In silico evaluation of antiviral activity of flavone derivatives and commercial drugs against SARS-CoV-2 main protease (3CLpro).

In this paper the in silco evaluation of the antiviaral activity against the current spread of severe acute respiratory syndrome novel coronavirus 2 (SARS-CoV-2) of several anti-viral components such as Chloroquine, Simeprevir, Lopinavir and a series of five natural and synthesized flavone derivative was investigated.Results of the molecular docking revealed that among of the five flavones studied and Chloroquine, Simeprevir and Lopinavir, three compounds correlate with a high affinity for the same binding sites with the major protein 3-chymotrypsin-like protease (3CLpro) and a small negative binding energy compared with the control N3 molecule in protein 6LU7 and the control WK1 molecule in protein 2OP9. This may disrupt the 3CLpro main protease function and efficiency

Deciphering the SARS-CoV-2 Delta Variant: Antiviral Compound Efficacy by Molecular Docking, ADMET, and Dynamics Studies

This research was conducted to discover potential antiviral compounds effective against the Delta variant of SARS-CoV-2 through computational screening methods. Our investigation encompassed nine established antiviral medications—Ritonavir, Remdesivir, Lopinavir, Ivermectin, Favipiravir, Ribavirin, Clofoctol, Chlorpromazine, and Artemisinin—and a flavone derivative, 2-(4-((6-hydroxyhexyl)oxy)phenyl)-4H-chroman-4-one (4c). These compounds were evaluated for their binding affinity to the Delta variant’s spike protein and their stability within the complex. We also examined their ADMET profiles and pharmacokinetic properties. he study found that all compounds exhibited strong binding to key amino acid residues within the spike protein’s active site, potentially inhibiting the enzyme’s function. Binding energy values ranged from -3.966 to -6.392 kcal/mol for the for the known drugs, with the flavone derivative exhibiting the highest binding affinity of -7.895 kcal/mol and an optimal ADMET profile. Molecular dynamics simulations further confirmed the stability of the 4c-spike protein complex. Our results indicate that the flavone derivative 4c is a promising lead for the development of novel antiviral therapies targeting the Delta variant of SARS-CoV-2

Layered LiNi0.5Co0.5O2 cathode materials grown by soft-chemistry via various solution methods

[Abstract] The lithiated nickel–cobalt oxide LiNi0.5Co0.5O2 used as cathode material was grown at low-temperature using different aqueous solution methods. The wet chemistry involved the mixture of metal salts (acetates or nitrates) with various carboxylic acid-based aqueous solutions. Physicochemical and electrochemical properties of LiNi0.5Co0.5O2 products calcined at 400–600°C were extensively investigated. The four methods used involved complexing agents such as either citric, oxalic, aminoacetic (glycine), or succinic acid in aqueous medium which functioned as a fuel, decomposed the metal complexes at low temperature, and yielded the free impurity LiNi0.5Co0.5O2 compounds. Thermal (TG–DTA) analyses and XRD data show that powders grown with a layered structure ( space group) have been obtained at temperatures below 400°C by the acidification reaction of the aqueous solutions. The local structure of synthesized products was characterized by Fourier transform infrared (FTIR) spectroscopy. The electrochemical properties of the synthesized products were evaluated in rechargeable Li cells using a non-aqueous organic electrolyte (1 M LiClO4 in propylene carbonate, PC). The LiNi0.5Co0.5O2 positive electrodes fired at 600°C exhibited good cycling behavior

Targeted knock-down of miR21 primary transcripts using snoMEN vectors induces apoptosis in human cancer cell lines

We have previously reported an antisense technology, 'snoMEN vectors', for targeted knock-down of protein coding mRNAs using human snoRNAs manipulated to contain short regions of sequence complementarity with the mRNA target. Here we characterise the use of snoMEN vectors to target the knock-down of micro RNA primary transcripts. We document the specific knock-down of miR21 in HeLa cells using plasmid vectors expressing miR21-targeted snoMEN RNAs and show this induces apoptosis. Knock-down is dependent on the presence of complementary sequences in the snoMEN vector and the induction of apoptosis can be suppressed by over-expression of miR21. Furthermore, we have also developed lentiviral vectors for delivery of snoMEN RNAs and show this increases the efficiency of vector transduction in many human cell lines that are difficult to transfect with plasmid vectors. Transduction of lentiviral vectors expressing snoMEN targeted to pri-miR21 induces apoptosis in human lung adenocarcinoma cells, which express high levels of miR21, but not in human primary cells. We show that snoMEN-mediated suppression of miRNA expression is prevented by siRNA knock-down of Ago2, but not by knock-down of Ago1 or Upf1. snoMEN RNAs colocalise with Ago2 in cell nuclei and nucleoli and can be co-immunoprecipitated from nuclear extracts by antibodies specific for Ago2

Accounting students' IT applicaton skills over a 10-year period

This paper reports on the changing nature of a range of information technology (IT) application skills that students declare on entering an accounting degree over the period from 1996 to 2006. Accounting educators need to be aware of the IT skills students bring with them to university because of the implications this has for learning and teaching within the discipline and the importance of both general and specific IT skills within the practice and craft of accounting. Additionally, IT skills constitute a significant element within the portfolio of employability skills that are increasingly demanded by employers and emphasized within the overall Higher Education (HE) agenda. The analysis of students' reported IT application skills on entry to university, across a range of the most relevant areas of IT use in accounting, suggest that their skills have continued to improve over time. However, there are significant differential patterns of change through the years and within cohorts. The paper addresses the generalizability of these findings and discusses the implications of these factors for accounting educators, including the importance of recognising the differences that are potentially masked by the general increase in skills; the need for further research into the changing nature, and implications, of the gender gap in entrants' IT application skills; and the low levels of entrants' spreadsheet and database skills that are a cause for concern

Genetic determinants of co-accessible chromatin regions in activated T cells across humans.

