Role Of Retroelements In The Development Of COVID-19 Neurological Consequences

Retroelements play a key role in brain functioning in humans and other animals, since they represent dynamic regulatory elements controlling the expression of specific neuron types. The activity of retroelements in the brain is impaired under the influence of SARS-CoV-2, penetrating the blood-brain barrier. We propose a new concept, according to which the neurological complications of COVID-19 and their long-term effects are caused by modified expression of retroelements in neurons due to viral effect. This effect is implemented in several ways: a direct effect of the virus on the promoter regions of retroelement-encoding genes, virus interaction with miRNAs causing silencing of transposons, and an effect of the viral RNA on the products of retroelement transcription. Aging-related physiological activation of retroelements in the elderly is responsible for more severe course of COVID-19. The associations of multiple sclerosis, Parkinson’s disease, Guillain-Barré syndrome, acute disseminated encephalomyelitis with coronavirus lesions also indicate the role of retroelements in such complications, because retroelements are involved in the mechanisms of the development of these diseases. According to meta-analyses, COVID-19-caused neurological complications ranged 36.4-73%. The neuropsychiatric consequences of COVID-19 are observed in patients over a long period after recovery, and their prevalence may exceed those during the acute phase of the disease. Even 12 months after recovery, unmotivated fatigue, headache, mental disorders, and neurocognitive impairment were observed in 82%, 60%, 26.2-45%, and 16.2-46.8% of patients, correspondingly. These manifestations are explained by the role of retroelements in the integration of SARS-CoV-2 into the human genome using their reverse transcriptase and endonuclease, which results in a long-term viral persistence. The research on the role of specific retroelements in these changes can become the basis for developing targeted therapy for neurological consequences of COVID-19 using miRNAs, since epigenetic changes in the functioning of the genome in neurons, affected by transposons, are reversible

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

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

The Ratio of human and intellectual capital in innovative economy

Within last several decades the scientists had paid especial attention on intellectual capital (IC) problem, determination of its structure, components, calculation methods (Stewart, 1997; Thurow, 1997; Pulic, 1998 and others). According to opinion of many scientists, for creation of a new innovative economic the increase of intellectual capital is necessary. So, it could be useful for developing countries. Because sufficient investments into a human capital, social infrastructure are able to allow the creation of effective internal market. Using analysis of existing scientific articles and also theoretic abstraction in this article, we are stating a brief overview of existing methods of intellectual capital estimation, its structure. Also we paid special attention to application of intellectual capital estimation in innovative economic as the main driver of economic growth. The continuous process of accounting and control of mental capital would allow to invest resources in the most effective manner. We proposed the IC classification which allows to understand its structure in a better manner, and also to develop universal methods of its quantitative calculation consequently. We hope that this article will contribute into understanding of intellectual capital significance as the major factor of production in economic, same as people's needs are satisfied after the target-setting process which is undoubtedly a mind's prerogative

The role of transposable elements in the ecological morphogenesis under the influence of stress

In natural selection, insertional mutagenesis is an important source of genome variability. Transposons are sensors of environmental stress effects, which contribute to adaptation and speciation. These effects are due to changes in the mechanisms of morphogenesis, since transposons contain regulatory sequences that have cis and trans effects on specific protein-coding genes. In variability of genomes, the horizontal transfer of transposons plays an important role, because it contributes to changing the composition of transposons and the acquisition of new properties. Transposons are capable of site-specific transpositions, which lead to the activation of stress response genes. Transposons are sources of non-coding RNA, transcription factors binding sites and protein-coding genes due to domestication, exonization, and duplication. These genes contain nucleotide sequences that interact with non-coding RNAs processed from transposons transcripts, and therefore they are under the control of epigenetic regulatory networks involving transposons. Therefore, inherited features of the location and composition of transposons, along with a change in the phenotype, play an important role in the characteristics of responding to a variety of environmental stressors. This is the basis for the selection and survival of organisms with a specific composition and arrangement of transposons that contribute to adaptation under certain environmental conditions. In evolution, the capability to transpose into specific genome sites, regulate gene expression, and interact with transcription factors, along with the ability to respond to stressors, is the basis for rapid variability and speciation by altering the regulation of ontogenesis. The review presents evidence of tissue-specific and stage-specific features of transposon activation and their role in the regulation of cell differentiation to confirm their role in ecological morphogenesis

