Sequencing Closterium moniliferum: Future prospects in nuclear waste disposal

AbstractGenome sequencing can play a vital role in health and several other domains such as in nuclear outflow related environmental issues. The power of information derived out of sequencing has been used in the field of health care, evolutionary studies and for better understanding of the biological framework of life. Through the recent advancements in sequencing studies, now the researchers are aiming to use its power in non conventional areas. Here we have discussed on the importance of sequencing the Closterium moniliferum genome which will prove to be a future endeavour in nuclear cleanup and radioactive waste disposal

Computational evaluation of small molecule inhibitors of RGS4 to regulate the dopaminergic control of striatal LTD

Parkinson’s disease is a neurodegenerative disease which is the result of the degradation of the dopaminergic neurons in the substantia nigra pars compacta, leading to a disregulation of thalamocortical circuits. Traditional treatment involves the use of levodopa which increases the dopamine level in the striatum. There is a need for alternative non-dopamine therapy to prevent the side effects of the conventional drugs used. Recently small molecule inhibitors of RGS have become the prime candidates in studies related to regulating RGS by binding to its allosteric site and thus changing its structure. Through the docking studies we observed that these small molecule modulators of RGS4 make stable complexes with RGS4 when compared to native RGS4. The Gq(alpha)–GS4–rug complexes are less stable. The increase in flexibility of the RGS4–rug complex could be the reason for the inability of the RGS4–rug complex to bind to the G protein. In our docking results, CCG63802 formed the most promising drug as a RGS4 inhibitor as it formed the most stable complex with RGS4 and also formed the least stable complex, Gq(alpha)–RGS4–CCG63802 complex. In our studies we evaluated the therapeutic potential of the small molecule inhibitors to provide a prospective treatment for Parkinson’s disease.Keywords: RGS4 inhibitor; Parkinson disease; Flexibility; MGlu receptors; Neural plasticityThe Egyptian Journal of Medical Human Genetics (2013) 14, 135–14

Single Nucleotide Polymorphisms in MicroRNA Binding Sites: Implications in Colorectal Cancer

Cancer is a complex genetic disorder, characterised by uncontrolled cell proliferation and caused by altered expression of oncogenes and tumour suppressor genes. When cell proliferation pertains to colon, it is called colorectal cancer. Most of colorectal cancer causing genes are potential targets for the miRNA (microRNA) that bind to 3′UTR (untranslated regions) of mRNA and inhibit translation. Mutations occurring in miRNA binding regions can alter the miRNA, mRNA combination, and can alter gene expression drastically. We hypothesized that 3′UTR mutation in miRNA binding site could alter the miRNA, mRNA interaction, thereby altering gene expression. Altered gene expression activity could promote tumorigenesis in colon. Therefore, we formulated a systematic in silico procedure that integrates data from various databases, followed rigorous selection criteria, and identified mutations that might alter the expression levels of cancer causing genes. Further we performed expression analysis to shed light on the potential tissues that might be affected by mutation, enrichment analysis to find the metabolic functions of the gene, and network analysis to highlight the important interactions of cancer causing genes with other genes to provide insight that complex network will be disturbed upon mutation. We provide in silico evidence for the effect of these mutations in colorectal cancer

AKT Kinase Pathway: A Leading Target in Cancer Research

AKT1, a serine/threonine-protein kinase also known as AKT kinase, is involved in the regulation of various signalling downstream pathways including metabolism, cell proliferation, survival, growth, and angiogenesis. The AKT kinases pathway stands among the most important components of cell proliferation mechanism. Several approaches have been implemented to design an efficient drug molecule to target AKT kinases, although the promising results have not been confirmed. In this paper we have documented the detailed molecular insight of AKT kinase protein and proposed a probable doxorubicin based approach in inhibiting miR-21 based cancer cell proliferation. Moreover, the inhibition of miR-21 activation by raising the FOXO3A concentration seems promising in reducing miR-21 mediated cancer activation in cell. Furthermore, the use of next generation sequencing and computational drug design approaches will greatly assist in designing a potent drug molecule against the associated cancer cases

Immuno-informatics analysis predicts B and T cell consensus epitopes for designing peptide vaccine against SARS-CoV-2 with 99.82% global population coverage.

The current global pandemic due to Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) has taken a substantial number of lives across the world. Although few vaccines have been rolled-out, a number of vaccine candidates are still under clinical trials at various pharmaceutical companies and laboratories around the world. Considering the intrinsic nature of viruses in mutating and evolving over time, persistent efforts are needed to develop better vaccine candidates. In this study, various immuno-informatics tools and bioinformatics databases were deployed to derive consensus B-cell and T-cell epitope sequences of SARS-CoV-2 spike glycoprotein. This approach has identified four potential epitopes which have the capability to initiate both antibody and cell-mediated immune responses, are non-allergenic and do not trigger autoimmunity. These peptide sequences were also evaluated to show 99.82% of global population coverage based on the genotypic frequencies of HLA binding alleles for both MHC class-I and class-II and are unique for SARS-CoV-2 isolated from human as a host species. Epitope number 2 alone had a global population coverage of 98.2%. Therefore, we further validated binding and interaction of its constituent T-cell epitopes with their corresponding HLA proteins using molecular docking and molecular dynamics simulation experiments, followed by binding free energy calculations with molecular mechanics Poisson-Boltzmann surface area, essential dynamics analysis and free energy landscape analysis. The immuno-informatics pipeline described and the candidate epitopes discovered herein could have significant impact upon efforts to develop globally effective SARS-CoV-2 vaccines

Immuno-informatics analysis predicts B and T cell consensus epitopes for designing peptide vaccine against SARS-CoV-2 with 99.82% global population coverage.