Over 90% of genetic variants associated with complex human traits map to non-coding regions, but little is understood about how they modulate gene regulation in health and disease. One possible mechanism is that genetic variants affect the activity of one or more cis-regulatory elements leading to gene expression variation in specific cell types. To identify such cases, we analyzed ATAC-seq and RNA-seq profiles from stimulated primary CD4+ T cells in up to 105 healthy donors. We found that regions of accessible chromatin (ATAC-peaks) are co-accessible at kilobase and megabase resolution, consistent with the three-dimensional chromatin organization measured by in situ Hi-C in T cells. Fifteen percent of genetic variants located within ATAC-peaks affected the accessibility of the corresponding peak (local-ATAC-QTLs). Local-ATAC-QTLs have the largest effects on co-accessible peaks, are associated with gene expression and are enriched for autoimmune disease variants. Our results provide insights into how natural genetic variants modulate cis-regulatory elements, in isolation or in concert, to influence gene expression

Removal of AU Bias from Microarray mRNA Expression Data Enhances Computational Identification of Active MicroRNAs

Elucidation of regulatory roles played by microRNAs (miRs) in various biological networks is one of the greatest challenges of present molecular and computational biology. The integrated analysis of gene expression data and 3′-UTR sequences holds great promise for being an effective means to systematically delineate active miRs in different biological processes. Applying such an integrated analysis, we uncovered a striking relationship between 3′-UTR AU content and gene response in numerous microarray datasets. We show that this relationship is secondary to a general bias that links gene response and probe AU content and reflects the fact that in the majority of current arrays probes are selected from target transcript 3′-UTRs. Therefore, removal of this bias, which is in order in any analysis of microarray datasets, is of crucial importance when integrating expression data and 3′-UTR sequences to identify regulatory elements embedded in this region. We developed visualization and normalization schemes for the detection and removal of such AU biases and demonstrate that their application to microarray data significantly enhances the computational identification of active miRs. Our results substantiate that, after removal of AU biases, mRNA expression profiles contain ample information which allows in silico detection of miRs that are active in physiological conditions

miR-22 Forms a Regulatory Loop in PTEN/AKT Pathway and Modulates Signaling Kinetics

Background: The tumor suppressor PTEN (phosphatase and tensin homolog) is a lipid phosphatase that converts PIP3 into PIP2 and downregulates the kinase AKT and its proliferative and anti-apoptotic activities. The FoxO transcription factors are PTEN downstream effectors whose activity is negatively regulated by AKT-mediated phosphorylation. PTEN activity is frequently lost in many types of cancer, leading to increased cell survival and cell cycle progression. Principal Findings: Here we characterize the widely expressed miR-22 and report that miR-22 is a novel regulatory molecule in the PTEN/AKT pathway. miR-22 downregulates PTEN levels acting directly through a specific site on PTEN 39UTR. Interestingly, miR-22 itself is upregulated by AKT, suggesting that miR-22 forms a feed-forward circuit in this pathway. Timeresolved live imaging of AKT-dependent FoxO1 phosphorylation revealed that miR-22 accelerated AKT activity upon growth factor stimulation, and attenuated its down regulation by serum withdrawal. Conclusions: Our results suggest that miR-22 acts to fine-tune the dynamics of PTEN/AKT/FoxO1 pathway

MicroRNAs can generate thresholds in target gene expression

MicroRNAs (miRNAs) are short, highly conserved noncoding RNA molecules that repress gene expression in a sequence-dependent manner. We performed single-cell measurements using quantitative fluorescence microscopy and flow cytometry to monitor a target gene's protein expression in the presence and absence of regulation by miRNA. We find that although the average level of repression is modest, in agreement with previous population-based measurements, the repression among individual cells varies dramatically. In particular, we show that regulation by miRNAs establishes a threshold level of target mRNA below which protein production is highly repressed. Near this threshold, protein expression responds sensitively to target mRNA input, consistent with a mathematical model of molecular titration. These results show that miRNAs can act both as a switch and as a fine-tuner of gene expression.National Institutes of Health (U.S.). Director's Pioneer Award (1DP1OD003936)National Cancer Institute (U.S.). Physical Sciences-Oncology Center (U54CA143874)United States. Public Health Service (Grant R01-CA133404)United States. Public Health Service (Grant R01-GM34277)National Cancer Institute (U.S.) (PO1-CA42063)National Cancer Institute (U.S.) Cancer Center Support (Grant P30-CA14051)Howard Hughes Medical Institute. Predoctoral FellowshipCleo and Paul Schimmel Foundation. FellowshipNatural Sciences and Engineering Research Council of Canada PGS Scholarshi