Dystopie und Methode: zur fiktionalen Verhandlung moralischer Überzeugungen in der Bioethik

Definition of the problem

The role of stories is well established in the traditions of narrative ethics and casuistry. However, from a methodological point of view, the inclusion of fictional works in moral deliberation remains yet unanswered. The paper explains the potential of dystopias for bioethics by means of selected examples and a critical reconstruction and expansion of existing approaches.

Arguments

By means of literary theories, it is proposed to include moral beliefs that motivate dystopias in coherent reflection and reasoning procedures. Furthermore, dystopia’s potential through socioculturally dense scenarios, a contemporary-historical context, and a sensitization to the moral relevance of language for bioethical research are systematically presented.

Conclusion

The methodological considerations provide, on the one hand, practical points of reference for didactic approaches and, on the other hand, for public deliberation. However, the analysis also shows that dystopias introduce their own moral positions beyond a mere illustration or warning.

     

Hydrophobicity engineering of cholera toxin A1 subunit in the strong adjuvant fusion protein CTA1-DD

Protein engineering of the cholera toxin A1 subunit (CTA1) fusedto a dimer of the Ig-binding D-region of Staphylococcus aureusprotein A (DD) was employed to investigate the effect of specificamino acid changes on solubility, stability, enzymatic activityand capacity to act as an adjuvant in vivo. A series of CTA1-DDanalogues were selected by a rational modeling approach, inwhich surface-exposed hydrophobic amino acids of CTA1 were exchangedfor hydrophilic counterparts modeled for best structural fit.Of six different mutants initially produced, two analogues,CTA1Phe132Ser-DD and CTA1Pro185Gln-DD, were demonstrated tohave 50 and 70% increased solubility, respectively, at neutralpH. The double mutant CTA1Phe132Ser/Pro185Gln-DD was at leastthreefold more soluble, demonstrating an additive effect ofthe two mutations. Only the Phe132Ser analogue retained fullbiological activity and stability compared with the native CTA1-DDfusion protein. Two mutants, Pro185Gln and Phe31His mutations,exhibited unaltered ADP-ribosyltransferase activity in vitro,but demonstrated markedly reduced adjuvant function. Since thePro185 and Phe31 amino acids are located in close vicinity onthe distal side of the molecule relative to the enzymaticallyactive cleft, it is conceivable that this region is involvedin mediating a biological function, separate from the enzymaticactivity but intrinsic to the adjuvant activity of CTA1.     

Optimizing the Kinetics and Thermodynamics of DNA i‐Motif Folding

Under slightly acidic conditions, single cytidine‐rich DNA strands can form four‐stranded structures called i‐motifs. The stability of the i‐motif structure is based on the intercalation of hemiprotonated C–C⁺ base pairs. In addition, the stability of these structures is influenced by pH, temperature, salt concentration, number of cytidines per C‐rich stretch, and length of sequence; it also depends on the nucleotides in the connecting loop regions. Here, we investigated the influence of the loop nucleotides on i‐motif stability, structure, and kinetics of folding, in five structures with the same loop‐size but different adenosine and thymidine residues within the loop. The stabilities of the i‐motif structures were determined by CD melting, and structure and kinetics of folding were studied by static and time‐resolved NMR experiments.     

Metal Organic Frameworks for Natural Gas Storage in Vehicles

With the increasing demand for alternative fuels the storage of natural gas (NG) in adsorbents like metal organic frameworks (MOFs) will become more important. In order to use MOFs as storage media in fuel delivery systems, the optimization of mass and energy transfer of the system is crucial. For rapid NG filling of a tank, molecules need to reach the adsorption sites within a reasonable time while the heat of adsorption should be dissipated to the environment. In this article, mass transfer in shaped bodies of MOFs was determined by permeability measurements and pulsed field gradient (PFG) NMR spectroscopy. The heat dissipation was also experimentally measured and both data sets were used to set up a theoretical density function theory model to predict the behavior of MOFs for NG storage.     