Involvement of transposable elements in neurogenesis

The article is about the role of transposons in the regulation of functioning of neuronal stem cells and mature neurons of the human brain. Starting from the first division of the zygote, embryonic development is governed by regular activations of transposable elements, which are necessary for the sequential regulation of the expression of genes specific for each cell type. These processes include differentiation of neuronal stem cells, which requires the finest tuning of expression of neuron genes in various regions of the brain. Therefore, in the hippocampus, the center of human neurogenesis, the highest transposon activity has been identified, which causes somatic mosai cism of cells during the formation of specific brain structures. Similar data were obtained in studies on experimental animals. Mobile genetic elements are the most important sources of long non-coding RNAs that are coexpressed with important brain protein-coding genes. Significant activity of long non-coding RNA was detected in the hippocampus, which confirms the role of transposons in the regulation of brain function. MicroRNAs, many of which arise from transposon transcripts, also play an important role in regulating the differentiation of neuronal stem cells. Therefore, transposons, through their own processed transcripts, take an active part in the epigenetic regulation of differentiation of neurons. The global regulatory role of transposons in the human brain is due to the emergence of protein-coding genes in evolution by their exonization, duplication and domestication. These genes are involved in an epigenetic regulatory network with the participation of transposons, since they contain nucleotide sequences complementary to miRNA and long non-coding RNA formed from transposons. In the memory formation, the role of the exchange of virus-like mRNA with the help of the Arc protein of endogenous retroviruses HERV between neurons has been revealed. A possible mechanism for the implementation of this mechanism may be reverse transcription of mRNA and site-specific insertion into the genome with a regulatory effect on the genes involved in the memory

The relationship of lamins with epigenetic factors during aging

The key factor of genome instability during aging is transposon dysregulation. This may be due to senile changes in the expression of lamins, which epigenetically modulate transposons. Lamins directly physically interact with transposons. Epigenetic regulators such as SIRT7, BAF, and microRNA can also serve as intermediaries for their interactions. There is also an inverse regulation, since transposons are sources of miRNAs that affect lamins. We suggest that lamins can be attributed to epigenetic factors, since they are part of the NURD, interact with histone deacetylases and regulate gene expression without changing the nucleotide sequences. The role of lamins in the etiopathogenesis of premature aging syndromes may be associated with interactions with transposons. In various human cells, LINE1 is present in the heterochromatin domains of the genome associated with lamins, while SIRT7 facilitates the interaction of this retroelement with lamins. Both retroelements and the nuclear lamina play an important role in the antiviral response of organisms. This may be due to the role of lamins in protection from both viruses and transposons, since viruses and transposons are evolutionarily related. Transposable elements and lamins are secondary messengers of environmental stressors that can serve as triggers for aging and carcinogenesis. Transposons play a role in the development of cancer, while the microRNAs derived from them, participating in the etiopathogenesis of tumors, are important in human aging. Lamins have similar properties, since lamins are dysregulated in cancer, and microRNAs affecting them are involved in carcinogenesis. Changes in the expression of specific microRNAs were also revealed in laminopathies. Identification of the epigenetic mechanisms of interaction of lamins with transposons during aging can become the basis for the development of methods of life extension and targeted therapy of age-associated cancer

