Hofmeister series for metal-cation–RNA interactions: the interplay of binding affinity and exchange kinetics

A large variety of physicochemical properties involving RNA depends on the type of metal cation present in solution. In order to gain microscopic insight into the origin of these ion specific effects, we apply molecular dynamics simulations to describe the interactions of metal cations and RNA. For the three most common ion binding sites on RNA, we calculate the binding affinities and exchange rates of eight different mono- and divalent metal cations. Our results reveal that binding sites involving phosphate groups preferentially bind metal cations with high charge density (such as Mg2+) in inner-sphere conformations while binding sites involving N7 or O6 atoms preferentially bind cations with low charge density (such as K+). The binding affinity therefore follows a direct Hofmeister series at the backbone but is reversed at the nucleobases leading to a high selectivity of ion binding sites on RNA. In addition, the exchange rates for cation binding cover almost 5 orders of magnitude, leading to a vastly different time scale for the lifetimes of contact pairs. Taken together, the site-specific binding affinities and the specific lifetime of contact pairs provide the microscopic explanation of ion specific effects observed in a wide variety of macroscopic RNA properties. Finally, combining the results from atomistic simulations with extended Poisson-Boltzmann theory allows us to predict the distribution of metal cations around double-stranded RNA at finite concentrations and to reproduce the results of ion counting experiments with good accuracy

Evaluation of Active Affiliates to the SIS Multidimensional Analysis in R Shiny

This article presents a study that uses multiple linear regression analysis to examine the factors influencing the number of people affiliated with different insurance plans within the Comprehensive Health Insurance (SIS) system in Peru.The study highlights the importance of multiple linear regression analysis in understanding the factors that affect SIS Comprehensive Health Insurance affiliates. It also showcases the value of utilizing interactive tools like RShiny to enhance data analysis, providing a dynamic and participatory experience for researchers and users interested in the subject.To facilitate the analysis and visualization of SIS-related data, the researchers developed an interactive application using RShiny. This tool allows for the easy loading, visualization, and analysis of data in a user-friendly and practical manner. By providing an interactive platform, users can effectively explore and understand the factors that impact SIS affiliates.The results of the analysis indicate that the selected variables have a significant positive influence on the total number of affiliates. This suggests that the specific insurance plan examined in this study has a favorable effect on the enrollment of individuals in SIS. Additionally, the data shows a linear trend, supporting the use of a linear regression model to describe this relationship. Active affiliates,Comprehensive health insurance SIS,Data Visualization,Multiple Linear Regression Analysis,RShin

Optimized magnesium force field parameters for biomolecular simulations with accurate solvation, ion-binding, and water-exchange properties

Magnesium ions play an essential role in many vital processes. To correctly describe their interactions in molecular dynamics simulations, an accurate parametrization is crucial. Despite the importance and considerable scientific effort, current force fields based on the commonly used 12-6 Lennard-Jones interaction potential fail to reproduce a variety of experimental solution properties. In particular, no parametrization exists so far that simultaneously reproduces the solvation free energy and the distance to the water oxygens in the first hydration shell. Moreover, current Mg2+ force fields significantly underestimate the rate of water exchange leading to unrealistically slow exchange kinetics. In order to make progress in the development of improved models, we systematically optimize the Mg2+ parameters in combination with the TIP3P water model in a much larger parameter space than previously done. The results show that a long-ranged interaction potential and modified Lorentz-Berthelot combination rules allow us to accurately reproduce multiple experimental properties including the solvation free energy, the distances to the oxygens of the first hydration shell, the hydration number, the activity coefficient derivative in MgCl2 solutions, the self-diffusion coefficient, and the binding affinity to the phosphate oxygen of RNA. Matching this broad range of thermodynamic properties, we present two sets of optimal parameters: MicroMg yields water exchange on the microsecond timescale in agreement with experiments. NanoMg yields water exchange on the nanosecond timescale facilitating the direct observation of ion-binding events. As shown for the example of the add A-riboswitch, the optimized parameters correctly reproduce the structure of specifically bound ions and permit the de novo prediction of Mg2+-binding sites in biomolecular simulations

