Ultrasound-induced release of nimodipine from drug-loaded block copolymer micelles: in vivo analysis

Nimodipine prevents cerebral vasospasm and improves functional outcome after aneurysmal subarachnoid hemorrhage (aSAH). The beneficial effect is limited by low oral bioavailability of nimodipine, which resulted in an increasing use of nanocarriers with sustained intrathecal drug release in order to overcome this limitation. However, this approach facilitates only a continuous and not an on-demand nimodipine release during the peak time of vasospasm development. In this study, we aimed to assess the concept of controlled drug release from nimodipine-loaded copolymers by ultrasound application in the chicken chorioallantoic membrane (CAM) model. Nimodipine-loaded copolymers were produced with the direct dissolution method. Vasospasm of the CAM vessels was induced by means of ultrasound (Physiomed, continuous wave, 3 MHz, 1.0 W/cm(2)). The ultrasound-mediated nimodipine release (Physiomed, continuous wave, 1 MHz, 1.7 W/cm(2)) and its effect on the CAM vessels were evaluated. Measurements of vessel diameter before and after ultrasound-induced nimodipine release were performed using ImageJ. The CAM model could be successfully carried out in all 25 eggs. After vasospasm induction and before drug release, the mean vessel diameter was at 57% (range 44–61%) compared to the baseline diameter (set at 100%). After ultrasound-induced drug release, the mean vessel diameter of spastic vessels increased again to 89% (range 83–91%) of their baseline diameter, which was significant (p = 0.0002). We were able to provide a proof of concept for in vivo vasospasm induction by ultrasound application in the CAM model and subsequent resolution by ultrasound-mediated nimodipine release from nanocarriers. This concept merits further evaluation in a rat SAH model. GRAPHICAL ABSTRACT: [Image: see text

Lunar surface mechanical properties — Surveyor 1

Engineering telemetry data and lunar surface photographs by Surveyor 1 have been evaluated for information on the mechanical properties of the lunar surface material at the Surveyor 1 landing site. Based primarily on photographic evidence, estimates of soil density, cohesion, and other soil characteristics are presented. Also, the mechanisms in which the lunar material is believed to have failed under the footpad impacts are discussed. Because dynamic soil reactions cannot be interpreted directly from the available data, a comparative study using computer-simulated landings was initiated. Preliminary results of this study, which is still in progress, are presented

Policy Feedback and the Politics of the Affordable Care Act

There is a large body of literature devoted to how “policies create politics” and how feedback effects from existing policy legacies shape potential reforms in a particular area. Although much of this literature focuses on self‐reinforcing feedback effects that increase support for existing policies over time, Kent Weaver and his colleagues have recently drawn our attention to self‐undermining effects that can gradually weaken support for such policies. The following contribution explores both self‐reinforcing and self‐undermining policy feedback in relationship to the Affordable Care Act, the most important health‐care reform enacted in the United States since the mid‐1960s. More specifically, the paper draws on the concept of policy feedback to reflect on the political fate of the ACA since its adoption in 2010. We argue that, due in part to its sheer complexity and fragmentation, the ACA generates both self‐reinforcing and self‐undermining feedback effects that, depending of the aspect of the legislation at hand, can either facilitate or impede conservative retrenchment and restructuring. Simultaneously, through a discussion of partisan effects that shape Republican behavior in Congress, we acknowledge the limits of policy feedback in the explanation of policy stability and change

Agriculture, Forestry and Other Land Use (AFOLU)

Agriculture, Forestry, and Other Land Use (AFOLU) is unique among the sectors considered in this volume, since the mitigation potential is derived from both an enhancement of removals of greenhouse gases (GHG), as well as reduction of emissions through management of land and livestock (robust evidence; high agreement). The land provides food that feeds the Earth’s human population of ca. 7 billion, fibre for a variety of purposes, livelihoods for billions of people worldwide, and is a critical resource for sustainable development in many regions. Agriculture is frequently central to the livelihoods of many social groups, especially in developing countries where it often accounts for a significant share of production. In addition to food and fibre, the land provides a multitude of ecosystem services; climate change mitigation is just one of many that are vital to human well-being (robust evidence; high agreement). Mitigation options in the AFOLU sector, therefore, need to be assessed, as far as possible, for their potential impact on all other services provided by land. [Section 11.1

