Using In Silico Bioinformatics Algorithms for the Accurate Prediction of the Impact of Spike Protein Mutations on the Pathogenicity, Stability, and Functionality of the SARS-CoV-2 Virus and Analysis of Potential Therapeutic Targets.

Coronavirus disease 2019 is caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). We have used bioinformatics to investigate seventeen mutations in the spike protein of SARS-CoV-2, as this mediates infection of human cells and is the target of most vaccine strategies and antibody-based therapies. Two mutations, H146Y and S221W, were identified as being most pathogenic. Mutations at positions D614G, A829T, and P1263L might also have deleterious effects on protein function. We hypothesized that candidate small molecules may be repurposed to combat viral infection. We investigated changes in binding energies of the ligands and the mutant proteins by assessing molecular docking. For an understanding of cellular function and organization, protein-protein interactions are also critical. Protein-protein docking for naïve and mutated structures of SARS-CoV-2 S protein was evaluated for their binding energy with the angiotensin-converting enzyme 2 (ACE2). These interactions might limit the binding of the SARS-CoV-2 spike protein to the ACE2 receptor or may have a deleterious effect on protein function that may limit infection. These results may have important implications for the transmission of SARS-CoV-2, its pathogenesis, and the potential for drug repurposing and immune therapies.

Data-Mining of Barley to Identify Salt Stress Hub Genes, Gene Expression Analysis and Recombinant Plasmid Construction.

Background: Salinity is one of the major abiotic stresses that limit the production and yields of agricultural crops worldwide. Objectives: In order to identify key barley genes under salinity stress, the available metadata were examined by two methods of Cytoscape and R software. Next, the hub expression of the selected gene was evaluated under different salinity stress treatments and finally, this gene was cloned into cloning and expression vector and recombinant plasmid was made. Materials and Methods: In this study, we extracted salinity stress tolerant genes from several kinds of literature and also microarray data related to barley under salinity conditions from various datasets. The list of genes related to literature analyzed using string and Cytoscape. The genes from the datasets were first filtered and then the hub genes were identified by Cytoscape and R methods. Next, these hub genes were analyzed for the promoter. Results: Ten hub genes were selected and their promoters were analyzed, the cis-element of which was often cis-acting regulatory element involved in the methyl jasmonate -responsiveness, common cis-acting element in promoter and enhancer regions and MYBHv1 binding site. Finally, the sedoheptulose-1,7-bisphosp gene (SBPase), which had the highest interaction in both gene lists and both types of gene networks, was selected as hub gene. Next, the expression of SBPase gene was examined in two variety of Youssef variety (salt tolerant) and Fajr variety (salt sensitive) under salinity stress (NaCl 100mM) at 0 (control), 3, 6, 12 and 24 hours after stress. The results showed that the expression of this gene increased with increasing the duration of stress in both varieties. Comparison of the two varieties showed that the expression of SBPase gene in the tolerant genotype was twice as high as sensitive. Finally, SBPase gene as a key gene for salinity stress was cloned in both cloning (pTG19) and expression (pBI121) vectors. Conclusions: According to our results, SBPase gene increased growth and photosynthesis in barley under various abiotic stresses, therefore, over-expression of this gene in barley is recommended to produce plants resistant to abiotic stresses.

Screening of potential inhibitors of COVID-19 with repurposing approach via molecular docking.

SARS-CoV-2 (COVID-19) is the causative organism for a pandemic disease with a high rate of infectivity and mortality. In this study, we aimed to assess the affinity between several available small molecule and proteins, including Abl kinase inhibitors, Janus kinase inhibitor, dipeptidyl peptidase 4 inhibitors, RNA-dependent RNA polymerase inhibitors, and Papain-like protease inhibitors, using binding simulation, to test whether they may be effective in inhibiting COVID-19 infection through several mechanisms. The efficiency of inhibitors was evaluated based on docking scores using AutoDock Vina software. Strong ligand-protein interactions were predicted among some of these drugs, that included: Imatinib, Remdesivir, and Telaprevir, and this may render these compounds promising candidates. Some candidate drugs might be efficient in disease control as potential inhibitors or lead compounds against the SARS-CoV-2. It is also worth highlighting the powerful immunomodulatory role of other drugs, such as Abivertinib that inhibits pro-inflammatory cytokine production associated with cytokine release syndrome (CRS) and the progression of COVID-19 infection. The potential role of other Abl kinase inhibitors, including Imatinib in reducing SARS-CoV and MERS-CoV viral titers, immune regulatory function and the development of acute respiratory distress syndrome (ARDS), indicate that this drug may be useful for COVID-19, as the SARS-CoV-2 genome is similar to SARS-CoV.

