Assessing the potential for precision medicine in body weight reduction with regard to type 2 diabetes mellitus therapies: A meta‐regression analysis of 120 randomized controlled trials

Aims: To assess the potential for precision medicine in type 2 diabetes by quantifying the variability of body weight as response to pharmacological treatment and to identify predictors which could explain this variability. Methods: We used randomized clinical trials (RCTs) comparing glucose‐lowering drugs (including but not limited to sodium‐glucose cotransporter‐2 inhibitors, glucagon‐like peptide‐1 receptor agonists and thiazolidinediones) to placebo from four recent systematic reviews. RCTs reporting on body weight after treatment to allow for calculation of its logarithmic standard deviation (log[SD], i.e., treatment response heterogeneity) in verum (i.e., treatment) and placebo groups were included. Meta‐regression analyses were performed with respect to variability of body weight after treatment and potential predictors. Results: A total of 120 RCTs with a total of 43 663 participants were analysed. A slightly larger treatment response heterogeneity was shown in the verum groups, with a median log(SD) of 2.83 compared to 2.79 from placebo. After full adjustment in the meta‐regression model, the difference in body weight log(SD) was −0.026 (95% confidence interval −0.044; 0.008), with greater variability in the placebo groups. Scatterplots did not show any slope divergence (i.e., interaction) between clinical predictors and the respective treatment (verum or placebo). Conclusions: We found no major treatment response heterogeneity in RCTs of glucose‐lowering drugs for body weight reduction in type 2 diabetes. The precision medicine approach may thus be of limited value in this setting

Second Law Analysis based on the Extended Optimal Triple Tensor Decomposition for Vortical Flows over Multi-Delta Wings

Vortices and vortex breakdown flow structures over a multi-delta wing configuration are often analyzed by applying flow field invariant analysis techniques from critical point theory and flow topology research. In particular the three invariants of the velocity gradient tensor are used to classify and analyze flow fields, mainly for the assignment of vortical flow regions and assessment of their stability. In this work, the extended optimal triple tensor decomposition is applied to the vortical flow field, delivering new tensor fields which allow for the recalculation of the rate of strain and rotation tensors in an associated basic reference frame. These new tensor fields contain separated distinct flow properties. After inverse transformation into the original coordinate system, flow field invariant analysis techniques applied to these newly derived tensor fields provide further insights into the dynamics of vortical flows over delta wings. It also opens the path to Second Law Analysis gaining detailed information about dominant contributors to entropy generation and energy dissipation

Low Speed Experimental and Numerical Investigations on Unconventional Control Concepts for Agile and Highly Swept Aircraft Configurations

Various unconventional control concepts are considered for placement on the SACCON aircraft. The scaled-down DLR-F17E model is used as the numerical and experimental vehicle. The first category of control concepts is motivated by the desire to improve aircraft stability and control while maintaining a clean signature from ground-based sensors. The second category is motivated by the promise of smooth surface deformations eliminating control surface gaps. Each concept is studied at Re = 762,000 and U∞ = 52m/s using the DLR TAU code with the intention of verifying results through a test campaign in the low speed 1 Meter Tunnel, Göttingen. Only a limited number of control concepts were built and tested in the wind tunnel, and their results are compared with the CFD results to highlight differences in the methods. The CFD results for each concept are presented and their merits are discussed

Need for a Smart Solution: Developing a Sourcing Strategy for a Policy System at a German Insurance Company

The direct insurer Gothaer Insurance Group is among the largest insurance companies in Germany. A project started during the 1990s is still facing the task to introduce a policy system for the commercial sector. The project had its origin in a merger with another German insurer and the system has since evolved over about 18 years. The project team encounters manifold technical and organisational issues as well as external factors which have led the project to a state which requires a decision about its continuance. Driven by a new political agenda that fosters the replacement of mainframe solutions and the use of standard rather than in-house solutions, decisions needed to be made concerning the sourcing strategy: should the system be implemented in-house or with the help of an external partner? Should it be realised by standard software or custom development? A steering committee meeting is set up to decide how to proceed. This case chronicles the series of events leading to that upcoming steering committee and the status quo of the system

Assembly of differently sized supercharged protein nanocages into superlattices for construction of binary nanoparticle-protein materials

This study focuses on the design and characterization of binary nanoparticle superlattices: Two differently sized, supercharged protein nanocages are used to create a matrix for nanoparticle arrangement. We have previously established the assembly of protein nanocages of the same size. Here, we present a novel approach for biohybrid material synthesis by successfully assembling two differently sized supercharged protein nanocages with different symmetries. Typically, the ordered assembly of objects with non-matching symmetry is challenging, but our electrostatic-based approach overcomes the symmetry mismatch by exploiting electrostatic interactions between oppositely charged cages. Moreover, our study showcases the use of nanoparticles as contrast enhancer in an elegant way to gain insights into the structural details of crystalline biohybrid materials. The assembled materials were characterized with various methods, including transmission electron microscopy (TEM) and single-crystal small-angle X-ray scattering (SAXS). We employed focused ion beam milling (FIB) under cryogenic temperatures to further characterize the nanoparticle sublattices via cryo-TEM. Notably, for the first time, we refined superlattice structure data obtained from single-crystal SAXS experiments, providing conclusive evidence of the final assembly type. Our findings highlight the versatility of protein nanocages for creating novel types of binary superlattices. Because the nanoparticles do not influence the type of assembly, protein cage matrices can combine various nanoparticle in the solid state. This study not only contributes to the expanding repertoire of nanoparticle assembly methods but also demonstrates the power of advanced characterization techniques in elucidating the structural intricacies of these biohybrid materials

