Semantic and Population Analysis of the Genetic Targets Related to COVID-19 and Its Association with Genes and Diseases.

SARS-CoV-2 is a coronavirus responsible for one of the most serious, modern worldwide pandemics, with lasting and multifaceted effects. By late 2021, SARS-CoV-2 has infected more than 180 million people and has killed more than 3 million. The virus gains entrance to human cells through binding to ACE2 via its surface spike protein and causes a complex disease of the respiratory system, termed COVID-19. Vaccination efforts are being made to hinder the viral spread, and therapeutics are currently under development. Toward this goal, scientific attention is shifting toward variants and SNPs that affect factors of the disease such as susceptibility and severity. This genomic grammar, tightly related to the dark part of our genome, can be explored through the use of modern methods such as natural language processing. We present a semantic analysis of SARS-CoV-2-related publications, which yielded a repertoire of SNPs, genes, and disease ontologies. Population data from the 1000 Genomes Project were subsequently integrated into the pipeline. Data mining approaches of this scale have the potential to elucidate the complex interaction between COVID-19 pathogenesis and host genetic variation; the resulting knowledge can facilitate the management of high-risk groups and aid the efforts toward precision medicine.

ADRA2B and HTR1A: An Updated Study of the Biogenic Amine Receptors Reveals Novel Conserved Motifs Which Play Key Role in Mental Disorders.

Mental disorders are strongly connected with several psychiatric conditions including depression, bipolar disorder, schizophrenia, eating disorder, and suicides. There are many biological conditions and pathways that define these complicated illnesses. For example, eating disorders are complex mental health conditions that require the intervention of geneticists, psychiatrists, and medical experts in order to alleviate their symptoms. A patient with suicidal ideation should first be identified and consequently monitored by a similar team of specialists. Both genetics and epigenetics can shed light on eating disorders and suicides as they are found in the main core of such investigations. In the present study, an analysis has been performed on two specific members of the GPCR family toward drawing conclusions regarding their functionality and implementation in mental disorders. Specifically, evolutionary and structural studies on the adrenoceptor alpha 2b (ADRA2B) and the 5-hydroxytryptamine receptor 1A (HTR1A) have been carried out. Both receptors are classified in the biogenic amine receptors sub-cluster of the GPCRs and have been connected in many studies with mental diseases and malnutrition conditions. The major goal of this study is the investigation of conserved motifs among biogenic amine receptors that play an important role in this family signaling pathway, through an updated evolutionary analysis and the correlation of this information with the structural features of the HTR1A and ADRA2B. Furthermore, the structural comparison of ADRA2B, HTR1A, and other members of GPCRs related to mental disorders is performed.

A Genomic Study of the Japanese Population Focusing on the Glucocorticoid Receptor Interactome Highlights Distinct Genetic Characteristics Associated with Stress Response.

All living organisms have been programmed to maintain a complex inner equilibrium called homeostasis, despite numerous adversities during their lifespan. Any threatening or perceived as such stimuli for homeostasis is termed a stressor, and a highly conserved response system called the stress response system has been developed to cope with these stimuli and maintain or reinstate homeostasis. The glucocorticoid receptor, a transcription factor belonging to the nuclear receptors protein superfamily, has a major role in the stress response system, and research on its interactome may provide novel information regarding the mechanisms underlying homeostasis maintenance. A list of 149 autosomal genes that have an essential role in GR function or are prime examples of GRE-containing genes was composed in order to gain a comprehensive view of the GR interactome. A search for SNPs on those particular genes was conducted on a dataset of 3554 Japanese individuals, with mentioned polymorphisms being annotated with relevant information from the ClinVar, LitVar, and dbSNP databases. Forty-two SNPs of interest and their genomic locations were identified. These SNPs have been associated with drug metabolism and neuropsychiatric, metabolic, and immune system disorders, while most of them were located in intronic regions. The frequencies of those SNPs were later compared with a dataset consisting of 1465 Korean individuals in order to find population-specific characteristics based on some of the identified SNPs of interest. The results highlighted.that rs1043618 frequencies were different in the two populations, with mentioned polymorphism having a potential role in chronic obstructive pulmonary disease in response to environmental stressors. This SNP is located in the HSPA1A gene, which codes for an essential GR co-chaperone, and such information showcases that similar gene may be novel genomic targets for managing or combatting stress-related pathologies.

DRDs and Brain-Derived Neurotrophic Factor Share a Common Therapeutic Ground: A Novel Bioinformatic Approach Sheds New Light Toward Pharmacological Treatment of Cognitive and Behavioral Disorders.