Prediction of Genes Involved in Lung Cancer with a Systems Biology Approach Based on Comprehensive Gene Information.

Over the past few years, hundreds of genes have been reported in relation to lung cancer. Systems biology studies can help validate this association and find the most valid genes to use in the diagnosis and treatment. We reviewed the candidate genes for lung cancer in 120 published articles from September 1, 1993, to September 1, 2020. We obtained 134 up- and 36 downregulated genes for lung cancer in this article. The genes extracted from the articles were imported to Search Tool for the Retrieval of Interacting genes/proteins (STRING) to construct the protein-protein interaction (PPI) Network and pathway enrichment. GO ontology and Reactome databases were used for describing the genes, average length of survival, and constructing networks. Then, the ClusterONE plugin of Cytoscape software was used to analyze and cluster networks. Hubs and bottleneck nodes were defined based on their degree and betweenness. Common genes between the ClusterONE plugin and network analysis consisted of seven genes (BRCA1-TP53-CASP3-PLK1-VEGFA-MDM2-CCNB1 and PLK1), and two genes (PLK1 and TYMS) were selected as survival factors. Our drug-gene network showed that CASP3, BRCA1, TP53, VEGFA, and MDM2 are common genes that are involved in this network. Also, among the drugs recognized in the drug-gene network, five drugs such as paclitaxel, oxaliplatin, carboplatin, irinotecan, and cisplatin were examined in different studies. It seems that these seven genes, with further studies and confirmatory tests, could be potential markers for lung cancer, especially PLK1 that has a significant effect on the survival of patients. We provide the novel genes into the pathogenesis of lung cancer, and we introduced new potential biomarkers for this malignancy.

An Integrated Bioinformatics Analysis of the Potential Regulatory Effects of miR-21 on T-cell Related Target Genes in Multiple Sclerosis.

BACKGROUND: Overexpression of miR-21 is a characteristic feature of patients with Multiple Sclerosis (MS) and is involved in gene regulation and the expression enhancement of pro-inflammatory factors including IFNγ and TNF-α following stimulation of T-cells via the T Cell Receptor (TCR). In this study, a novel integrated bioinformatics analysis was used to obtain a better understanding of the involvement of miR-21 in the development of MS, its protein biomarker signatures, RNA levels, and drug interactions through existing microarray and RNA-seq datasets of MS. METHODS: In order to obtain data on the Differentially Expressed Genes (DEGs) in patients with MS and normal controls, the GEO2R web tool was used to analyze the Gene Expression Omnibus (GEO) datasets, and then Protein-Protein Interaction (PPI) networks of co-expressed DEGs were designed using STRING. A molecular network of miRNA-genes and drugs based on differentially expressed genes was created for T-cells of MS patients to identify the targets of miR-21, that may act as important regulators and potential biomarkers for early diagnosis, prognosis and, potential therapeutic targets for MS. RESULTS: It found that seven genes (NRIP1, ARNT, KDM7A, S100A10, AK2, TGFßR2, and IL-6R) are regulated by drugs used in MS and miR-21. Finally, three overlapping genes (S100A10, NRIP1, KDM7A) were identified between miRNA-gene-drug network and nineteen genes as hub genes which can reflect the pathophysiology of MS. CONCLUSION: Our findings suggest that miR-21 and MS-related drugs can act synergistically to regulate several genes in the existing datasets, and miR-21 inhibitors have the potential to be used in MS treatment.

