Specific cation effects at aqueous solution-vapor interfaces: Surfactant-like behavior of Li⁺ revealed by experiments and simulations

It is now well established by numerous experimental and computational studies that the adsorption propensities of inorganic anions conform to the Hofmeister series. The adsorption propensities of inorganic cations, such as the alkali metal cations, have received relatively little attention. Here we use a combination of liquid-jet X-ray photoelectron experiments and molecular dynamics simulations to investigate the behavior of K+ and Li+ ions near the interfaces of their aqueous solutions with halide ions. Both the experiments and the simulations show that Li+ adsorbs to the aqueous solution−vapor interface, while K+ does not. Thus, we provide experimental validation of the “surfactant-like” behavior of Li+ predicted by previous simulation studies. Furthermore, we use our simulations to trace the difference in the adsorption of K+ and Li+ ions to a difference in the resilience of their hydration shells

Estimación del precio social del carbono. Una aproximación para Argentina

Actualmente los países enfrentan diversos desafíos en materia de crecimiento y desarrollo económico. Uno de ellos corresponde a las políticas de preservación del medio ambiente como un factor de crecimiento sustentable. El Protocolo de Kioto, con el objetivo de mitigar el cambio climático, contempla las emisiones de seis gases de efecto invernadero (GEI). Si bien estas emisiones proceden fundamentalmente de la utilización de energía y de la producción de combustibles fósiles; las actividades como la agricultura, la ganadería y desforestación son las responsables de un porcentaje no despreciable de emisiones (gas metano, dióxido de Carbono, etc.)La emisión de GEI, generados a partir de los procesos productivos, se considera una externalidad negativa, que debe ser tenida en cuenta a la hora de adoptar decisiones más complejas y eficientes. Actualmente, para evaluar proyectos que impliquen reducción de emisiones, se utiliza como «precio sommitigationbra» de la tonelada de Carbono, el que surge del Mercado de Bonos de Carbono. Este precio recibe diversas críticas y surge la necesidad de buscar métodos alternativos de estimación. Por lo tanto, con el presente trabajo, se pretende estimar el precio social del carbono para Argentina y analizar las posibles diferencias con el precio establecido en el Mercado de Bonos de Carbono, para el año 2018. La metodologíaque se utilizará será cuanti-cualitativa y para ello se realizará relevamiento y análisis de datos sobre los componentes que determinan y afectan el precio social del carbono y su evolución en el tiempo. Para establecer el costo social, se estimaran las Curvas de Mitigación, que representan el sacrificio de recursos para la sociedad que implica financiar medidas de reducción de GEI. Se espera que este precio o valor estimado represente el verdadero valor del Carbono a diferencia del valor establecido en el Mercado de Bonos

Dendrimers in Nanoscale Confinement: The Interplay between Conformational Change and Nanopore Entrance

Hyperbranched dendrimers are nanocarriers for drugs, imaging agents, and catalysts. Their nanoscale confinement is of fundamental interest and occurs when dendrimers with bioactive payload block or pass biological nanochannels or when catalysts are entrapped in inorganic nanoporous support scaffolds. The molecular process of confinement and its effect on dendrimer conformations are, however, poorly understood. Here, we use single-molecule nanopore measurements and molecular dynamics simulations to establish an atomically detailed model of pore dendrimer interactions. We discover and explain that electrophoretic migration of polycationic PAMAM dendrimers into confined space is not dictated by the diameter of the branched molecules but by their size and generation-dependent compressibility. Differences in structural flexibility also rationalize the apparent anomaly that the experimental nanopore current read-out depends in nonlinear fashion on dendrimer size. Nanoscale confinement is inferred to reduce the protonation of the polycationic structures. Our model can likely be expanded to other dendrimers and be applied to improve the analysis of biophysical experiments, rationally design functional materials such as nanoporous filtration devices or nanoscale drug carriers that effectively pass biological pores

