Precise identification of correct exon–intron boundaries is a prerequisite to analyze the location and structure of genes. The existing framework for genomic signals, delineating exon and introns in a genomic segment, seems insufficient, predominantly due to poor sequence consensus as well as limitations of training on available experimental data sets. We present here a novel concept for characterizing exon–intron boundaries in genomic segments on the basis of structural and energetic properties. We analyzed boundary junctions on both sides of all the exons (3 28 368) of protein coding genes from human genome (GENCODE database) using 28 structural and three energy parameters. Study of sequence conservation at these sites shows very poor consensus. It is observed that DNA adopts a unique structural and energy state at the boundary junctions. Also, signals are somewhat different for housekeeping and tissue specific genes. Clustering of 31 parameters into four derived vectors gives some additional insights into the physical mechanisms involved in this biological process. Sites of structural and energy signals correlate well to the positions playing important roles in pre-mRNA splicing.
With almost no consensus promoter sequence in prokaryotes, recruitment of RNA polymerase (RNAP) to precise transcriptional start sites (TSSs) has remained an unsolved puzzle. Uncovering the underlying mechanism is critical for understanding the principle of gene regulation. We attempted to search the hidden code in ∼16,500 promoters of 12 prokaryotes representing two kingdoms in their structure and energetics. Twenty-eight fundamental parameters of DNA structure including backbone angles, basepair axis, and interbasepair and intrabasepair parameters were used, and information was extracted from x-ray crystallography data. Three parameters (solvation energy, hydrogen-bond energy, and stacking energy) were selected for creating energetics profiles using in-house programs. DNA of promoter regions was found to be inherently designed to undergo a change in every parameter undertaken for the study, in all prokaryotes. The change starts from some distance upstream of TSSs and continues past some distance from TSS, hence giving a signature state to promoter regions. These signature states might be the universal hidden codes recognized by RNAP. This observation was reiterated when randomly selected promoter sequences (with little sequence conservation) were subjected to structure generation; all developed into very similar three-dimensional structures quite distinct from those of conventional B-DNA and coding sequences. Fine structural details at important motifs (viz. -11, -35, and -75 positions relative to TSS) of promoters reveal novel to our knowledge and pointed insights for RNAP interaction at these locations; it could be correlated with how some particular structural changes at the -11 region may allow insertion of RNAP amino acids in interbasepair space as well as facilitate the flipping out of bases from the DNA duplex.
Biologically important three different pharmacophores, forskolin, indole and 1,2,3-triazoles are coupled to obtain a hybrid molecule. Here, we described the synthesis of novel series of forskolin-indole-triazole conjugates 5a-5l by using the Cu(I) catalyzed 1,3-dipolar cycloaddition reaction. Furthermore, the biological significance of the synthesized molecules was assessed by in silico and in vitro modes. All the synthesized compounds were evaluated for in vitro anticancer activity against PC-3, MCF-7, MDA-MB-231, COLO-205, HeLa, WRL-68, RAJI, CHANG and RAW-264.7 cell lines. Compound 5g was found to be the most potent in all the tested cell lines (IC 50 range 9.6-21.66 μg/ml, except COLO-205), 5a, 5b and 5k were observed to exert its effect only against WRL-68 (IC 50 range 27.69-48.18 μg/ml), when compared to parent 3 (IC 50 > 100 μg/ml, tested concentrations 10-50 μg/ml) and standard Doxorubicin (IC 50 range 0.42-3.16 μg/ml). The most potent compound 5g (MEF 50 0.57) was found non-toxic to human erythrocytes as compared to control (MEF 50 0.60) at tested concentration (50 μg/ml). In silico-based succinate dehydrogenase inhibition showed that the synthesized compounds were having potent binding affinity compared to forskolin. Predictive ADMET and toxicity risk assessment analysis revealed that most of the compounds were complying with the standard limit of Lipinski's rule of five for oral bioavailability.
Background:The entropy electrode is centrally placed on the forehead over the muscles of frontalis, orbicularis oculi, and corrugator supercilii. It determines response entropy (RE), which is the electromyogram component, and state entropy (SE), which is the electroencephalogram component. We hypothesized that due to the central location of entropy, the decreasing value of RE-SE ≤ 2 with SE ≤ 45 could denote an adequate combination of hypnosis, muscle paralysis, and analgesia required for endotracheal intubation. This could result in earlier intubation compared to when guided by train-of-four (TOF) = 0.Objectives: The primary objective of the study was to evaluate if entropy values of RE-SE ≤ 2 with SE ≤ 45 can be used as a measure of adequate condition for endotracheal intubation. We also sought to determine the TOF at this point. Methods: Endotracheal intubation was performed in group E (Entropy; n = 30) at RE-SE ≤ 2 with SE ≤ 45 and in group T (TOF; n = 30) at TOF = 0. A propofol bolus (20 mg) was administered if the patient had a hypertensive response or moved in response to endotracheal intubation. The TOF was noted at the time of intubation in group E. We also measured the time to intubation, jaw and vocal cord relaxation, patient movement or coughing, SE, TOF, and vital parameters. Statistical analysis was performed with two-tailed students' t test, paired t test, chi-square test, and ANOVA. The difference between groups was considered significant if the p value was < 0.05. Results:The time to intubation was significantly shorter in group E than in group T (92.5 ± 63.5 seconds vs. 209.2 ± 59.6 seconds; P < 0.001) with a mean TOF of 87.3% ± 8.4% in group E. Intubating conditions in terms of jaw relaxation, patient movement, and coughing were not significantly different between the two groups. Vocal cord relaxation was significantly inadequate in six patients in group E (P < 0.01); however, there was no difficulty in introducing the endotracheal tube with no postoperative adverse effects such as sore throat. Conclusions: Adequate conditions for endotracheal intubation were achieved 90 seconds after the administration of fentanyl, propofol, and vecuronium for anesthesia induction when it is guided by RE-SE ≤ 2 with SE ≤ 45, which is earlier than when guided by TOF = 0.
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