The role of nonlinear DNA in replication, recombination, and transcription has become evident in recent years. Although several studies have predicted and characterized regulatory elements at the sequence level, very few have investigated DNA structure as regulatory motifs. Here, using G-quadruplex or G4 DNA motifs as a model, we have researched the role of DNA structure in transcription on a genome-wide scale. Analyses of >61,000 open reading frames (ORFs) across 18 prokaryotes show enrichment of G4 motifs in regulatory regions and indicate its predominance within promoters of genes pertaining to transcription, secondary metabolite biosynthesis, and signal transduction. Based on this, we predict that G4 DNA may present regulatory signals. This is supported by conserved G4 motifs in promoters of orthologous genes across phylogenetically distant organisms. We hypothesized a regulatory role of G4 DNA during supercoiling stress, when duplex destabilization may result in G4 formation. This is in line with our observations from target site analysis for 55 DNA-binding proteins in Escherichia coli, which reveals significant (P < 0.001) association of G4 motifs with target sites of global regulators FIS and Lrp and the sigma factor RpoD ( 70 ). These factors together control >1000 genes in the early growth phase and are believed to be induced by supercoiled DNA. We also predict G4 motif-induced supercoiling sensitivity for >30 operons in E. coli, and our findings implicate G4 DNA in DNA-topology-mediated global gene regulation in E. coli.
Using a combination of in silico and experimental approaches, we present evidence that the G-quadruplex (G4) motif (an alternative higher-order DNA conformation) has regulatory potential. Genome-wide analyses of 99980 human, chimpanzee, mouse, and rat promoters showed enrichment of sequence with potential to adopt G4 (potential G4 or PG4) motifs near transcription start sites (TSS; P < 0.0001), supporting earlier findings. Interestingly, we found >700 orthologously related promoters in human, mouse, and rat conserve PG4 motif(s). The corresponding genes have enriched (z score > 4.0) tissue-specific expression in 75 of 79 human tissues and are significantly overrepresented in signaling and regulation of cell-cycle (P < 10(-05)). This is supported by results from whole genome expression experiments in human HeLa S3 cells following treatment with TMPyP4 [5,10,15,20-tetra(N-methyl-4-pyridyl) porphine chloride], which is known to bind the G4 motif inside cells. Our results implicate G4-motif mediated regulation as a more general mode of transcription control than currently appreciated.
A considerable amount is being invested by the vehicle developers in reducing the power needed for propulsion. The vehicle is optimized such to reduce the aerodynamic drag as the drag force is the leading resistance to the motion of vehicle. The flow separation at the rear end of the vehicle is one of the major causes of this drag. This paper investigates the effect of the delta shaped aerodynamic devices, known as vortex generators, installed at the roof of a hatchback type car to delay the flow separation. Mostly vortex generators are used in aircrafts and faster road vehicles with a notch at rear like the sedans. This experiment, unlike the previous researches, investigates and compares the aerodynamic drag and lift of the hatch back vehicle with and without Vortex Generator. Here it is represented that the improvement in aerodynamic drag force reduction, although of very minimal amount, can be achieved by using VGs on hatch back type cars.
Background of the Topic: Drug discovery employs bioinformatics and computational biology (CADD) approaches for the identification and optimization of lead compounds. The PARP-1 is the member of the PARP family. PARP-1 is the enzyme that repairs the DNA damage in cancer cell hence it is selected as the target for the study. PARP inhibitors were shown the prominent results in the treatment of different kinds of malignancies due to loss of function of BRCA1/2 genes. Methodology: Based on literature review, database search, ADME and MD simulation, top 10 selected ligands were screened and tested against PARP-1 (4R6E) protein using molecular docking (Glide and Gold software), protein ligand interaction by LIGPLOT analysis. Molecular simulation studies were performed using DESMOND software afterwards on the top compound (CHEMBL378794). Results: All top 10 compounds showed binding affinity based inhibitory potential against the PARP-1 protein. The highest binding affinities from top 10 compounds towards anticancer targets were exhibited by CHEMBL378794 and CHEMBL245559. Discussion: The comparative analysis of 4R6E and the identified hits using MD simulation exhibited better stability of the binding domain with these molecules suggesting their strong interaction and selectivity towards PARP-1. Conclusion: This study showed the significant results in cancer treatment and their strong interaction with PARP-1 binding BRCT domain. Hence, these molecules could further be carried forward to explore their potency against PARP-1 sensitive cancer.
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