Analysis of RNA sequence and structure in key genes of Mycobacterium ulcerans reveals conserved structural motifs and regions with apparent pressure to remain unstructured

Buruli Ulcer is a neglected tropical disease that results in disfiguring and potentially dangerous lesions in affected persons across a wide geographic area, which includes much of West Africa. The causative agent of Buruli Ulcer is Mycobacterium ulcerans, a relative of the bacterium that causes tuberculosis and leprosy. Few therapeutic options exist for the treatment of this disease beyond the main approach, surgical removal, which is frequently ineffective. In this study we analyze six genes in Mycobacterium ulcerans that have high potential of therapeutic targeting. We focus our analysis on a combined in silico and comparative sequence study of potential RNA secondary structure across these genes. The end result of this work was the comprehensive local RNA structural landscape across each of these significant genes. This revealed multiple sites of ordered and evolved RNA structure interspersed between sequences that either have no bias for structure or, indeed, appear to be ordered to be unstructured and (potentially) accessible. In addition to providing data that could be of interest to basic biology, our results provide guides for efforts aimed at targeting this pathogen at the RNA level. We explore this latter possibility through the in silico analysis of antisense oligonucleotides that could be used to target pathogen RNA.

GENESIS AND BLACK HOLE UNIVERSE: THE THIRD DAY

Recently the author has fully addressed the first two days of Genesis according to his well-developed black hole universe model (see Paper-I and Paper-II). In accordance with this new interpretation of Genesis, God first created the infinite entire universe called “earth” with matter named “water”, and light, space and time, fundamental forces and motion. Then, he hierarchically structured the entire universe by separating the matter and space with infinite layers bounded by event horizons (called “vaults”) and further formed our finite black hole universe. The efforts bridged the gap between Genesis and observations of the universe and brought us a scientific understanding of the Genesis. In this sequence study as Paper-III, we describe how God constructed the interiors of our finite black hole universe. It includes the formation of celestial objects by gathering the water or gravitationally collapsing the initial super fluidal matter under the sky or inside the even horizon of our black hole universe. These formed celestial objects could be stars and planets called dry grounds or lands, in which matter is not in the water state any more, and galaxies and clusters called, respectively, seas of stars and seas of galaxies.

An open-label, fixed-sequence study to evaluate the effect of encequidar (HM30181) an oral P-gp inhibitor, on the pharmacokinetics of dabigatran etexilate (a P-gp substrate) in healthy male volunteers.

e15060 Background: Oral co-administration of encequidar (a selective, minimally absorbed oral P-gp inhibitor) 12.9 mg with paclitaxel (a P-gp substrate) 205 mg/m2 for 3 consecutive days per week can achieve comparable AUC exposure to that of IV paclitaxel 80mg/m2 with a significantly lowered Cmax and has been demonstrated its improved tumor response with reduced neuropathy compared to IV paclitaxel 175 mg/m2 Q3W for the treatment of patients with metastatic breast cancer. Because of its pharmacology as an inhibitor of P-gp, encequidar may increase the bioavailability of orally administered drugs that are substrates of P-gp, such as dabigatran etexilate. Methods: To determine the effect of a therapeutic dose and regimen (3 once-daily 12.9 mg doses) of encequidar on the single dose PK of dabigatran etexilate, an open-label, fixed-sequence study was performed in 20 healthy male subjects. Participants received a single oral dose of dabigatran etexilate 75 mg on Day 1 of Treatment Period 1 (reference) and, after a washout period of at least 7 days, on Days 3, 17 and 31 of Treatment Period 2, after receiving once-daily oral doses 12.9 mg encequidar on Days 1 to 3 of Period 2. The PK sampling for determination of plasma concentrations of total and unconjugated dabigatran lasted up to 48 hours postdose of each dabigatran etexilate dosr. Results: Mean AUC and Cmax values for dabigatran were both increased ̃ 95% without changing t½ when dabigatran etexilate was administered 1 hour post the 3rd dose of 12.9 mg encequidar compared to when dabigatran etexilate was administered alone. When dabigatran etexilate was administered 2 weeks after encequidar administration, no apparent differences in dabigatran AUC or Cmax were detected compared to those of dabigatran etexilate alone. When administered 4 weeks after discontinuation of encequidar, dabigatran AUC and Cmax were both slightly lower than Reference dabigatran etexilate (̃ 25% lower for AUC and 34% lower for Cmax). Both unconjugated and total dabigatran PK data were analyzed and shown to be similar. Encequidar and dabigatran etexilate were well tolerated and had acceptable safety findings in this healthy subject population. Conclusions: Concomitant dosing of encequidar with dabigatran etexilate resulted in < 2-fold increase in exposure to dabigatran, which had abated by the time of the first re-test, 14 days after the last dose of encequidar. The observed changes do not warrant dose adjustment of dabigatran etexilate when administered with encequidar. Clinical trial information: ACTRN12618000791235.

Entropy Based Biological Sequence Study

SARS-CoV-2 virus strains are taken into consideration for the analysis of digitized sequences of information by means of the notions of entropy. The occurrence of a particular pattern in the corona viral sequence is paid a special attention. The incidence of genetic word is represented in a density means. The incidence frequency of the q-gram genetic word is determined with the help of finite impulse response (FIR) filter along the sequence. It is in turn, used for the determination of the probability distribution of the genetic word incidence as the input for the calculation of entropy in the sequence. The sequence entropy is further used for principal component analysis (PCA) to determine the similarity/dissimilarity between the viral sequences. We have considered seven human corona virus sequences. Entropy based similarity study for SARS-CoV-2 strains is presented in this work.

Epidemiology, Pathogenesis, and Healing Strategies of COVID-19

In the present chapter, some notable features (epidemiology, pathogenesis, and clinical characteristics) regarding recent outbreak COVID-19 have been reviewed. Most significant features related to COVID-19 such as (i) roots of infection and disease manifestation, (ii) shape and structure of viral S-protein, (iii) genome sequence study and replication in host cell, (iv) role of environmental factors, (v) diagnosis tools and (vi) role of biosensor have been critically investigated. The biological and behavioral risk factors for pregnant women before and after child birth have been dictated clearly. Pulmonary abnormalities due to COVID-19 of the patient having diabetes, cancer etc. history have been clarified with help of CT imaging. Finally, prevention and cure strategies adopted by many health professionals based on the existing drugs are mentioned with their side effects.

Advice Padded With Encouragement: A Preliminary Assessment of an Extended Integrated Model of Advice Giving in Supportive Interactions

The integrated model of advice giving (IMA) proposes that advising in supportive interactions should be carried out in three sequential moves: emotional support—problem inquiry and analysis—advice (EPA). Prior research indicates the utility of this framework for effective advising in supportive interactions. The current project proposed and tested an extended integrated model of advice giving, adding eSteem support (S) as a fourth move in the sequence. Two experiments were conducted. Study 1 included 371 participants recruited from Amazon Mechanical Turk. Results showed that the emotional support—problem inquiry and analysis—advice—eSteem support (EPAS) sequence did not elicit significantly higher evaluations of advice quality compared with the EPA or emotional support—problem inquiry and analysis—eSteem support—advice (EPSA) sequence. Study 2 replicated Study 1 with 364 college students and found that, compared with the other two sequences, the EPAS sequence did not produce significantly higher evaluations of advice quality or intention to follow advice. Theoretical implications and directions for future research are discussed.