Disaccharide topology induces slow down in local water dynamics

Molecular level insight into water structure and structural dynamics near proteins, lipids and nucleic acids is critical to the quantitative understanding of many biophysical processes. Un- fortunately, understanding hydration and hydration dynamics around such large molecules is challenging because of the necessity of deconvoluting the effects of topography and chemical heterogeneity. Here we study, via classical all atom simulation, water structure and structural dynamics around two biologically relevant solutes large enough to have significant chemical and topological heterogeneity but small enough to be computationally tractable: the disaccharides Kojibiose and Trehalose. We find both molecules to be strongly amphiphilic (as quantified from normalized local density fluctuations) and to induce nonuniform local slowdown in water translational and rotational motion. Detailed analysis of the rotational slowdown shows that while the rotational mechanism is similar to that previously identified in other aqueous systems by Laage, Hynes and coworkers, two novel characteristics are observed: broadening of the transition state during hydrogen bond exchange (water rotation) and a subpopulation of water for which rotation is slowed because of hindered access of the new accepting water molecule to the transition state. Both of these characteristics are expected to be generic features of water rotation around larger biomolecules and, taken together, emphasize the difficulty in transferring insight into water rotation around small molecules to much larger amphiphilic solutes.This work is part of the research program of the “Stichting voor Fundamenteel Onderzoek der Materie (FOM)” which is financially supported by the “Nederlandse organisatie voor Wetenschap- pelijk Onderzoek (NWO)”. Further financial support was provided by a Marie Curie Incoming International Fellowship (RKC). We gratefully acknowledge SARA, the Dutch center for high- performance computing, for computational time and Huib Bakker and Daan Frenkel for useful critical reviews on an earlier version of this work. We thank two anonymous reviewers for their excellent work, especially for bringing to our attention calculations done on the transition state geometry of dimers and the overstructuring of the O-O radial distribution function of SPC/E water

Amphilimus- vs. zotarolimus-eluting stents in patients with diabetes mellitus and coronary artery disease: the SUGAR trial

Aim: Patients with diabetes mellitus are at high risk of adverse events after percutaneous revascularization, with no differences in outcomes between most contemporary drug-eluting stents. The Cre8 EVO stent releases a formulation of sirolimus with an amphiphilic carrier from laser-dug wells, and has shown clinical benefits in diabetes. We aimed to compare Cre8 EVO stents to Resolute Onyx stents (a contemporary polymer-based zotarolimus-eluting stent) in patients with diabetes. Methods and results: We did an investigator-initiated, randomized, controlled, assessor-blinded trial at 23 sites in Spain. Eligible patients had diabetes and required percutaneous coronary intervention. A total of 1175 patients were randomly assigned (1:1) to receive Cre8 EVO or Resolute Onyx stents. The primary endpoint was target-lesion failure, defined as a composite of cardiac death, target-vessel myocardial infarction, and clinically indicated target-lesion revascularization at 1-year follow-up. The trial had a non-inferiority design with a 4% margin for the primary endpoint. A superiority analysis was planned if non-inferiority was confirmed. There were 106 primary events, 42 (7.2%) in the Cre8 EVO group and 64 (10.9%) in the Resolute Onyx group [hazard ratio (HR) 0.65, 95% confidence interval (CI) 0.44 to 0.96; pnon-inferiority <0.001; psuperiority = 0.030]. Among the secondary endpoints, Cre8 EVO stents had significantly lower rate than Resolute Onyx stents of target-vessel failure (7.5% vs 11.1%, HR 0.67, 95% CI 0.46 to 0.99; p = 0.042). Probable or definite stent thrombosis and all-cause death were not significantly different between groups. Conclusions: In patients with diabetes, Cre8 EVO stents were non-inferior to Resolute Onyx stents with regard to target-lesion failure composite outcome. An exploratory analysis for superiority at 1 year suggests that the Cre8 EVO stents might be superior to Resolute Onyx stents with regard to the same outcome

Conformational Changes and Slow Dynamics through Microsecond Polarized Atomistic Molecular Simulation of an Integral Kv1.2 Ion Channel