Gold and Cobalt Oxide Nanoparticles Modified Poly-Propylene Poly-Ethylene Glycol Membranes in Poly (ε-Caprolactone) Conduits Enhance Nerve Regeneration in the Sciatic Nerve of Healthy Rats

Reconstruction of nerve defects is a clinical challenge. Autologous nerve grafts as the gold standard treatment may result in an incomplete restoration of extremity function. Biosynthetic nerve conduits are studied widely, but still have limitations. Here, we reconstructed a 10 mm sciatic nerve defect in healthy rats and analyzed nerve regeneration in poly (ε-caprolactone) (PCL) conduits longitudinally divided by gold (Au) and gold-cobalt oxide (AuCoO) nanoparticles embedded in poly-propylene poly-ethylene glycol (PPEG) membranes (AuPPEG or AuCoOPPEG) and compared it with unmodified PPEG-membrane and hollow PCL conduits. After 21 days, we detected significantly better axonal outgrowth, together with higher numbers of activated Schwann cells (ATF3-labelled) and higher HSP27 expression, in reconstructed sciatic nerve and in corresponding dorsal root ganglia (DRG) in the AuPPEG and AuCoOPPEG groups; whereas the number of apoptotic Schwann cells (cleaved caspase 3-labelled) was significantly lower. Furthermore, numbers of activated and apoptotic Schwann cells in the regenerative matrix correlated with axonal outgrowth, whereas HSP27 expression in the regenerative matrix and in DRGs did not show any correlation with axonal outgrowth. We conclude that gold and cobalt-oxide nanoparticle modified membranes in conduits improve axonal outgrowth and increase the regenerative performance of conduits after nerve reconstruction.     

Primary Cilia Structure Is Prolonged in Enteric Neurons of 5xFAD Alzheimer’s Disease Model Mice

Neurodegenerative diseases such as Alzheimer’s disease (AD) have long been acknowledged as mere disorders of the central nervous system (CNS). However, in recent years the gut with its autonomous nervous system and the multitude of microbial commensals has come into focus. Changes in gut properties have been described in patients and animal disease models such as altered enzyme secretion or architecture of the enteric nervous system. The underlying cellular mechanisms have so far only been poorly investigated. An important organelle for integrating potentially toxic signals such as the AD characteristic A-beta peptide is the primary cilium. This microtubule-based signaling organelle regulates numerous cellular processes. Even though the role of primary cilia in a variety of developmental and disease processes has recently been recognized, the contribution of defective ciliary signaling to neurodegenerative diseases such as AD, however, has not been investigated in detail so far. The AD mouse model 5xFAD was used to analyze possible changes in gut functionality by organ bath measurement of peristalsis movement. Subsequently, we cultured primary enteric neurons from mutant mice and wild type littermate controls and assessed for cellular pathomechanisms. Neurite mass was quantified within transwell culturing experiments. Using a combination of different markers for the primary cilium, cilia number and length were determined using fluorescence microscopy. 5xFAD mice showed altered gut anatomy, motility, and neurite mass of enteric neurons. Moreover, primary cilia could be demonstrated on the surface of enteric neurons and exhibited an elongated phenotype in 5xFAD mice. In parallel, we observed reduced β-Catenin expression, a key signaling molecule that regulates Wnt signaling, which is regulated in part via ciliary associated mechanisms. Both results could be recapitulated via in vitro treatments of enteric neurons from wild type mice with A-beta. So far, only a few reports on the probable role of primary cilia in AD can be found. Here, we reveal for the first time an architectural altered phenotype of primary cilia in the enteric nervous system of AD model mice, elicited potentially by neurotoxic A-beta. Potential changes on the sub-organelle level—also in CNS-derived neurons—require further investigations.     

Expression of Connexin43 Stimulates Endothelial Angiogenesis Independently of Gap Junctional Communication In Vitro

Connexins (Cx) form gap junctions (GJ) and allow for intercellular communication. However, these proteins also modulate gene expression, growth, and cell migration. The downregulation of Cx43 impairs endothelial cell migration and angiogenetic potential. Conversely, endothelial Cx43 expression is upregulated in an in vivo angiogenesis model relying on hemodynamic forces. We studied the effects of Cx43 expression on tube formation and proliferation in HUVECs and examined its dependency on GJ communication. Expectedly, intercellular communication assessed by dye transfer was linked to Cx43 expression levels in HUVECs and was sensitive to a GJ blockade by the Cx43 mimetic peptide Gap27. The proliferation of HUVECs was not affected by Cx43 overexpression using Cx43 cDNA transfection, siRNA-mediated knockdown of Cx43, or the inhibition of GJ compared to the controls (transfection of an empty vector, scrambled siRNA, and the solvent). In contrast, endothelial tube and sprout formation in HUVECs was minimized after Cx43 knockdown and significantly enhanced after Cx43 overexpression. This was not affected by a GJ blockade (Gap27). We conclude that Cx43 expression positively modulates the angiogenic potential of endothelial cells independent of GJ communication. Since proliferation remained unaffected, we suggest that Cx43 protein may modulate endothelial cell migration, thereby supporting angiogenesis. The modulation of Cx43 expression may represent an exploitable principle for angiogenesis induction in clinical therapy.     

