Erythropoiesis is a multi-step process that involves the differentiation of hematopoietic stem cells into mature red blood cells (RBCs). This process is regulated by several signaling pathways, transcription factors and microRNAs (miRNAs). Many studies have shown that dysregulation of this process can lead to hematologic disorders. PI3K/AKT is one of the most important pathways that control many cellular processes including, cell division, autophagy, survival, and differentiation. In this review, we focus on the role of PI3K/AKT pathway in erythropoiesis and discuss the function of some of the most important genes, transcription factors, and miRNAs that regulate different stages of erythropoiesis which play roles in differentiation and maturation of RBCs, prevention of apoptosis, and autophagy induction. Understanding the role of the PI3K pathway in erythropoiesis may provide new insights into diagnosing erythrocyte disorders.

PI3K/AKT/mTOR pathway is one of the most important signaling pathways involved in normal cellular processes. Its aberrant activation modulates autophagy, epithelialmesenchymal transition, apoptosis, chemoresistance, and metastasis in many human cancers.Emerging evidence demonstrates that some infections as well as epigenetic regulatory mechanisms can control PI3K/AKT/mTOR signaling pathway. In this review, we focused on the role of this pathway in gastric cancer development, prognosis, and metastasis, with an emphasis on epigenetic alterations including DNA methylation, histone modifications, and post-transcriptional modulations through non-coding RNAs fluctuations as well as H. pylori and Epstein-Barr virus infections. Finally, we reviewed different molecular targets and therapeutic agents in clinical trials as a potential strategy for gastric cancer treatment through the PI3K/AKT/mTOR pathway.

To cite this article: Alireza Paniri, Mohammad Mahdi Hosseini & Haleh Akhavan-Niaki (2020): First comprehensive computational analysis of functional consequences of TMPRSS2 SNPs in susceptibility to SARS-CoV-2 among different populations, Journal of Biomolecular Structure and Dynamics, ABSTRACT Current SARS-CoV-2 pandemy mortality created the hypothesis that some populations may be more susceptible to SARS-CoV-2. TMPRSS2 encodes a transmembrane serine protease which plays a crucial role in SARS-CoV-2 cell entry. Single nucleotide polymorphisms (SNPs) in TMPRSS2 might influence SARS-CoV2 entry into the cell. This study aimed to investigate the impact of SNPs on TMPRSS2 function and structure. In silico tools such as Ensembl, Gtex, ExPASY 2, GEPIA, CCLE, KEGG and GO were engaged to characterize TMPRSS2 and its expression profile. The functional effects of SNPs were analyzed by PolyPhen-2, PROVEN, SNAP2, SIFT and HSF. Also, Phyre2, GOR IV and PSIPRED were used to predict the secondary structure of TMPRSS2. Moreover, post-translational modification (PTM) and secretory properties were analyzed through Modpredand Phobius, respectively. Finally, miRNA profiles were investigated by PolymiRTS and miRSNPs. Out of 11,184 retrieved SNPs from dbSNP, 92 showed a different frequency between Asians and other populations. Only 21 SNPs affected the function and structure of TMPRSS2 by influencing the protein folding, PTM, splicing and miRNA function. Particularly, rs12329760 may create a de novo pocket protein. rs875393 can create a donor site, silencer and broken enhancer motifs. rs12627374 affects a wide spectrum of miRNAs profile. This study highlighted the role of TMPRSS2 SNPs and epigenetic mechanisms especially non-coding RNAs in appearance of different susceptibility to SARS-CoV-2 among different populations. Also, this study could pave the way to potential therapeutic implication of TMPRSS2 in designing antiviral drugs. ARTICLE HISTORY

DNA methylation is a significant regulator of gene expression, and its role in carcinogenesis recently has been a subject of remarkable interest. The aim of this review is to analyze the mechanism and cell regulatory effects of both hypo- and hyper-DNA methylation on cancer. In this review, we report new developments and their implications regarding the effects of DNA methylation on cancer development. Indeed, alteration of the pattern of DNA methylation has been a constant finding in cancer cells of the same type and differences in the pattern of DNA methylation not only occur in a variety of tumor types, but also in developmental processes Furthermore, the pattern of histone modification appears to be a predicator of the risk of recurrence of human cancers. It is well known that hypermethylation represses transcription of the promoter sections of tumor-suppressor genes leading to gene silencing. However, hypomethylation also has been identified as a cause of oncogenesis. Furthermore, experiments concerning the mechanism of methylation and its control have led to the discovery of many regulatory enzymes and proteins. This review reports on methods developed for the detection of 5-hydroxymethylcytosine methylation at the 5-methylcytosine of protein domains in the CpG context compared to non-methylated DNA, histone modification, and microRNA change.