Defining a sustainable development target space for 2030 and 2050

With the establishment of the sustainable development goals (SDGs), countries worldwide agreed to a prosperous, socially inclusive, and environmentally sustainable future for all. This ambition, however, exposes a critical gap in science-based insights, namely on how to achieve the 17 SDGs simultaneously. Quantitative goal-seeking scenario studies could help explore the needed systems' transformations. This requires a clear definition of the "target space." The 169 targets and 232 indicators used for monitoring SDG implementation cannot be used for this; they are too many, too broad, unstructured, and sometimes not formulated quantitatively. Here, we propose a streamlined set of science-based indicators and associated target values that are quantifiable and actionable to make scenario analysis meaningful, relevant, and simple enough to be transparent and communicable. The 36 targets are based on the SDGs, existing multilateral agreements, literature, and expert assessment. They include 2050 as a longer-term reference point. This target space can guide researchers in developing new sustainable development pathways

FitEM2EM—Tools for Low Resolution Study of Macromolecular Assembly and Dynamics

Studies of the structure and dynamics of macromolecular assemblies often involve comparison of low resolution models obtained using different techniques such as electron microscopy or atomic force microscopy. We present new computational tools for comparing (matching) and docking of low resolution structures, based on shape complementarity. The matched or docked objects are represented by three dimensional grids where the value of each grid point depends on its position with regard to the interior, surface or exterior of the object. The grids are correlated using fast Fourier transformations producing either matches of related objects or docking models depending on the details of the grid representations. The procedures incorporate thickening and smoothing of the surfaces of the objects which effectively compensates for differences in the resolution of the matched/docked objects, circumventing the need for resolution modification. The presented matching tool FitEM2EMin successfully fitted electron microscopy structures obtained at different resolutions, different conformers of the same structure and partial structures, ranking correct matches at the top in every case. The differences between the grid representations of the matched objects can be used to study conformation differences or to characterize the size and shape of substructures. The presented low-to-low docking tool FitEM2EMout ranked the expected models at the top

Hot Brownian motion and photophoretic self-propulsion

We describe the motion of heated particles in a simple liquid, for which we can theoretically derive generalized fluctuation-dissipation relations that hold far from equilibrium, as we demonstrate both experimentally and via molecular-dynamics simulations. Due to persistent laser-light absorption, these particles excite a radially symmetric or asymmetric (Janus particles) temperature profile in the solvent, which affects their random (Brownian) and systematic (self-phoretic) motion. In case of a radially symmetric temperature profile, we show that the particles perform “hot Brownian motion” (HBM), with different effective temperatures pertaining to their various degrees of freedom. We moreover predict and experimentally observe a peculiar dependence of their diffusivity on the particle size. In case of an asymmetric temperature profile, we find a superimposed self-phoretic directed motion. To adjust the importance of this “active” motion relative to the random hot Brownian motion, the shape of the particle is modified by binding DNA molecules and DNA origami to Janus beads. The persistence of the directed transport can thereby greatly be enhanced

The group II intron ribonucleoprotein precursor is a large, loosely packed structure

Group II self-splicing introns are phylogenetically diverse retroelements that are widely held to be the ancestors of spliceosomal introns and retrotransposons that insert into DNA. Folding of group II intron RNA is often guided by an intron-encoded protein to form a catalytically active ribonucleoprotein (RNP) complex that plays a key role in the activity of the intron. To date, possible structural differences between the intron RNP in its precursor and spliced forms remain unexplored. In this work, we have trapped the native Lactococcus lactis group II intron RNP complex in its precursor form, by deleting the adenosine nucleophile that initiates splicing. Sedimentation velocity, size-exclusion chromatography and cryo-electron microscopy provide the first glimpse of the intron RNP precursor as a large, loosely packed structure. The dimensions contrast with those of compact spliced introns, implying that the RNP undergoes a dramatic conformational change to achieve the catalytically active state