The current global pandemic due to Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) has taken a substantial number of lives across the world. Although few vaccines have been rolled-out, a number of vaccine candidates are still under clinical trials at various pharmaceutical companies and laboratories around the world. Considering the intrinsic nature of viruses in mutating and evolving over time, persistent efforts are needed to develop better vaccine candidates. In this study, various immuno-informatics tools and bioinformatics databases were deployed to derive consensus B-cell and T-cell epitope sequences of SARS-CoV-2 spike glycoprotein. This approach has identified four potential epitopes which have the capability to initiate both antibody and cell-mediated immune responses, are non-allergenic and do not trigger autoimmunity. These peptide sequences were also evaluated to show 99.82% of global population coverage based on the genotypic frequencies of HLA binding alleles for both MHC class-I and class-II and are unique for SARS-CoV-2 isolated from human as a host species. Epitope number 2 alone had a global population coverage of 98.2%. Therefore, we further validated binding and interaction of its constituent T-cell epitopes with their corresponding HLA proteins using molecular docking and molecular dynamics simulation experiments, followed by binding free energy calculations with molecular mechanics Poisson-Boltzmann surface area, essential dynamics analysis and free energy landscape analysis. The immuno-informatics pipeline described and the candidate epitopes discovered herein could have significant impact upon efforts to develop globally effective SARS-CoV-2 vaccines

Role of ELA region in auto-activation of mutant KIT receptor: a molecular dynamics simulation insight

<div><p>KIT receptor is the prime target in gastrointestinal stromal tumor (GISTs) therapy. Second generation inhibitor, Sunitinib, binds to an inactivated conformation of KIT receptor and stabilizes it in order to prevent tumor formation. Here, we investigated the dynamic behavior of wild type and mutant D816H KIT receptor, and emphasized the extended A-loop (EAL) region (805–850) by conducting molecular dynamics simulation (∼100 ns). We analyzed different properties such as root mean square cutoff or deviation, root mean square fluctuation, radius of gyration, solvent-accessible surface area, hydrogen bonding network analysis, and essential dynamics. Apart from this, clustering and cross-correlation matrix approach was used to explore the conformational space of the wild type and mutant EAL region of KIT receptor. Molecular dynamics analysis indicated that mutation (D816H) was able to alter intramolecular hydrogen bonding pattern and affected the structural flexibility of EAL region. Moreover, flexible secondary elements, specially, coil and turns were dominated in EAL region of mutant KIT receptor during simulation. This phenomenon increased the movement of EAL region which in turn helped in shifting the equilibrium towards the active kinase conformation. Our atomic investigation of mutant KIT receptor which emphasized on EAL region provided a better insight into the understanding of Sunitinib resistance mechanism of KIT receptor and would help to discover new therapeutics for KIT-based resistant tumor cells in GIST therapy.</p></div

In Silico Screening and Molecular Dynamics Simulation of Disease-Associated nsSNP in TYRP1 Gene and Its Structural Consequences in OCA3

Oculocutaneous albinism type III (OCA3), caused by mutations of TYRP1 gene, is an autosomal recessive disorder characterized by reduced biosynthesis of melanin pigment in the hair, skin, and eyes. The TYRP1 gene encodes a protein called tyrosinase-related protein-1 (Tyrp1). Tyrp1 is involved in maintaining the stability of tyrosinase protein and modulating its catalytic activity in eumelanin synthesis. Tyrp1 is also involved in maintenance of melanosome structure and affects melanocyte proliferation and cell death. In this work we implemented computational analysis to filter the most probable mutation that might be associated with OCA3. We found R326H and R356Q as most deleterious and disease associated by using PolyPhen 2.0, SIFT, PANTHER, I-mutant 3.0, PhD-SNP, SNP&GO, Pmut, and Mutpred tools. To understand the atomic arrangement in 3D space, the native and mutant (R326H and R356Q) structures were modelled. Finally the structural analyses of native and mutant Tyrp1 proteins were investigated using molecular dynamics simulation (MDS) approach. MDS results showed more flexibility in native Tyrp1 structure. Due to mutation in Tyrp1 protein, it became more rigid and might disturb the structural conformation and catalytic function of the structure and might also play a significant role in inducing OCA3. The results obtained from this study would facilitate wet-lab researches to develop a potent drug therapies against OCA3