Structure and dynamics of voltage-gated ion channels, in particular the motion of the S4 helix, is a highly interesting and hotly debated topic in current membrane protein research. It has critical implications for insertion and stabilization of membrane proteins as well as for finding how transitions occur in membrane proteins—not to mention numerous applications in drug design. Here, we present a full 1 µs atomic-detail molecular dynamics simulation of an integral Kv1.2 ion channel, comprising 120,000 atoms. By applying 0.052 V/nm of hyperpolarization, we observe structural rearrangements, including up to 120° rotation of the S4 segment, changes in hydrogen-bonding patterns, but only low amounts of translation. A smaller rotation (∼35°) of the extracellular end of all S4 segments is present also in a reference 0.5 µs simulation without applied field, which indicates that the crystal structure might be slightly different from the natural state of the voltage sensor. The conformation change upon hyperpolarization is closely coupled to an increase in 310 helix contents in S4, starting from the intracellular side. This could support a model for transition from the crystal structure where the hyperpolarization destabilizes S4–lipid hydrogen bonds, which leads to the helix rotating to keep the arginine side chains away from the hydrophobic phase, and the driving force for final relaxation by downward translation is partly entropic, which would explain the slow process. The coordinates of the transmembrane part of the simulated channel actually stay closer to the recently determined higher-resolution Kv1.2 chimera channel than the starting structure for the entire second half of the simulation (0.5–1 µs). Together with lipids binding in matching positions and significant thinning of the membrane also observed in experiments, this provides additional support for the predictive power of microsecond-scale membrane protein simulations

Intensified treatment with high dose Rifampicin and Levofloxacin compared to standard treatment for adult patients with Tuberculous Meningitis (TBM-IT): protocol for a randomized controlled trial

<p>Abstract</p> <p>Background</p> <p>Tuberculous meningitis is the most severe form of tuberculosis. Mortality for untreated tuberculous meningitis is 100%. Despite the introduction of antibiotic treatment for tuberculosis the mortality rate for tuberculous meningitis remains high; approximately 25% for HIV-negative and 67% for HIV positive patients with most deaths occurring within one month of starting therapy. The high mortality rate in tuberculous meningitis reflects the severity of the condition but also the poor antibacterial activity of current treatment regimes and relatively poor penetration of these drugs into the central nervous system. Improving the antitubercular activity in the central nervous system of current therapy may help improve outcomes. Increasing the dose of rifampicin, a key drug with known poor cerebrospinal fluid penetration may lead to higher drug levels at the site of infection and may improve survival. Of the second generation fluoroquinolones, levofloxacin may have the optimal pharmacological features including cerebrospinal fluid penetration, with a ratio of Area Under the Curve (AUC) in cerebrospinal fluid to AUC in plasma of >75% and strong bactericidal activity against <it>Mycobacterium tuberculosis</it>. We propose a randomized controlled trial to assess the efficacy of an intensified anti-tubercular treatment regimen in tuberculous meningitis patients, comparing current standard tuberculous meningitis treatment regimens with standard treatment intensified with high-dose rifampicin and additional levofloxacin.</p> <p>Methods/Design</p> <p>A randomized, double blind, placebo-controlled trial with two parallel arms, comparing standard Vietnamese national guideline treatment for tuberculous meningitis with standard treatment <it>plus </it>an increased dose of rifampicin (to 15 mg/kg/day total) and additional levofloxacin. The study will include 750 patients (375 per treatment group) including a minimum of 350 HIV-positive patients. The calculation assumes an overall mortality of 40% vs. 30% in the two arms, respectively (corresponding to a target hazard ratio of 0.7), a power of 80% and a two-sided significance level of 5%. Randomization ratio is 1:1. The primary endpoint is overall survival, i.e. time from randomization to death during a follow-up period of 9 months. Secondary endpoints are: neurological disability at 9 months, time to new neurological event or death, time to new or recurrent AIDS-defining illness or death (in HIV-positive patients only), severe adverse events, and rate of treatment interruption for adverse events.</p> <p>Discussion</p> <p>Currently very few options are available for the treatment of TBM and the mortality rate remains unacceptably high with severe disabilities seen in many of the survivors. This trial is based on the hypothesis that current anti-mycobacterial treatment schedules for TBM are not potent enough and that outcomes will be improved by increasing the CSF penetrating power of this regimen by optimising dosage and using additional drugs with better CSF penetration.</p> <p>Trial registration</p> <p>International Standard Randomised Controlled Trial Number <a href="http://www.controlled-trials.com/ISRCTN61649292">ISRCTN61649292</a></p