Specific Features of Ovarian Cancer Metastasis

This review presents data on the predominant mechanisms of metastatic progression of ovarian cancer. The  morphological and functional features of the greater omentum are shown, both promoting the spread of  cancer cells and having an antitumour effect. The ratio of these two mutually opposite properties depends on  the cellular composition, the content of extracellular matrix molecules and the biomechanical properties of the greater omentum during carcinogenesis. Milky spots are the main site of cancer cell implantation. They differ  from lymph nodes in a simpler structure and a unique cellular composition (macrophages, B cells, CD4+ and CD8+ T lymphocytes, other immune cells) changing significantly during metastasis. М2­macrophages,  adipocytes, CD33+ and CD4+ CD25high CD127low Т­suppressors promote migration, invasion, growth and colonization of cancer cells. The majority of the molecules synthesized in the greater omentum during metastasis also stimulate this process. The exceptions are E­cadherin, CXCL10, CXCL11, CXCR3, which inhibit the growth of tumour foci. In addition, CD8+ T lymphocytes and M1 macrophages also have antitumor  effects. Since ovarian cancer is characterized by high mortality, mainly due to metastases, the issue of  optimizing methods for predicting the treatment effectiveness depending on the cellular composition and expression of specific molecules in the milky spots of the greater omentum is urgent. These indicators can be applied in clinical practice using molecular genetic and immunohistochemical methods. In order to determine the need for omenectomy in the surgical treatment of ovarian cancer and to predict the outcome, it is advisable to study the morphological and functional properties of the greater omentum and to determine the number of immunocompetent cells and the nature of the expression of genes associated with the worst prognosis, those encoding activin­A, N­cadherin, CCL23, CD36, CD44, CF­1/M­CSF, FABP4, GRO­α, GRO­β, IL­8, ITGA2, MMP9, TP53, VEGF, VEGFR. These molecules are associated with adhesion and angiogenesis systems that play a key role in metastasis. Promising directions in the therapy of metastatic ovarian cancer can be stimulation of the transition of M2­ to M1­macrophages, activation of the anti­tumour antigen­specific response of CD8+ T cells using phagocytes, adaptive transfer of natural killer cells, the use of inhibitors of Wnt pathways,  CCR1, CD36, FABP4, PAD4, ITGA2

ЭПИГЕНЕТИКА КАНЦЕРОГЕНЕЗА

Currently, the key mechanisms of carcinogenesis are epigenetic events. Epigenetic factors include DNA methylation, histone modifications, microRNA expression and higher chromatin organization. Non-coding RNAs include microRNAs, small interfering RNAs or siRNAs, piRNAs, long noncoding RNAs or lncRNAs. According to recent data, most of these RNAs are directly formed from mobile genetic elements or have a transposon origin. Non-coding RNAs specifically affect the methylation of the genome and the modification of histones in ontogenesis. This is facilitated by evolutionarily programmed features of activation of transposons, since non-coding RNAs are formed from transposons. Thus, the material basis of epigenetic heredity are the transposons. Stress and aging increase the likelihood of developing cancer. This can be explained by an increase in the number of abnormal activation of mobile genetic elements that are sensitive to stress and hormones. Abnormal activation of transposons in cells leads to genomic instability-most such cells undergo apoptosis. However, in some cases, progressive genomic instability leads to damage to oncospressor genes and oncogenes activation - as a result of apoptosis does not occur, and cells acquire the ability of uncontrolled proliferation with the accumulation of a variety of mutations due to the progressive genomic instability caused by the mobilization of transposons. In each type of malignant tumors, specific cascade mechanisms of activation of mobile genetic elements with the participation of non-coding RNA are triggered. The study of epigenetic mechanisms of development of each type of cancer will enable to develop effective methods for early molecular genetic diagnosis of cancer, as well as targeted therapy at different stages of carcinogenesis.В настоящее время ключевыми механизмами канцерогенеза признаны эпигенетические события, к которым относятся специфические изменения метилирования ДНК, модификации гистонов, экспрессия микроРНК и высшая хроматиновая организация. Согласно последним данным, некодирующие РНК (микроРНК, малые интерферирующие РНК или siРНК, piРНК, длинные некодирующие РНК или lncРНК) в большинстве своем либо непосредственно образуются из мобильных генетических элементов, либо имеют транспозонное происхождение. Некодирующие РНК специфически влияют на метилирование генома и модификации гистонов в онтогенезе, чему способствуют эволюционно запрограммированные особенности активации транспозонов, из последовательностей которых происходят данные РНК. Таким образом, материальной основой эпигенетической наследственности служат транспозоны. Под действием стресса и при старении увеличивается вероятность развития онкопатологии, что объясняется повышенной вероятностью аномальной активации мобильных генетических элементов, чувствительных к стрессовым воздействиям и изменению уровня гормонов. Аномальная активация транспозонов в клетках ведет к геномной нестабильности – большинство подобных клеток подвергаются апоптозу. Однако в некоторых случаях прогрессирующая геномная нестабильность ведет к повреждению генов онкосупрессоров и активации онкогенов - в результате апоптоза не происходит, а клетки обретают способность неконтролирующей пролиферации с накоплением множества мутаций вследствие прогрессирующей геномной нестабильности, вызванной мобилизацией транспозонов. В каждом типе злокачественных опухолей запускаются свои каскадные механизмы активации мобильных генетических элементов с участием некодирующих РНК. Исследование эпигенетических механизмов развития каждого типа рака даст возможность разработать эффективные методы ранней молекулярно-генетической диагностики онкопатологии, а также таргетной терапии на разных стадиях развития патологического процесса