Fullerene-like Re-Doped MoS2 Nanoparticles as an Intercalation Host with Fast Kinetics for Sodium Ion Batteries

Sodium ion batteries (SIBs) are considered as a promising alternative to threaten the reign of lithium ion batteries (LIBs) among various next-generation rechargeable energy storage systems, including magnesium ion, metal air, and metal sulfur batteries. Since both sodium and lithium are located in Group 1 of the periodic table, they share similar (electro)chemical properties with regard to ionization pattern, electronegativity, and electronic configuration; thus the vast number of compounds developed from LIBs can provide guidance to design electrode materials for SIBs. However, the larger ionic radius of the sodium cation and unique (de)sodiation processes may also lead to uncertainties in terms of thermodynamic or kinetic properties. Herein, we present the first construction of SIBs based on inorganic fullerene-like (IF) MoS₂ nanoparticles. Closed-shell-type structures, represented by C₆₀ fullerene, have largely been neglected for studies of alkali-metal hosting materials due to their inaccessibility for intercalating ions into the inner spaces. However, IF-MoS₂, with faceted surfaces, can diffuse sodium ions through the defective channels, thereby allowing reversible sodium ion intercalation/deintercalation. Interestingly, Re-doped MoS₂ showed good electrochemical performances with fast kinetics (ca. 74 mA h g⁻¹ at 20 C). N-type doping caused by Re substitution of Mo in IF-MoS₂ revealed enhanced electrical conductivity and an increased number of diffusion defect sites. Thus, chemical modification of fullerene-like structures through doping is proven to be a promising synthetic strategy to prepare improved electrodes.     

Associations among 25-year trends in diet, cholesterol and BMI from 140,000 observations in men and women in Northern Sweden

ABSTRACT: BACKGROUND: In the 1970s, men in northern Sweden had among the highest prevalences of cardiovascular diseases (CVD) worldwide. An intervention program combining population- and individual-oriented activities was initiated in 1985. Concurrently, collection of information on medical risk factors, lifestyle and anthropometry started. Today, these data make up one of the largest databases in the world on diet intake in a population-based sample, both in terms of sample size and follow-up period. The study examines trends in food and nutrient intake, serum cholesterol and body mass index (BMI) from 1986 to 2010 in northern Sweden. METHODS: Cross-sectional information on self-reported food and nutrient intake and measured body weight, height, and serum cholesterol were compiled for over 140,000 observations. Trends and trend breaks over the 25-year period were evaluated for energy- providing nutrients, foods contributing to fat intake, serum cholesterol and BMI. RESULTS: Reported intake of fat exhibited two significant trend breaks in both sexes: a decrease between 1986 and 1992 and an increase from 2002 (women) or 2004 (men). A reverse trend was noted for carbohydrates, whereas protein intake remained unchanged during the 25-year period. Significant trend breaks in intake of foods contributing to total fat intake were seen. Reported intake of wine increased sharply for both sexes (more so for women) and export beer increased for men. BMI increased continuously for both sexes, whereas serum cholesterol levels decreased during 1986 - 2004, remained unchanged until 2007 and then began to rise. The increase in serum cholesterol coincided with the increase in fat intake, especially with intake of saturated fat and fats for spreading on bread and cooking. CONCLUSIONS: Men and women in northern Sweden decreased their reported fat intake in the first 7 years (1986-1992) of an intervention program. After 2004 fat intake increased sharply for both genders, which coincided with introduction of a positive media support for low carbohydrate-high-fat (LCHF) diet. The decrease and following increase in cholesterol levels occurred simultaneously with the time trends in food selection, whereas a constant increase in BMI remained unaltered. These changes in risk factors may have important effects on primary and secondary prevention of cardiovascular disease (CVD).