Cognitive and behavioral disorders are subgroups of mental health disorders. Both cognitive and behavioral disorders can occur in people of different ages, genders, and social backgrounds, and they can cause serious physical, mental, or social problems. The risk factors for these diseases are numerous, with a range from genetic and epigenetic factors to physical factors. In most cases, the appearance of such a disorder in an individual is a combination of his genetic profile and environmental stimuli. To date, researchers have not been able to identify the specific causes of these disorders, and as such, there is urgent need for innovative study approaches. The aim of the present study was to identify the genetic factors which seem to be more directly responsible for the occurrence of a cognitive and/or behavioral disorder. More specifically, through bioinformatics tools and software as well as analytical methods such as systemic data and text mining, semantic analysis, and scoring functions, we extracted the most relevant single nucleotide polymorphisms (SNPs) and genes connected to these disorders. All the extracted SNPs were filtered, annotated, classified, and evaluated in order to create the "genomic grammar" of these diseases. The identified SNPs guided the search for top suspected genetic factors, dopamine receptors D and neurotrophic factor BDNF, for which regulatory networks were built. The identification of the "genomic grammar" and underlying factors connected to cognitive and behavioral disorders can aid in the successful disease profiling and the establishment of novel pharmacological targets and provide the basis for personalized medicine, which takes into account the patient's genetic background as well as epigenetic factors.

An Updated Evolutionary and Structural Study of TBK1 Reveals Highly Conserved Motifs as Potential Pharmacological Targets in Neurodegenerative Diseases.

TANK-binding kinase 1 protein (TBK1) is a kinase that belongs to the IκB (IKK) family. TBK1, also known as T2K, FTDALS4, NAK, IIAE8, and NF-κB, is responsible for the phosphorylation of the amino acid residues, serine and threonine. This enzyme is involved in various key biological processes, including interferon activation and production, homeostasis, cell growth, autophagy, insulin production, and the regulation of TNF-α, IFN-ß, and IL-6. Mutations in the TBK1 gene alter the protein's normal function and may lead to an array of pathological conditions, including disorders of the central nervous system. The present study sought to elucidate the role of the TBK1 protein in amyotrophic lateral sclerosis (ALS), a human neurodegenerative disorder. A broad evolutionary and phylogenetic analysis of TBK1 was performed across numerous organisms to distinguish conserved regions important for the protein's function. Subsequently, mutations and SNPs were explored, and their potential effect on the enzyme's function was investigated. These analytical steps, in combination with the study of the secondary, tertiary, and quaternary structure of TBK1, enabled the identification of conserved motifs, which can function as novel pharmacological targets and inform therapeutic strategies for amyotrophic lateral sclerosis.

Ebola Virus Disease and Current Therapeutic Strategies: A Review.

The Ebola virus disease is a severe hemorrhagic fever that affects humans and other primates. Ebola virus, the causative agent of the disease, is transmitted to humans from wild animals and is highly contagious and aggressive with an estimated fatality rate to be around 50%. Since 1976, 11 outbreaks of Ebola virus disease have been reported in total, affecting mostly sub-Saharan Africa, while the most recent ongoing outbreak in the Democratic Republic of the Congo has more than 3000 reported cases and 72 deaths. Although an effective vaccine against Ebola virus disease has become available, no targeted treatment with proven efficacy upon infection is developed. Herein, we review the epidemiology of Ebola virus and the current situation in terms of prevention, diagnosis, and treatment of the disease.

Efficient treatment of chronic endometritis through a novel approach of intrauterine antibiotic infusion: a case series.

BACKGROUND: Early diagnosis and efficient management of Chronic Endometritis (CE) in patients seeking fertility treatment are two components every practitioner wishes to address. With respect to endometrial restoration, antibiotic treatment appears to perform well. However, regarding the improvement of In Vitro Fertilization (IVF) success rates, literature evidence is inconclusive, and consensus on optimal treatment has yet to be reached. This manuscript uniquely brings to literature the first report on effective employment of intrauterine antibiotic infusion to treat CE and contribute to addressing the infertility related to it. CASE PRESENTATION: In this case series, we present 3 patients reporting numerous previous failed IVF attempts accompanied with diagnosed CE which failed to be properly treated in the past. Following initial assessment in our clinic and verification of CE findings, an oral antibiotic regime was administered based on the infectious agent detected. Re-evaluation concluded slightly improved microbiological environment in the endometrium but persisting inflammation. Antibiotic intrauterine infusion was proposed to the patients as an alternative practice. All our patients achieved a pregnancy shortly following intrauterine treatment with one patient reporting a live birth of twin babies and two patients currently reporting an ongoing pregnancy. CONCLUSIONS: The implications of this case series contribute to medical knowledge and extend to both effective treatment of CE and subsequent management of related infertility. The current line of treatment of CE through oral antibiotic regimes highlights the need for exploring new options and calls for larger studies on the clinical implication of their use. This novel approach enabled natural conception for patients presenting with established Recurrent Implantation Failure (RIF) having undergone numerous futile IVF attempts. The clinical impact from the practitioner's perspective is considerable allowing for an alternative line of treatment that merits further investigation.