Extended magnesium and calcium force field parameters for accurate ion–nucleic acid interactions in biomolecular simulations

Magnesium and calcium play an essential role in the folding and function of nucleic acids. To correctly describe their interactions with DNA and RNA in biomolecular simulations, an accurate parameterization is crucial. In most cases, the ion parameters are optimized based on a set of experimental solution properties such as solvation free energies, radial distribution functions, water exchange rates, and activity coefficient derivatives. However, the transferability of such bulk-optimized ion parameters to quantitatively describe biomolecular systems is limited. Here, we extend the applicability of our previous bulk-optimized parameters by including experimental binding affinities toward the phosphate oxygen on nucleic acids. In particular, we systematically adjust the combination rules that are an integral part of the pairwise interaction potentials of classical force fields. This allows us to quantitatively describe specific ion binding to nucleic acids without changing the solution properties in the most simple and efficient way. We show the advancement of the optimized Lorentz combination rule for two representative nucleic acid systems. For double-stranded DNA, the optimized combination rule for Ca2+>/sup> significantly improves the agreement with experiments, while the standard combination rule leads to unrealistically distorted DNA structures. For the add A-riboswitch, the optimized combination rule for Mg2+>/sup> improves the structure of two specifically bound Mg2+>/sup> ions as judged by the experimental distance to the binding site. Including experimental binding affinities toward specific ion binding sites on biomolecules, therefore, provides a promising perspective to develop a more accurate description of metal cations for biomolecular simulations

Knock‐out of multidrug efflux pump MexXY‐OprM results in increased susceptibility to antimicrobial peptides in Pseudomonas aeruginosa

Multidrug efflux systems of the resistance-nodulation-cell division family play a crucial role in resistance of Pseudomonas aeruginosa to a large variety of antibiotics. Here, we investigated the role of clinically relevant efflux pumps MexAB$^−$OprM, MexCD$^−$OprJ, and MexXY$^−$OprM in resistance against different cationic antimicrobial peptides (AMPs). Our results indicate that a knock-out in efflux pump MexXY-OprM increased susceptibility to some AMPs by two- to eightfold. Our data suggest a contribution of MexXY-OprM in resistance to certain AMPs in P. aeruginosa, which should be considered in the future development of new and highly active antimicrobial peptides to fight multidrug resistant infections

Prognostic Value of Myocardial Blush Grade in ST-elevation MI: A Systematic Review and Meta-analysis

Background: Ineffective myocardial perfusion despite angiographic success after angioplasty occurs frequently and is associated with an increased risk of mortality. Hence, this study determined whether myocardial perfusion measured by myocardial blush grade (MBG) identifies ST-elevation MI (STEMI) patients at high risk for poor outcomes after successful angioplasty. Methods: The search employed strategies designed for research databases. An article was eligible if it included adults who underwent coronary angioplasty for STEMI, post-angioplasty MBG was assessed, and mortality or major adverse cardiovascular events (MACE) were determined. Risk for bias was assessed using the Quality In Prognosis Studies tool and forest plots in a Mantel-Haenszel fixed effects model were created using RevMan5.4. Results/discussion: Eight observational studies with an overall low risk of bias were included, involving 8,044 patients. MBG 0/1 with no to poor myocardial perfusion had a negative prognostic value for mortality (OR 2.68; 95% CI [2.22–3.23]) and MACE (OR 1.20; 95% CI [1.01–1.41]). Furthermore, MBG 2 with moderate myocardial perfusion and MBG 3 with normal myocardial perfusion were associated with increased survival with a logHR of 0.47 (95% CI [0.43–0.52]) and 0.20 percutaneous coronary intervention (95% CI [0.18–0.23]). These results imply MBG is a useful prognostic marker for STEMI patients. Conclusion: MBG 0/1 after primary angioplasty is a strong negative prognostic marker for long-term all-cause mortality and MACE among STEMI patients, and a post-primary angioplasty MBG of 2 or 3 is a robust prognostic marker for long-term survival

Impacto del mercado de suelo informal en la fragmentación urbana: Asociación de viviendas “Las Brisas de Santa Rosa”, Lima 2023