The prevalence of ataxia telangiectasia mutated (ATM) variants in patients with breast cancer patients: a systematic review and meta-analysis.

Breast cancer is the most common cancer in women, and its high mortality has become one of the biggest health problems globally. Several studies have reported an association between breast cancer and ATM gene variants. This study aimed to demonstrate and analyze the relationship between ATM gene polymorphisms and breast cancer prevalence rate. A systematic literature review was undertaken using the following databases: Medline (PubMed), Web of sciences, Scopus, EMBASE, Cochrane, Ovid, and CINHAL to retrieve all cross-sectional studies between January 1990 and January 2020, which had reported the frequency of ATM variants in patients with breast cancer. A random-effects model was applied to calculate the pooled prevalence with a 95% confidence interval. The pooled prevalence of ATM variants in patients with breast cancer was 7% (95% CI: 5-8%). Also, the pooled estimate based on type of variants was 6% (95% CI: 4-8%; I square: 94%; P: 0.00) for total variants¸ 0% (95% CI: 0-1%; I square: 0%; P: 0.59) for deletion variants, 12% (95% CI: 7-18%; I square: 99%; P: 0.00) for substitution variants, and 2% (95% CI: 4-9%; I square: 67%; P: 0.08) for insertion variants. This meta-analysis showed that there is a significant relationship between ATM variants in breast cancer patients. Further studies are required to determine which of the variants of the ATM gene are associated with BRCA mutations.

The tissue expression of MCT3, MCT8, and MCT9 genes in women with breast cancer.

BACKGROUND: Breast cancer (BC) is a common malignancy with a high mortality rate. Malignant cell transformation is associated with metabolic changes. One group of proteins that are affected is the monocarboxylate transporters (MCTs-SLC16A). The MCTs comprise 14 members, and they play an important role in the growth, proliferation, and metabolism of cancer cells by transporting monocarboxylates such as lactate, pyruvate and thyroid hormones. OBJECTIVE: We aimed to evaluate the expression of MCT3 (SLC16A8), MCT8 (SLC16A2) and MCT9 (SLC16A9) genes in breast cancer samples, comparing to normal adjacent tissues. METHODS: Forty paired breast cancer tumor samples, the adjacent non-tumor and five healthy tissues were collected. Three cancer cell lines (MCF-7, MDA-MB-231, and SKBR3) were also analyzed. The expression of SLC16A8, SLC16A2 and SLC16A9 were assessed using quantitative real-time PCR. The relationship between gene expression with the pathological features of the tumors, and the hormone receptors status of the patient's tumors were also analyzed. RESULTS: There was a significantly lower expression of the MCT3 gene in tumor samples compared to adjacent normal tissue and healthy samples (p value < 0.05). There was a significant difference in the expression of all three candidate genes between the BC tissues and normal tissues, and for the, tissues with different hormone receptor status and the molecular subtypes. Altered MCT8 and MCT9 gene expression was associated with a reduced survival CONCLUSION: MCT3 expression is significantly downregulated in breast cancer tissue. MCT3 may represent a novel therapeutic target in breast cancer patients, or in some hormone receptor subgroups.

An Integrated Data Analysis of mRNA, miRNA and Signaling Pathways in Pancreatic Cancer.