Роль эпигенетических факторов в патогенезе нейрофиброматоза 1-го типа

The article describes the role of epigenetic processes in the tumorigenesis of neurofibromatosis type 1. The clinical manifestations of neurofibromatosis type 1 is characterized by a pronounced polymorphism erased from with single neurofibromas to severe forms with thousands  of tumors and complications even in patients with the same mutations. More than 1400 mutations in the NF1 gene have been reported, but have not yet identified genotype-phenotype correlations. Detected in the majority of neurofibromas mutation of the second allele of the gene NF1 and loss of heterozygosity may result from common disorders of genome stability and cell cycle regulation. Chance of tissue-specific  inactivation of the second allele is extremely low and can not prove the detection of neurofibromas in most patients with neurofibromatosis type 1. At the same time, the role of epigenetic factors for blocking of oncosupressors has been proven and can be applied to the development  of malignant tumors and neurofibromas. This assumption is proved by the fact that the majority of neurofibromas are formed in puberty, while inheriting the disease from mother to clinical manifestations more severe. This review presents the research on the role of miRNAs and specific methylation in the promoter region of NF1 tumorogenesis in neurofibromatosis type 1. Mutations in the NF1 gene are of great importance in the development of many malignancies. Due to the possibility of pharmacological correction of activity of microRNAs using antisense sequences, the study of epigenetic processes in neurofibromatosis type 1 promising to diagnose and treat not only the disease but also sporadic malignancies.В обзорной статье описана роль эпигенетических факторов в туморогенезе нейрофиброматоза 1-го типа (НФ1). Клиническая картина НФ1 характеризуется выраженным полиморфизмом – от стертых форм с единичными нейрофибромами до тяжелых проявлений с тысячами опухолей и злокачественными осложнениями. Несмотря на выявление более 1400 типов мутаций в гене NF1, большинством исследователей не обнаружено генофенотипических корреляций. Второе генетическое событие в гене NF1, выявляемое в шванноцитах большинства нейрофибром, может быть результатом общих нарушений стабильности генома и регуляции клеточного цикла. Вероятность тканеспецифической инактивации второго аллеля чрезвычайно мала и не может объяснить образование опухолей у большинства больных НФ1. В то же время роль эпигенетических факторов в блокировании онкосупрессоров доказана и может иметь значение в развитии данного заболевания, в пользу чего говорит закономерное начало образования нейрофибром в пубертатном периоде, утяжеление клиники при наследовании болезни от матери. Представлены исследования роли определенных микроРНК и особенностей метилирования промоторной области NF1 в туморогенезе при НФ1, а также роли мутаций в гене NF1 в развитии спорадических злокачественных новообразований. В связи с возможностью фармакологической коррекции активности микроРНК с использованием антисмысловых последовательностей изучение эпигенетических процессов при НФ1 перспективно для диагностики и лечения не только данной болезни, но и спорадических злокачественных новообразований