La presente investigación se centró en el análisis del mercado de suelo informal y su impacto en la fragmentación urbana, considerando ambos fenómenos complejos y desafiantes para la planificación urbana. En nuestro país, se ha observado un alto índice de ocupaciones informales, alcanzando el 93% entre los años 2000 y 2018 (Espinoza y Ford, 2020). La demanda de vivienda y la necesidad de cubrir necesidades básicas han impulsado el surgimiento del mercado de suelo informal en áreas urbanas. Este trabajo se llevó a cabo con la finalidad de determinar en qué medida el mercado de suelo informal impacta en la fragmentación urbana. Se presentan dos escenarios en momentos diferentes generando una investigación longitudinal, obteniéndose datos cuantitativos como cualitativos, siendo de esta manera un enfoque mixto con un diseño no experimental, alcanzando una metodología básica y descriptiva. Teniendo como caso de estudio la asociación de viviendas “Las Brisas de Santa Rosa” en el distrito de Santa Rosa, y se trabajó con una muestra de 48 individuos. De esta manera, los resultados que se adquirieron en la investigación proporcionaron evidencia clara del impacto del mercado de suelo informal en la fragmentación urbana. A través de un estudio exhaustivo realizado en la Asociación de Vivienda "Las Brisas de Santa Rosa", se constató una relación entre las variables, siendo de manera significativa y directa. Se concluye, como los ocupantes buscan suelos más accesibles, lo cual conduce a una expansión urbana informal, esta expansión informal se suma al porcentaje ya existente y, lamentable dado que no se considera adecuada para la capacidad del ocupante

Morning-evening Types İn Kindergarten, Time-of-day And Performance On Basic Learning Skills

Research on the combined effect of diurnal type and time of day on school/ preschool performance is still scarce, probably because until recently there were no non-invasive questionnaires measuring diurnal type in younger children. To our knowledge, in the literature studies on the so-called synchrony effect only exist for adolescents and adults and no work has been conducted on prepubertal children. This study investigated in kindergarten the relationship between morningevening types with time-of-day and performance on a battery of tests covering basic skills involved in preschool learning. The sample comprised 80 children between 5 and 6 years old (M = 5.42, SD ± 0.495): 36 morning (45%) and 44 evening (55%) types, classified according to the Children’s Chronotype Questionnaire (Werner et al., 2009; PT version, Couto et al., 2014). The children completed a battery of tests related to kindergarten learning (Vitória de La Cruz, PT version, 2012) at four times in the kindergarten day (9:30-10:00; 11:30-12:00; 13:30-14:00; 15:00-15:30). Analyses indicated: an asynchrony effect on the Constancy of Form test, as M-E types performed better in their non-optimal moments, reaching significance in M-types; time-of-day effects in the Verbal (13:3014:00 > 11:30-12:00), Quantitative Concepts (15:00-15:30 > 9:30-10:00/ 11:30-12:00/ 13: 30-14:00) and Position in Space (11:30-12:00 > 13:30-14:00) tests. These results suggest the “synchrony effect” may be a simplistic hypothesis, and better performances are not necessarily associated to early times in the school day. Replication studies are necessary

Twisting DNA by salt

The structure and properties of DNA depend on the environment, in particular the ion atmosphere. Here, we investigate how DNA twist -one of the central properties of DNA- changes with concentration and identity of the surrounding ions. To resolve how cations influence the twist, we combine single-molecule magnetic tweezer experiments and extensive all-atom molecular dynamics simulations. Two interconnected trends are observed for monovalent alkali and divalent alkaline earth cations. First, DNA twist increases monotonously with increasing concentration for all ions investigated. Second, for a given salt concentration, DNA twist strongly depends on cation identity. At 100 mM concentration, DNA twist increases as Na+ + + 2+ + ≈ Cs+ 2+ 2+ 2+. Our molecular dynamics simulations reveal that preferential binding of the cations to the DNA backbone or the nucleobases has opposing effects on DNA twist and provides the microscopic explanation of the observed ion specificity. However, the simulations also reveal shortcomings of existing force field parameters for Cs+ and Sr2+. The comprehensive view gained from our combined approach provides a foundation for understanding and predicting cation-induced structural changes both in nature and in DNA nanotechnology