Although many genes and miRNAs have been reported for various cancers, pancreatic cancer's specific genes or miRNAs have not been studied precisely yet. Therefore, we have analyzed the gene and miRNA expression profile of pancreatic cancer data in the gene expression omnibus (GEO) database. The microarray-derived miRNAs and mRNAs were annotated by gene ontology (GO) and signaling pathway analysis. We also recognized mRNAs that were targeted by miRNA through the mirDIP database. An integrated analysis of the microarray revealed that only 6 out of 43 common miRNAs had significant differences in their expression profiles between the tumor and normal groups (P value < 0.05 and |log Fold Changes (logFC)|> 1). The hsa-miR-210 had upregulation, whereas hsa-miR-375, hsa-miR-216a, hsa-miR-217, hsa-miR-216b and hsa-miR-634 had downregulation in pancreatic cancer (PC). The analysis results also revealed 109 common mRNAs by microarray and mirDIP 4.1 databases. Pathway analysis showed that amoebiasis, axon guidance, PI3K-Akt signaling pathway, absorption and focal adhesion, adherens junction, platelet activation, protein digestion, human papillomavirus infection, extracellular matrix (ECM) receptor interaction, and riboflavin metabolism played important roles in pancreatic cancer. GO analysis revealed the significant enrichment in the three terms of biological process, cellular component, and molecular function, which were identified as the most important processes associated strongly with pancreatic cancer. In conclusion, DTL, CDH11, COL5A1, ITGA2, KIF14, SMC4, VCAN, hsa-mir-210, hsa-mir-217, hsa-mir-216a, hsa-mir-216b, hsa-mir-375 and hsa-mir-634 can be reported as the novel diagnostic or even therapeutic markers for the future studies. Also, the hsa-mir-107 and hsa-mir-125a-5p with COL5A1, CDH11 and TGFBR1 genes can be introduced as major miRNA and genes on the miRNA-drug-mRNA network. The new regulatory network created in our study could give a deeper knowledge of the pancreatic cancer.

The association between ATM variants and risk of breast cancer: a systematic review and meta-analysis.

BACKGROUND: Ataxia telangiectasia-mutated (ATM) gene contributes to repair damaged DNA and to regulate cell cycle; therefore, ATM variants seem to increase breast cancer risk; however, the results are controversial. So we conducted a systematic review and meta-analysis to clarify the pooled association between various ATM variants and the risk of breast cancer. METHODS: The relevant studies were searched through Scopus, Web of Science, PubMed and Cochrane. Stratified and subgroup analyses were performed to explore heterogeneity between studies and assess effects of study quality. The pooled estimates logarithm with standard error logarithm of odds ratio and relative risk with confidence interval were calculated. RESULTS: This study revealed that there is association between ATM variants and the risk of breast cancer; according to the seven adjusted case-control studies, OR of this association was estimated as 1.67 (95%CI: 0.73-3.82), according to nine unadjusted case-control studies, the crude OR was 2.27 (95% CI: 1.17-4.40) and according to two cohorts, the RR was estimated as 1.68 (95% CI: 1.17-2.40). CONCLUSIONS: The ATM variants are associated with an increased risk of breast cancer that ATM V2424G mutation is detected as the most predisposing factor while ATM D1853V, L546V, and S707P variants have the least predictive ability.

The Effect of LINC01296 Expression in Patients with Cancer: A Systematic Review and Meta-Analysis.

BACKGROUND: Recently has been suggested that LINC01296 has an important role in tumor-promoting in different malignancies. We performed first meta-analysis to assess the association between the LINC01296 expression and clinicopathological criteria and the survival of patients with cancers. METHODS: Relevant articles Identified by PubMed, EMBASE, Web of Science, and Scopus searching between December 2000 and 28 December 2018. Binomial data were evaluated by the odds ratio (OR) as the rapid statistic. The association between overall survival (OS) and the LINC01296 expression was evaluated using pooling the hazard ratio (HR) with its corresponding 95% confidence interval (CI). RESULTS: Finally, 9 studies with 720 patients with cancer were included. The expression of LINC01296 showed a significant positive association with TNM stage (OR = 2.67, 95% CI = 1.83-3.88), tumor stage (OR= 2.22, 95% CI= 1.34-3.66) and lymph node metastasis (OR = 3.07, 95% CI = 2.23-4.21). A shorter OS was significantly associated with the expression of LINC01296 (HR = 3.95, 95% CI = 2.65-5.25) and lymph node metastasis (HR = 2.39, 95% CI =1.16-3.63). The OS did not show significant association with gender (HR = 0.83, 95% CI = -0.63-2.30) and tumor stage (HR= 2.66, 95% CI= -0.22-5.54). CONCLUSION: In conclusion, the results of this meta-analysis suggest that the expression of LINC01296 might be considered as a potential biomarker in patients with cancer.