Role of non­coding RNAs as biomarkers and the application of omics technologies in Alzheimer's disease (Review).

Alzheimer's disease (AD) is a neurodegenerative disorder that has a significant association with age. Despite its increasing incidence in the population, the etiology of the disease remains poorly understood, and there are currently no effective treatments readily available. The main genes that are associated with AD are the amyloid precursor protein, presenilin­1 and presenilin­2, as well as the apolipoprotein E gene. In addition to genetic factors, a wide range of environmental and lifestyle factors are equally characterized as risk factors for the development of AD, while non­coding RNAs (ncRNAs) and other epigenetic mechanisms play a key role in their detrimental effects. Multiple types of ncRNAs, such as microRNAs, circular RNAs, Piwi­interacting RNAs and long non­coding RNAs are being increasingly implicated in AD. Alterations in ncRNAs can be detected in cerebrospinal fluid, as well in as the brain, highlighting these as promising biomarkers for the detection and treatment of AD. Developments in high­throughput technologies have led to the so­called 'omics' era, which involves the collection of big data and information at both molecular and protein levels, while combining the development of novel computational and statistical tools capable of analyzing and filtering such data. The present review discusses the role of ncRNAs and their use as biomarkers for AD, and summarizes the findings from the application of omics technologies in AD.

Recent approaches on Huntington's disease (Review).

Huntington's disease (HD) is a neurodegenerative disorder characterized by severe motor, cognitive and psychiatric symptoms. Patients of all ages can present with a dysfunction of the nervous system, which leads to the progressive loss of movement control and disabilities in speech, swallowing, communications, etc. The molecular basis of the disease is well-known, as HD is related to a mutated gene, a trinucleotide expansion, which encodes to the huntingtin protein. This protein is linked to neurogenesis and the loss of its function leads to neurodegenerative disorders. Although the genetic cause of the disorder has been known for decades, no effective treatment is yet available to prevent onset or to eliminate the progression of symptoms. Thus, the present review focused on the development of novel methods for the timely and accurate diagnosis of HD in an aim to aid the development of therapies which may reduce the severity of the symptoms and control their progression. The majority of the therapies include gene-silencing mechanisms of the mutated huntingtin gene aiming to suppress its expression, and the use of various substances as drugs with highly promising results. In the present review, the latest approaches on the diagnosis of HD are discussed along with the need for genetic counseling and an up-to-date presentation of the applied treatments.

Dark DNA and stress (Review).

Over the past few decades, research at the molecular level has focused on the part of the genome that does not encode protein sequences. Since the discovery of transcriptional evidence from the hitherto considered 'junk' DNA, this region of the genome, which is currently termed dark DNA, is constantly gaining interest. The term borrows an analogy from the corresponding eminent fields of dark matter and dark energy in physics and cosmology. In fact, an increasing number of attempts are being made to enhance the current understanding of the non­coding RNA (ncRNA) transcripts produced by such regions. Although the base­pair length and gene number appear to be very diverse between species, it appears that the amount of the non­coding regions of the genome of an organism is a sign of evolutional superiority. ncRNA molecules are able to orchestrate the expression of genetic information in the most complex, rapid and reversible manner, participating in almost every major biological process. A prime example of such a process is the maintenance of homeostasis, the internal physiological balance, despite internal and external stressful stimuli. These molecules have been shown to be excellent regulators of gene expression, with marked spatiotemporal specificity, rendering them ideal tools for regulating stress responses. Herein, an attempt is made to extract and fuse information from a repertoire of studies, which have demonstrated that the expression of a number of these molecules was modified following exposure to acute and chronic stress, as well as in patients with anxiety disorders and their respective animal models. All in all, ncRNAs have the potential to be used either as biomarkers or as therapeutic targets for disorders resulting from the loss of equilibrium, the disruption of homeostasis and the destabilization of the hypothalamic­pituitary­adrenal axis.

Novel computational pipelines in antiviral structure­based drug design (Review).