Extracellular Vesicles-Loaded Fibrin Gel Supports Rapid Neovascularization for Dental Pulp Regeneration

Rapid vascularization is required for the regeneration of dental pulp due to the spatially restricted tooth environment. Extracellular vesicles (EVs) released from mesenchymal stromal cells show potent proangiogenic effects. Since EVs suffer from rapid clearance and low accumulation in target tissues, an injectable delivery system capable of maintaining a therapeutic dose of EVs over a longer period would be desirable. We fabricated an EV-fibrin gel composite as an in situ forming delivery system. EVs were isolated from dental pulp stem cells (DPSCs). Their effects on cell proliferation and migration were monitored in monolayers and hydrogels. Thereafter, endothelial cells and DPSCs were co-cultured in EV-fibrin gels and angiogenesis as well as collagen deposition were analyzed by two-photon laser microscopy. Our results showed that EVs enhanced cell growth and migration in 2D and 3D cultures. EV-fibrin gels facilitated vascular-like structure formation in less than seven days by increasing the release of VEGF. The EV-fibrin gel promoted the deposition of collagen I, III, and IV, and readily induced apoptosis during the initial stage of angiogenesis. In conclusion, we confirmed that EVs from DPSCs can promote angiogenesis in an injectable hydrogel in vitro, offering a novel and minimally invasive strategy for regenerative endodontic therapy

Carbazole-, Aspidofractinine-, and Aspidocarpamine-Type Alkaloids from Pleiocarpa pycnantha

Three new alkaloids, janetinine (1a), pleiokomenine A (2), and huncaniterine B (3a), and 13 known compounds, pleiomutinine (3b), huncaniterine A (3c), 1-carbomethoxy-β-carboline (4), evoxanthine (5), deformyltalbotine acid lactone (6), pleiocarpamine (7), N4-methyl-10-hydroxygeissoschizol (8), spegatrine (9), neosarpagine (10), aspidofractinine (11), N1-methylkopsinin (12), pleiocarpine (13), and N1-methylkopsinin- N4-oxide (14), were isolated from the stem bark of Pleiocarpa pycnantha. Janetinine (1a) is a carbazole alkaloid; in pleiokomenine A (2), two aspidofractinine-type alkaloids are bridged by a methylene unit in an unprecedented way, and huncaniterine B (3a) is a pleiocarpamine-aspidofractinine-type dimer. The structures and relative configurations of these compounds were elucidated on the basis of NMR and MS analyses. Their absolute configurations were defined by means of experimental and calculated ECD data, and additionally, the structures of 5 and 13 were determined by single crystal X-ray diffraction. Compounds 1a, 2, 3b, 4, 6, 9, and 12 displayed cancer chemopreventive properties through either quinone reductase induction ( CD = 30.7, 30.2, 29.9, 43.5, and 36.7 μM for 1a, 4, 6, 9, and 12, respectively) and/or NF-κB inhibition with IC50 values of 13.1, 8.4, 9.4, and 8.8 μM for 2, 3b, 6, and 12, respectively

Bone resorption and body reorganization during maturation induce maternal transfer of toxic metals in anguillid eels

During their once-in-a-lifetime transoceanic spawning migration, anguillid eels do not feed, instead rely on energy stores to fuel the demands of locomotion and reproduction while they reorganize their bodies by depleting body reserves and building up gonadal tissue. Here we show how the European eel (Anguilla anguilla) breaks down its skeleton to redistribute phosphorus and calcium from hard to soft tissues during its sexual development. Using multiple analytical and imaging techniques, we characterize the spatial and temporal degradation of the skeletal framework from initial to final gonadal maturation and use elemental mass ratios in bone, muscle, liver, and gonadal tissue to determine the fluxes and fates of selected minerals and metals in the eels' bodies. We find that bone loss is more pronounced in females than in males and eventually may reach a point at which the mechanical stability of the skeleton is challenged. P and Ca are released and translocated from skeletal tissues to muscle and gonads, leaving both elements in constant proportion in remaining bone structures. The depletion of internal stores from hard and soft tissues during maturation-induced body reorganization is accompanied by the recirculation, translocation, and maternal transfer of potentially toxic metals from bone and muscle to the ovaries in gravid females, which may have direct deleterious effects on health and hinder the reproductive success of individuals of this critically endangered species