PRIONS WITH NON-CODING RNAS

Prions are alternative infectious conformations for some cellular proteins. For the protein PrPC (PrP – prion protein, С – common), a prion conformation, called PrPSc (S – scrapie), is pathological. For example, in mammals the PrPSc prion causes transmissible spongiform encephalopathies accumulating in the brain tissues of PrPSc aggregates that have amyloid properties. MicroRNAs and long non-coding RNAs can be translated into functional peptides. These peptides can have a regulatory effect on genes from which their non-coding RNAs are transcribed. It has been assumed that prions, like peptides, due to the presence of specific domains, can also activate certain non-coding RNAs. Some of the activated non-coding RNAs can catalyze the formation of new prions from normal protein, playing their role in the pathogenesis of prion diseases. Confirmation of this assumption is the presence of the association of alleles of microRNA with the development of the disease, which indicates the role of the specific sequences of noncoding RNAs in the catalysis of prion formation. In the brain tissues of patients with prion diseases, as well as in exosomes containing an abnormal PrPSc isoform, changes in the levels of microRNA have been observed. A possible cause is the interaction of the spatial domains of PrPSc with the sequences of the non-coding RNA genes, which causes a change in their expression. MicroRNAs, in turn, affect the synthesis of long non-coding RNAs. We hypothesize that long noncoding RNAs and possibly microRNAs can interact with PrPC catalyzing its transformation into PrPSc. As a result, the number of PrPSc increases exponentially. In the brain of animals and humans, transposon activity has been observed, which has a regulatory effect on the differentiation of neuronal stem cells. Transposons form the basis of domain structures of long non-coding RNAs. In addition, they are important sources of microRNA. Since prion diseases can arise as sporadic and hereditary cases, and hereditary predisposition is important for the development of pathology, we hypothesize the role of individual features of activation of transposons in the pathogenesis of prion diseases. The activation of transposons in the brain at certain stages of development, as well as under the influence of stress, is reflected in the peculiarities of expression of specific non-coding RNAs that are capable of catalyzing the transition of the PrPC protein to PrPSc. Research in this direction can be the basis for targeted anti-microRNA therapy of prion diseases

Вероятная роль ретроэлементов в развитии опухоли Вильмса при хромосомных синдромах

The review article analyzes the data accumulated in the literature on the association of Wilms’ tumor with chromosomal syndromes and searches for possible causes of this phenomenon. In 10 % of all cases, nephroblastoma is represented by a hereditary tumor syndrome due to germline mutations in suppressor genes, mainly in the WT1 gene, less often in WT2, WTX, CTNNB1, TP53. These genes are associated with retroelements that play a role in the development of Wilms’ tumor, promoting carcinogenesis, causing genome instability. LINE-1 retroelement is a negative regulator of WT1 expression, while suppressor genes are characterized by suppression of retroelement activity. Part of the pathogenesis of Perlman, Beckwith-Wiedemann, WAGR, and trisomy 18 syndromes caused by germline microdeletions is the activation of retroelements that promote somatic chromosomal rearrangements, including deletions, insertions, and translocations, which are characteristic of sporadic Wilms’ tumor. Long noncoding RNAs and microRNAs are formed from retroelements during evolution or directly during the processing of their transcripts. At the same time, long noncoding RNAs affect the development of Wilms’ tumor by various mechanisms: due to the effect on ferroptosis (lncRNA AC007406.1, AC005208.1, LINC01770, DLGAP1-AS2, AP002761.4, STPG3-AS1, AC129507.1, AC234772.2, LINC02447, AC009570.1, ZBTB20-AS1 and LINC01179), Wnt/β-catenin signaling pathways (HOTAIR, MEG3), apoptosis (HAGLROS), regulation of expression of specific miRNAs (SNHG6, MEG8, XIST, SNHG16, DLEU1, CRNDE, SNHG6, DLGAP1, OSTM1-AS1, EMX2OS, H19). Analysis of the MDTE DB database revealed nephroblastoma-associated miRNAs that originate from retrotransposons. These include miR-192, -335, -378c, -562, -630, -1248. These molecules are promising for possible use in the pathogenetic treatment of Wilms’ tumor due to their effect on pathologically activated retrotransposons.В обзорной статье приведены результаты анализа накопленных в литературе данных об ассоциации опухоли Вильмса с хромосомными синдромами и поиск возможных причин данного феномена. В 10 % всех случаев нефробластома представлена наследственным опухолевым синдромом вследствие герминальных мутаций в генах-супрессорах, главным образом в гене WT1, реже в WT2, WTX, CTNNB1, TP53. Данные гены характеризуются связью с ретроэлементами, которые играют важную роль в развитии опухоли Вильмса, способствуя канцерогенезу, вызывая геномную нестабильность. Ретроэлемент LINE-1 – негативный регулятор экспрессии WT1, в то время как гены-супрессоры подавляют активность ретроэлементов. Частью патогенеза синдромов Перлмана, Беквита–Видемана, WAGR, трисомии 18, обусловленных герминальными микроделециями, является активация ретроэлементов, способствующих соматическим хромосомным перестройкам, включая делеции, инсерции и транслокации, которые характерны для спорадической опухоли Вильмса. Кроме этого, ретроэлементы являются источниками длинных некодирующих РНК и микроРНК при процессинге их транскриптов или в эволюции генов. При этом длинные некодирующие РНК влияют на развитие опухоли Вильмса различными механизмами: за счет влияния на ферроптоз (lncRNA AC007406.1, AC005208.1, LINC01770, DLGAP1-AS2, AP002761.4, STPG3-AS1, AC129507.1, AC234772.2, LINC02447, AC009570.1, ZBTB20-AS1 и LINC01179), на сигнальные пути Wnt/β-катенина (HOTAIR, MEG3), апоптоз (HAGLROS), на регуляцию экспрессии специфических микроРНК (SNHG6, MEG8, XIST, SNHG16, DLEU1, CRNDE, SNHG6, DLGAP1, OSTM1-AS1, EMX2OS, H19).Анализ базы данных MDTE DB позволил обнаружить ассоциированные с нефробластомой микроРНК, которые происходят от ретротранспозонов. К ним относятся miR-192, -335, -378c, -562, -630, -1248. Эти молекулы перспективны в отношении возможного использования для патогенетического лечения опухоли Вильмса вследствие воздействия на патологически активированные ретротранспозоны. 

