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•3D-printing of quinine loaded implants was established for 4 different polymers.•Drug release is highly dependent on the choice of the polymer.•Solid quinine dispersions in ...polycaprolactone formed for all tested drug loadings.
The 3D printing technique of fused deposition modeling® (FDM) has lately come into focus as a potential fabrication technique for pharmaceutical dosage forms and medical devices that allows the preparation of delivery systems with nearly any shape. This is particular promising for implants administered at application sites with a high anatomical variability where an individual shape adaption appears reasonable. In this work different polymers (Eudragit®RS, polycaprolactone (PCL), poly(l-lactide) (PLLA) and ethyl cellulose (EC)) were evaluated with respect to their suitability for FDM of drug loaded implants and their drug release behaviour was evaluated. The fluorescent dye quinine was used as a model drug to visualize drug distribution in filaments and implants. Quinine loaded filaments were produced by solvent casting and subsequent hot melt extrusion (HME) and model implants were printed as hollow cylinders using a standard FDM printer. Parameters were found at which model implants (hollow cylinders, outer diameter 4–5mm, height 3mm) could be produced from all tested polymers. The drug release which was examined by incubation of the printed implants in phosphate buffered saline solution (PBS) pH 7.4 was highly dependent on the used polymer. The fastest relative drug release of approximately 76% in 51days was observed for PCL and the lowest for Eudragit®RS and EC with less than 5% of quinine release in 78 and 100days, respectively. For PCL further filaments were prepared with different quinine loads ranging from 2.5% to 25% and thermal analysis proved the presence of a solid dispersion of quinine in the polymer for all tested concentrations. Increasing the drug load also increased the overall percentage of drug released to the medium since nearly the same absolute amount of quinine remained trapped in PCL at the end of drug release studies. This knowledge is valuable for future developments of printed implants with a desired drug release profile that might be controlled by the choice of the polymer and the drug load.
Locomotion in animals provides a model for adaptive behavior as it is able to deal with various kinds of perturbations. Work in insects suggests that this evolved flexibility results from a modular ...architecture, which can be characterized by a recurrent neural network allowing for various emerging attractor states. Whereas a lower control-level coordinates joint movements on a short timescale, a higher-level handles action selection on longer timescales. Implementation of such a control system on a walking hexapod robot was able to deal with various walking patterns including disturbances such as uneven terrain or loss of a leg. Here, we propose a cognitive expansion to the adaptive control system that allows dealing with novel challenging situations. This approach makes use of an internal simulation-based planner that is triggered when the model-free controller fails to recover from an unstable pose. Using a grounded internal body model, the planner then tries, in internal simulation, different solutions out of context, and thus, proposes a new plan to be executed on the real robot. We demonstrate the feasibility of this control approach for walking over terrain with uncertain footholds in three scenarios.
Biomaterials often display outstanding combinations of mechanical properties thanks to their hierarchical structuring, which occurs through a dynamically and biologically controlled growth and ...self-assembly of their main constituents, typically mineral and protein. However, it is still challenging to obtain this ordered multiscale structural organization in synthetic 3D-nanocomposite materials. Herein, we report a new bottom-up approach for the synthesis of macroscale hierarchical nanocomposite materials in a single step. By controlling the content of organic phase during the self-assembly of monodisperse organically-modified nanoparticles (iron oxide with oleyl phosphate), either purely supercrystalline or hierarchically structured supercrystalline nanocomposite materials are obtained. Beyond a critical concentration of organic phase, a hierarchical material is consistently formed. In such a hierarchical material, individual organically-modified ceramic nanoparticles (Level 0) self-assemble into supercrystals in face-centered cubic superlattices (Level 1), which in turn form granules of up to hundreds of micrometers (Level 2). These micrometric granules are the constituents of the final mm-sized material. This approach demonstrates that the local concentration of organic phase and nano-building blocks during self-assembly controls the final material's microstructure, and thus enables the fine-tuning of inorganic-organic nanocomposites' mechanical behavior, paving the way towards the design of novel high-performance structural materials.
The efficacy of transcranial electric stimulation (tES) to effectively modulate neuronal activity depends critically on the spatial orientation of the targeted neuronal population. Therefore, precise ...estimation of target orientation is of utmost importance. Different beamforming algorithms provide orientation estimates; however, a systematic analysis of their performance is still lacking. For fixed brain locations, EEG and MEG data from sources with randomized orientations were simulated. The orientation was then estimated (1) with an EEG and (2) with a combined EEG-MEG approach. Three commonly used beamformer algorithms were evaluated with respect to their abilities to estimate the correct orientation: Unit-Gain (UG), Unit-Noise-Gain (UNG), and Array-Gain (AG) beamformer. Performance depends on the signal-to-noise ratios for the modalities and on the chosen beamformer. Overall, the UNG and AG beamformers appear as the most reliable. With increasing noise, the UG estimate converges to a vector determined by the leadfield, thus leading to insufficient orientation estimates.