Protein phosphatase 2C (PP2C), an Mg2e-dependent enzyme that dephosphorylates serine and threonine residues, defines one of the three major families of structurally unrelated eukaryotic protein phosphatases. Members Eukaryotic protein phosphatases have traditionally been classified into five broad classes on the basis of substrate amino acid specificity and cofactor requirements (2). However, gene cloning and sequencing studies have revealed that there are in fact three major evolutionary families of eukaryotic protein phosphatases. One family includes members that dephosphorylate exclusively tyrosine together with the more recently recognized dual-specificity phosphatases such as Cdc25 that dephosphorylate tyrosine and threonine in vivo (reviewed in reference 25). This is a highly divergent family, but all of its members share a conserved active site that includes a cysteine residue that is the phosphate acceptor in the dephosphorylation reaction. The second major family consists of type 1 (PP1), type 2A (PP2A), and type 2B (PP2B) serine/threonine phosphatases (2). These enzymes share -40% identity of amino acid sequence in their catalytic domains, show sensitivity to certain phosphatase inhibitors such as okadaic acid, and do not require Mg" for enzymatic activity (2). A number of new phosphatase genes whose protein products have a structural similarity to this family have been identified in a variety of species (4), and the family continues to expand.The third major protein phosphatase family is made up of type 2C enzymes (PP2C). Like the second family, these enzymes predominantly dephosphorylate serine and threonine residues, but their activity is Mg2+ dependent and resistant to okadaic acid (2). These enzymes are ubiquitous in eukaryotes; PP2C activity has been detected in a variety of species, and PP2C genes have been cloned in rats (35,36), rabbits, humans (19), and most recently in the budding yeast Saccharomyces cerevisiae (18). PP2C enzymes share -25% identity in their catalytic domains, but they have no detectable sequence similarity to the phosphatases from the other families.Genetic studies have been instrumental in unraveling the biological functions of various members of the tyrosine phosphatases and PP1/PP2A/PP2B serine/threonine phosphatases. * Corresponding author. Phone: (619) 554-6165.In addition to functions in basic processes of cellular metabolism, these phosphatases have important roles in cell cycle control, as well as regulation of cell proliferation and differentiation. In contrast, very little is known about physiological functions of PP2C, mainly because of a lack of genetic studies or a specific inhibitor of PP2C. Here we report the cloning and characterization of a PP2C gene in Schizosaccharomyces pombe. This gene, ptcl +, was isolated as a multicopy suppressor of swol-26, a temperature-sensitive mutation of a gene encoding an 82-kDa protein that is closely related to the stress protein hsp9O. ptcl + mRNA is heat inducible, and ptcl deletion mutant cells are highly sensitive to ...

The world has witnessed a high morbidity and mortality caused by SARS-CoV-2, and global death toll is still rising. Exaggerated inflammatory responses are thought to be more responsible for infiltrated immune cells accumulation, organ damage especially lung, dyspnea, and respiratory failure rather than direct effect of viral replication. IL-6 and NLRP3 inflammasome are the major immune components in immune responses stimulation upon pathogen infection. It's noteworthy that the function and expression of these components are remarkably influenced by non-coding RNAs including long non-coding RNAs. Given the potential role of these components in organ damage and pathological manifestations of patients infected with COVID-19, their blockage might be a hopeful and promising treatment strategy. Notably, more study on long non-coding RNAs involved in inflammatory responses could elevate the efficacy of anti-inflammatory therapy. In this review we discuss the potential impact of IL-6 and NLRP3 inflammasome blocker drugs on inflammatory responses, viral clearance, and pathological and clinical manifestations. Collectively, anti-inflammatory strategy might pave the way to diminish clinical and pathological manifestations and thereby discharging patients infected with COVID-19 from hospital.

Gastric cancer is the third leading cause of cancer death with 5-year survival rate of about 30-35%. Since early detection is associated with decreased mortality, identification of novel biomarkers for early diagnosis and proper management of patients with the best response to therapy is urgently needed. Long noncoding RNAs (lncRNAs) due to their high specificity, easy accessibility in a noninvasive manner, as well as their aberrant expression under different pathological and physiological conditions, have received a great attention as potential diagnostic, prognostic, or predictive biomarkers. They may also serve as targets for treating gastric cancer. In this review, we highlighted the role of lncRNAs as tumor suppressors or oncogenes that make them potential biomarkers for the diagnosis and prognosis of gastric cancer.Relatively, lncRNAs such as H19, HOTAIR, UCA1, PVT1, tissue differentiation-inducing nonprotein coding, and LINC00152 could be potential diagnostic and prognostic markers in patients with gastric cancer. Also, the impact of lncRNAs such as ecCEBPA, MLK7-AS1, TUG1, HOXA11-AS, GAPLINC, LEIGC, multidrug resistance-related and upregulated lncRNA, PVT1 on gastric cancer epigenetic and drug resistance as well as their potential as therapeutic targets for personalized medicine was discussed.

Owing to the national prevention program and provided special care, the age distribution of thalassemic patients in Iran is getting adapted to a full prevention and treatment program and life expectancy of these patients has been increased considerably. This shift in the age distribution of thalassemia, a traditionally considered pediatric disease, will face us with new challenges and the health care system should be prepared for this new face of thalassemia.