Viral infections constitute a fundamental and continuous challenge for the global scientific and medical community, as highlighted by the ongoing COVID-19 pandemic. In combination with prophylactic vaccines, the development of safe and effective antiviral drugs remains a pressing need for the effective management of rare and common pathogenic viruses. The design of potent antivirals can be informed by the study of the three-dimensional structure of viral protein targets. Structure-based design of antivirals in silico provides a solution to the arduous and costly process of conventional drug development pipelines. Furthermore, rapid advances in high-throughput computing, along with the growth of available biomolecular and biochemical data, enable the development of novel computational pipelines in the hunt of antivirals. The incorporation of modern methods, such as deep-learning and artificial intelligence, has the potential to revolutionize the structure-based design and repurposing of antiviral compounds, with minimal side effects and high efficacy. The present review aims to provide an outline of both traditional computational drug design and emerging, high-level computing strategies.

Epitranscriptomics of cardiovascular diseases (Review).

RNA modifications have recently become the focus of attention due to their extensive regulatory effects in a vast array of cellular networks and signaling pathways. Just as epigenetics is responsible for the imprinting of environmental conditions on a genetic level, epitranscriptomics follows the same principle at the RNA level, but in a more dynamic and sensitive manner. Nevertheless, its impact in the field of cardiovascular disease (CVD) remains largely unexplored. CVD and its associated pathologies remain the leading cause of death in Western populations due to the limited regenerative capacity of the heart. As such, maintenance of cardiac homeostasis is paramount for its physiological function and its capacity to respond to environmental stimuli. In this context, epitranscriptomic modifications offer a novel and promising therapeutic avenue, based on the fine­tuning of regulatory cascades, necessary for cardiac function. This review aimed to provide an overview of the most recent findings of key epitranscriptomic modifications in both coding and non­coding RNAs. Additionally, the methods used for their detection and important associations with genetic variations in the context of CVD were summarized. Current knowledge on cardiac epitranscriptomics, albeit limited still, indicates that the impact of epitranscriptomic editing in the heart, in both physiological and pathological conditions, holds untapped potential for the development of novel targeted therapeutic approaches in a dynamic manner.

Long non­coding RNAs and microRNAs as regulators of stress in cancer (Review).

Resistance to stress is a feature of cancer cells. Cellular stress includes oxidative, metabolic and genotoxic stress conditions, which under normal conditions lead to cell death. However, in contrast to normal cells, cancer cells overcome the checkpoints that normally restrict growth, and are able to resist cellular stress and subsequent cell death through a variety of mechanisms, which include several non­coding RNAs (ncRNAs). Within this context, long ncRNAs (lncRNAs) and microRNAs (miRNAs/miRs) are the main categories of ncRNAs that have been shown in the literature to function as regulators of stress resistance pathways in cancer. miRNAs play a key role in the majority of biological pathways, as they regulate the expression of hundreds of target genes, including genes involved in stress response and cell death, oncogenes, or tumor suppressor genes, by inhibiting protein translation or promoting the degradation of mRNAs. Respectively, lncRNAs are epigenetic regulators, which are also involved in cancer progression, stress response and metabolic pathways by promoting or inhibiting the transcription, splicing, translation and modulation of protein function. Thus, the present review summarizes recent knowledge related to the role of these molecules in the cancer response to stress, highlighting the ability of these non­coding molecules to be effective drug targets and biomarkers in cancer treatment.

Multiple sclerosis and computational biology (Review).

Multiple sclerosis (MS) is an autoimmune neurodegenerative disease whose prevalence has increased worldwide. The resultant symptoms may be debilitating and can substantially reduce the of patients. Computational biology, which involves the use of computational tools to answer biomedical questions, may provide the basis for novel healthcare approaches in the context of MS. The rapid accumulation of health data, and the ever-increasing computational power and evolving technology have helped to modernize and refine MS research. From the discovery of novel biomarkers to the optimization of treatment and a number of quality-of-life enhancements for patients, computational biology methods and tools are shaping the field of MS diagnosis, management and treatment. The final goal in such a complex disease would be personalized medicine, i.e., providing healthcare services that are tailored to the individual patient, in accordance to the particular biology of their disease and the environmental factors to which they are subjected. The present review article summarizes the current knowledge on MS, modern computational biology and the impact of modern computational approaches of MS.

Role of microRNAs and long non­coding RNAs in glucocorticoid signaling (Review).