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•UNG and AG beamformers show best orientation estimates in simulation•UG beamformer orientation estimate subject to noise-dependent bias•Combined EMEG can outperform pure EEG estimates depending on SNRs•Results hold in both, simulations and mathematical investigations
Neuroscience; Sensory neuroscience
Land-use transitions can enhance the livelihoods of smallholder farmers but potential economic-ecological trade-offs remain poorly understood. Here, we present an interdisciplinary study of the ...environmental, social and economic consequences of land-use transitions in a tropical smallholder landscape on Sumatra, Indonesia. We find widespread biodiversity-profit trade-offs resulting from land-use transitions from forest and agroforestry systems to rubber and oil palm monocultures, for 26,894 aboveground and belowground species and whole-ecosystem multidiversity. Despite variation between ecosystem functions, profit gains come at the expense of ecosystem multifunctionality, indicating far-reaching ecosystem deterioration. We identify landscape compositions that can mitigate trade-offs under optimal land-use allocation but also show that intensive monocultures always lead to higher profits. These findings suggest that, to reduce losses in biodiversity and ecosystem functioning, changes in economic incentive structures through well-designed policies are urgently needed.
We study here the effect of the electrode parameters on the terahertz emission efficiency of large-area emitters based on interdigitated electrodes. Electrode parameters are optimized to get maximum ...terahertz emission by optimizing the balance condition among the emission efficiency of individual electrode pairs, number of emitters per unit area, and fraction of semiconductor exposed for optical pumping. A maximum enhancement by about 50% in the peak to peak electric field is observed as compared to the previous state of the art design.
van der Waals heterostructures composed of transition metal dichalcogenide monolayers (TMDCs) are characterized by their truly rich excitonic properties which are determined by their structural, ...geometric, and electronic properties: In contrast to pure monolayers, electrons and holes can be hosted in different materials, resulting in highly tunable dipolar many-particle complexes. However, for genuine spatially indirect excitons, the dipolar nature is usually accompanied by a notable quenching of the exciton oscillator strength. Via electric and magnetic field dependent measurements, we demonstrate that a slightly biased pristine bilayer MoS2 hosts strongly dipolar excitons, which preserve a strong oscillator strength. We scrutinize their giant dipole moment, and shed further light on their orbital and valley physics via bias-dependent magnetic field measurements.
This article summarizes insights from the 36th Energy Modeling Forum study (EMF36) on the magnitude and distribution of economic adjustment costs of greenhouse gas emission reduction targets. Under ...the Paris Agreement, countries have committed to emission reduction targets – so-called Nationally Determined Contributions (NDCs) – in order to combat global warming. The study suggests that aligning NDCs with the commonly agreed 2°C temperature target will induce global economic costs of roughly 1% in 2030. However, these costs are unevenly distributed across regions. Countries exporting fossil fuels are most adversely affected from the transition towards a low-carbon economy. In order to reduce adjustment costs at the global and regional level, comprehensive emissions trading which exploits least-cost abatement options is strongly desirable to avoid contentious normative debates on equitable burden sharing. Lump-sum recycling of revenues from emissions pricing, in equal amounts to every household, appeals as an attractive strategy to mitigate regressive effects and thereby improving the social acceptability of stringent climate policy.
No prior systematic study on the extent of vasogenic edema (VE) in patients with brain metastases (BM) exists. Here, we aim to determine 1) the general volumetric relationship between BM and VE, 2) a ...threshold diameter above which a BM shows VE, and 3) the influence of the primary tumor and location of the BM in order to improve diagnostic processes and understanding of edema formation. This single center, retrospective study includes 173 untreated patients with histologically proven BM. Semi-manual segmentation of 1416 BM on contrast-enhanced T1-weighted images and of 865 VE on fluid-attenuated inversion recovery/T2-weighted images was conducted. Statistical analyses were performed using a paired-samples t-test, linear regression/generalized mixed-effects model, and receiver-operating characteristic (ROC) curve controlling for the possible effect of non-uniformly distributed metastases among patients. For BM with non-confluent edema (n = 545), there was a statistically significant positive correlation between the volumes of the BM and the VE (P < 0.001). The optimal threshold for edema formation was a diameter of 9.4 mm for all BM. The primary tumors as interaction term in multivariate analysis had a significant influence on VE formation whereas location had not. Hence VE development is dependent on the volume of the underlying BM and the site of the primary neoplasm, but not from the location of the BM.
Genome editing with CRISPR/Cas9 is a promising new approach for correcting or mitigating disease-causing mutations. Duchenne muscular dystrophy (DMD) is associated with lethal degeneration of cardiac ...and skeletal muscle caused by more than 3000 different mutations in the X-linked dystrophin gene (
). Most of these mutations are clustered in "hotspots." There is a fortuitous correspondence between the eukaryotic splice acceptor and splice donor sequences and the protospacer adjacent motif sequences that govern prokaryotic CRISPR/Cas9 target gene recognition and cleavage. Taking advantage of this correspondence, we screened for optimal guide RNAs capable of introducing insertion/deletion (indel) mutations by nonhomologous end joining that abolish conserved RNA splice sites in 12 exons that potentially allow skipping of the most common mutant or out-of-frame
exons within or nearby mutational hotspots. We refer to the correction of DMD mutations by exon skipping as myoediting. In proof-of-concept studies, we performed myoediting in representative induced pluripotent stem cells from multiple patients with large deletions, point mutations, or duplications within the
gene and efficiently restored dystrophin protein expression in derivative cardiomyocytes. In three-dimensional engineered heart muscle (EHM), myoediting of DMD mutations restored dystrophin expression and the corresponding mechanical force of contraction. Correcting only a subset of cardiomyocytes (30 to 50%) was sufficient to rescue the mutant EHM phenotype to near-normal control levels. We conclude that abolishing conserved RNA splicing acceptor/donor sites and directing the splicing machinery to skip mutant or out-of-frame exons through myoediting allow correction of the cardiac abnormalities associated with DMD by eliminating the underlying genetic basis of the disease.
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