Атипичные формы и гено-фенотипические корреляции нейрофиброматоза 1-го типа

Purpose of the study: Analysis of available data on geno-phenotypic correlations and atypical forms of neurofibromatosis type 1. Material and methods. We searched for relevant sources in the Scopus, Web of Science, PubMed systems, including publications from May 1993 to October 2021. Of the 318 studies  we identified, 59 were used to write a systematic review. Results. We found studies describing atypical forms of neurofibromatosis type 1 with an erased course without manifestation of a tumor syndrome, which are caused by specific mutations in the NF1 gene (causing substitutions of amino acids in neurofibromin: p.Arg1038, p.Met1149, p.Arg1809, or deletion of amino acids: p.Met990del, p.Met992del). NF1 patients with microdeletions are characterized by more severe disease symptoms (more often facial dysmorphism, skeletal and cardiovascular abnormalities, learning difficulties, and symptomatic spinal neurofibromas). mutations of splicing sites and extended deletions of the NF1 gene are associated with early manifestation of tumors, mutations at the 5’-end of the gene, causing a shortening of the protein product, are associated with optic nerve gliomas. the mutation c.3721C>T (p.R1241*) correlated with structural brain damage, and c.6855C>A (p.Y2285*)  with  endocrine  disorders. the  manifestations  of  NF1,  similar  to  lipomatosis  and Jaffe-Campanacci syndrome, not associated with a specific type of mutation are described. Conclusion.  In spite of pronounced clinical variability of the disease, even among members of the same family, several studies have described genotype-phenotype correlations. Therefore, the role of modifier genes and epigenetic factors in the pathogenesis of NF1 is assumed, since the neurofibromin protein has a complex structure with several functional domains. It has been shown that the severity of the tumor syndrome is influenced by the methylation characteristics of NF1 gene and adjacent areas. in addition, NF1 gene is associated with a variety of microRNAs. therefore, targeted therapy aimed at specific non-coding RNAs to restore normal expression of NF1 gene can become a promising treatment for NF1.Цель исследования – анализ данных об атипичных формах нейрофиброматоза 1-го типа и генофенотипических корреляциях при этом заболевании. Материал и методы. Поиск соответствующих источников проводился в системах Scopus, Web of Science, PubMed с включением публикаций с мая 1993 г. по октябрь 2021 г. Из 318 найденных исследований 59 были использованы для написания систематического обзора. Результаты. Найдены работы с описанием атипичных форм нейрофиброматоза 1-го типа со стертым течением без проявления опухолевого синдрома, которые обусловлены специфическими мутациями в гене NF1 (вызывающими замены аминокислот в нейрофибромине: p.Arg1038, p.Met1149, p.Arg1809, или делецию аминокислот: p.Met990del, p.Met992del). Для больных с микроделециями всего гена NF1 и прилегающих областей характерны более тяжелые проявления нейрофиброматоза 1-го типа (чаще проявляются лицевой дизморфизм, скелетные и сердечно-сосудистые аномалии, трудности в обучении и симптоматические спинальные нейрофибромы). С ранней манифестацией опухолей ассоциированы мутации сайтов сплайсинга и протяженные делеции гена NF1, с глиомами зрительных нервов – мутации на 5’-конце гена, вызывающие укорочение белкового продукта, со структурным поражением головного мозга – мутация c.3721C>T (p.R1241*), с эндокринными расстройствами – мутация c.6855C>A (p.Y2285*). Описана клиническая картина нейрофиброматоза 1-го типа, схожая с липоматозом и синдромом Джаффе–Кампаначчи, не связанная с конкретным типом мутации. Заключение. Несмотря на выраженную клиническую вариабельность нейрофиброматоза 1-го типа даже у членов одной семьи, в ряде работ описаны гено-фенотипические корреляции. Так как белок нейрофибромин имеет сложную структуру с несколькими функциональными доменами, предполагается роль генов-модификаторов и эпигенетических факторов в патогенезе нейрофиброматоза 1-го типа. Показано, что на выраженность опухолевого синдрома влияют особенности метилирования гена NF1 и прилегающих областей, а сам ген взаимосвязан с определенными микроРНК. Поэтому перспективным способом лечения нейрофиброматоза 1-го типа может стать таргетная терапия, нацеленная на специфические некодирующие РНК для восстановления нормальной экспрессии гена NF1