The synthesis and release of glucocorticoids in living organisms are related to their response to unfavorable stressful conditions in order to maintain homeostatic functions and survive. One such hormone in humans is cortisol, which is produced by the hypothalamic­pituitary­adrenal cortex axis and binds with the glucocorticoid receptor (GR) following its secretion. GR controls a number of distinct gene networks. Non­coding RNAs (ncRNAs), such as microRNAs (miRNAs) and long non­coding RNAs (lncRNAs), regulate the expression and function of GR, having a considerable impact on various biological processes and treatment approaches for numerous disorders. In the present review, the GR pathways and signaling as part of the stress response system are discussed. A detailed report on the role of miRNAs and lncRNAs in glucocorticoid signaling is also presented.

Study of the Langat virus RNA-dependent RNA polymerase through homology modeling.

Langat virus is a member of the Flaviviridae family and a close relative of a group of important tick-borne viruses that cause human encephalitis. RNA-dependent RNA polymerase is a significant component of the replication mechanism of the Flaviviridae viral family. In the present work, a three-dimensional model of the Langat virus RNA-dependent RNA polymerase was designed through homology modeling. The experimentally determined structure of the RNA-dependent RNA polymerase of Dengue virus type II, another member of the same viral family, was employed as template for the homology modeling process. The resulting model underwent a series of optimisations and its quality was verified using the Verify3D algorithm. Important functional characteristics of the family of viral RNA-dependent RNA polymerases were identified in the generated model, thus affirming the potential for its use in the possible design of anti-viral agents for Langat virus.

Haematological malignancies implications during the times of the COVID-19 pandemic.

The COVID-19 pandemic has complicated current healthcare services for cancer patients. Patients with haematological malignancies specifically seem vulnerable to SARS-CoV-2 infection due to their immunosuppressed status. The COVID-19 pandemic influences every step of the assessment and treatment of a haematological malignancy. Clinicians must adhere to strict policies to not spread the virus to their patients while they must also adjust their workflow for maximum productivity. These difficulties accentuate the ever-present need to improve the healthcare services for cancer patients. This improvement is needed not only to combat the problems that arose from the COVID-19 pandemic but also to establish a framework for the management of patients with haematological malignancies in potential future pandemics.

Molecular mechanisms of the novel coronavirus SARS-CoV-2 and potential anti-COVID19 pharmacological targets since the outbreak of the pandemic.

The novel coronavirus SARS-CoV-2 has emerged as a severe threat against public health and global economies. COVID-19, the disease caused by this virus, is highly contagious and has led to an ongoing pandemic. SARS-CoV-2 affects, mainly, the respiratory system, with most severe cases primarily showcasing acute respiratory distress syndrome. Currently, no targeted therapy exists, and since the number of infections and death toll keeps rising, it has become a necessity to study possible therapeutic targets. Antiviral drugs can target various stages of the viral infection, and in the case of SARS-CoV-2, both structural and non-structural proteins have been proposed as potential drug targets. This review focuses on the most researched SARS-CoV-2 proteins, their structure, function, and possible therapeutic approaches.

Exosomics.

Extracellular vesicles have been the focus of a large number of studies in the past five years. Exosomes, a subgroup of extracellular vesicles, are of particularly high interest because they partake in a wide number of biological pathways. Produced by a variety of cells, exosomes have an important role in both physiological and pathological conditions. Exosome cargo heavily defines the vesicles' unique characteristics, and the cargo with the most intriguing prospects in its' biomedical applications is the non-coding RNAs. Non-coding RNAs, and specifically microRNAs are implicated in the regulation of many biological processes and have been associated with numerous diseases. Exosomes containing such important cargo can be used as biomarkers, therapeutic biomaterials, or even drug carriers. The potential media use of exosomes seems promising. However, some obstacles should be overcome before their clinical application. Synthetic exosome-like biomolecules may be a solution, but their production is still in their beginning stages. This review provides concise information regarding the current trends in exosome studies.

A genomic data mining pipeline for 15 species of the genus Olea.

In the big data era, conventional bioinformatics seems to fail in managing the full extent of the available genomic information. The current study is focused on olive tree species and the collection and analysis of genetic and genomic data, which are fragmented in various depositories. Extra virgin olive oil is classified as a medical food, due to nutraceutical benefits and its protective properties against cancer, cardiovascular diseases, age-related diseases, neurodegenerative disorders, and many other diseases. Extensive studies have reported the benefits of olive oil on human health. However, available data at the nucleotide sequence level are highly unstructured. Towards this aim, we describe an in-silico approach that combines methods from data mining and machine learning pipelines to ontology classification and semantic annotation. Fusing and analysing all available olive tree data is a step of uttermost importance in classifying and characterising the various cultivars, towards a comprehensive approach under the context of food safety and public health.