Drug-resistant HIV-1 protease regains functional dynamics through cleavage site coevolution

Drug resistance is caused by mutations that change the balance of recognition favoring substrate cleavage over inhibitor binding. Here, a structural dynamics perspective of the regained wild-type functioning in mutant HIV-1 proteases with coevolution of the natural substrates is provided. The collective dynamics of mutant structures of the protease bound to p1-p6 and NC-p1 substrates are assessed using the Anisotropic Network Model (ANM). The drug-induced protease mutations perturb the mechanistically crucial hinge axes that involve key sites for substrate binding and dimerization and mainly coordinate the intrinsic dynamics. Yet with substrate coevolution, while the wild-type dynamic behavior is restored in both p1-p6 ((LP) (1\u27F)p1-p6D30N/N88D) and NC-p1 ((AP) (2) (V)NC-p1V82A) bound proteases, the dynamic behavior of the NC-p1 bound protease variants (NC-p1V82A and (AP) (2) (V)NC-p1V82A) rather resemble those of the proteases bound to the other substrates, which is consistent with experimental studies. The orientational variations of residue fluctuations along the hinge axes in mutant structures justify the existence of coevolution in p1-p6 and NC-p1 substrates, that is, the dynamic behavior of hinge residues should contribute to the interdependent nature of substrate recognition. Overall, this study aids in the understanding of the structural dynamics basis of drug resistance and evolutionary optimization in the HIV-1 protease system

Substrate specificity in HIV-1 protease by a biased sequence search method

Drug resistance in HIV-1 protease can also occasionally confer a change in the substrate specificity. Through the use of computational techniques, a relationship can be determined between the substrate sequence and three-dimensional structure of HIV-1 protease, and be utilized to predict substrate specificity. In this study, we introduce a biased sequence search threading (BSST) methodology to analyze the preferences of substrate positions and correlations between them that might also identify which positions within known substrates can likely tolerate sequence variability and which cannot. The potential sequence space was efficiently explored using a low-resolution knowledge-based scoring function. The low-energy substrate sequences generated by the biased search are correlated with the natural substrates. Octameric sequences were predicted using the probabilities of residue positions in the sequences generated by BSST in three ways: considering each position in the substrate independently, considering pairwise interdependency, and considering triple-wise interdependency. The prediction of octameric sequences using the triple-wise conditional probabilities produces the most accurate results, reproducing most of the sequences for five of the nine natural substrates and implying that there is a complex interdependence between the different substrate residue positions. This likely reflects that HIV-1 protease recognizes the overall shape of the substrate more than its specific sequence

Geometric optimization of thermoelectric generator using genetic algorithm considering contact resistance and Thomson effect

Contact resistance and Thomson heat are the two major factors in the analysis of thermoelectric modules that are often being ignored. Each of these factors has an adverse effect on the output performance of a thermoelectric module. In this study, expression for maximum power output that includes both the contact resistance and the Thomson effect has been optimized using genetic algorithm to obtain the optimum geometric parameters of a thermoelectric generator. Each leg has electrical and thermal contact resistances of 2 x 10(-9) Omega m(2) and 1.8 x 10(-4) m(2) K/W, respectively. The results of the optimization for the maximum power output and the energy conversion efficiency for Skutterudites thermoelectric materials operating at a maximum temperature difference of 500 K are 30.1 W and 9.87%, respectively. When only the contact resistances are not included, the results rise by 19.4% for the maximum power output and 11.65% for the energy conversion efficiency. When only the Thomson heat is not included, the result rise by 2.66% for the maximum power output and 5.67% for the energy conversion efficiency. These two factors should always be considered in the analysis of thermoelectric modules, neglecting them can lead to an overestimation of the output performance

Can Be Used Vital Signs As Valid Indicators to Assess Pain in Neurosurgery Intensive Care Units?,

Erden Sevilay, Demir Nevra, Altun Uğraş Gülay, Arslan Umut, Arslan Sevban (2016) Can Be Used Vital Signs As Valid Indicators to Assess Pain in Neurosurgery Intensive Care Units?, 8th.World Congress of The World Institute of Pain, New York, ABD, (Sözel Bildiri

Is the relationship between problematic mobile phone use and mental health problems mediated by fear of missing out and escapism?

INTRODUCTION: Individuals with problematic mobile phone use often report mental health problems, however, little is known about factors which mediate this association. Therefore, the aim of this study was to examine the mediating role of fear of missing out (FoMO) and escapism in an attempt to explain the relationship between problematic mobile phone use and mental health problems. METHOD: A total of 235 undergraduate students in Turkey participated in this study. These participants completed a set of questionnaires to measure fear of missing out, problematic mobile phone use, escapism, depression, anxiety, stress, and worry severity. RESULTS: Participants with a high level of problematic mobile phone use also had a high level of mental health problems, FoMO, and escapism. The association between problematic mobile phone use and mental health problems was not mediated by FoMO and escapism. CONCLUSION: Personal characteristics such as emotional regulation and self-regulation need to be examined in future studies in order to determine their potential mediating role in explaining the association between problematic mobile phone use and mental health problems

Vital signs: Valid indicators to assess pain in intensive care unit patients? An observational, descriptive study

Abstract Pain is a stressor for intensive care unit (ICU) patients, and inadequate pain assessment has been linked to increased morbidity and mortality. One hundred and twenty patients were evaluated during three periods: (T1) 1 min before, (T2) during, and (T3) 20 min after the nociceptive procedure. For each patient, data were obtained through at least two nociceptive procedures. Conscious patients’ self-reports of pain were assessed using the Numerical Rating Scale and Visual Analog Scale. For unconscious patients, the Behavioral Pain Scale was used instead. Descriptive statistical methods, Friedman's test, and Spearman’s rank correlation coefficient were used for the data analysis. Significant changes were observed in heart rate (HR), respiratory rate (RR), and peripheral oxygen saturation (SpO2) during nociceptive procedures. The HR, RR, and pain scores increased, while the SpO2 decreased. Positive correlation coefficients were observed between the pain intensity and HR and RR levels. According to our study findings, vital signs are not strong indicators for pain assessment in neurosurgery ICU patients. However, HR and RR can be used as cues when behavioral indicators are not valid in these unconscious patients