Alkaloids from marine organisms, Part 5. Biomimetic total synthesis of lamellarin L by coupling of two different arylpyruvic acid units

Reaction of the ethyl 3-arylpyruvate 5a with the methyl 2-bromo-3-arylpyruvate 6b in the presence of the 2-arylethylamine 4 afforded the pyrrole derivative 10, which could be transformed into lamellarin L (1) in five steps. The synthesis proceeds with 38% overall yield and mimics the probable biosynthesis of these marine alkaloids.     

Remodeling of the Fibrillation Pathway of α-Synuclein by Interaction with Antimicrobial Peptide LL-III

Liquid-liquid phase separation (LLPS) has emerged as a key mechanism for intracellular organization, and many recent studies have provided important insights into the role of LLPS in cell biology. There is also evidence that LLPS is associated with a variety of medical conditions, including neurodegenerative disorders. Pathological aggregation of α-synuclein, which is causally linked to Parkinson's disease, can proceed via droplet condensation, which then gradually transitions to the amyloid state. We show that the antimicrobial peptide LL-III is able to interact with both monomers and condensates of α-synuclein, leading to stabilization of the droplet and preventing conversion to the fibrillar state. The anti-aggregation activity of LL-III was also confirmed in a cellular model. We anticipate that studying the interaction of antimicrobial-type peptides with liquid condensates such as α-synuclein will contribute to the understanding of disease mechanisms (that arise in such condensates) and may also open up exciting new avenues for intervention.     

Laser-pulse interferometry applied to high-pressure fluid flow in micro channels

The miniaturization of hydraulic systems together with ever increasing static and dynamic fluid pressure as is happening in fuel injection systems leads to complex flow effects with very high local and temporal pressure gradients. System optimization for hydraulic efficiency, components durability or spray formation quality needs the understanding of relevant flow properties. Fluid flow simulation models support such understanding, but with the complex nature of flow conditions, they are in need for precise and comprehensive verification and validation data. This work reports on measurement methods and analysis results for local fluid density and pressure measurements under overall stationary, highly turbulent and cavitating flow conditions in planar, optically accessed, model flow experiments. Laser-pulsed interferometry is applied for the measurement of fluid density fields under high spatial (∼3 μm) and temporal (∼5 ns) resolution. Interferometric imaging and image evaluation techniques provide ensemble mean pressure field data, local pressure fluctuation and differential pressure data. This yields information about local flow features such as flow vortex generation frequency, spatial size and shape of vortices and local pressure distribution inside of vortex structures. Features of bubble collapse process and corresponding pressure shock waves have been observed. The analysis method is applied to a forward-facing step and a target flow geometry. Experimental method, evaluation procedures and results are presented in this paper.     

Semisynthetic murine prion protein equipped with a GPI anchor mimic incorporates into cellular membranes

Conversion of cellular prion protein (PrP(C)) into the pathological conformer (PrP(Sc)) has been studied extensively by using recombinantly expressed PrP (rPrP). However, due to inherent difficulties of expressing and purifying posttranslationally modified rPrP variants, only a limited amount of data is available for membrane-associated PrP and its behavior in vitro and in vivo. Here, we present an alternative route to access lipidated mouse rPrP (rPrP(Palm)) via two semisynthetic strategies. These rPrP variants studied by a variety of in vitro methods exhibited a high affinity for liposomes and a lower tendency for aggregation than rPrP. In vivo studies demonstrated that double-lipidated rPrP is efficiently taken up into the membranes of mouse neuronal and human epithelial kidney cells. These latter results enable experiments on the cellular level to elucidate the mechanism and site of PrP-PrP(Sc) conversion.     

Laser induced fluorescence and flame photography-Tools in gasoline engine combustion analysis

The development of engine combustion systems aims at exploiting the targets set by thermodynamics within the constraints of practical mechanical systems. This, in particular, involves the supply of a combustible mixture, its ignition and combustion. The fluid dynamic and thermo-chemical processes involved therein must be controlled in a way to provide: a temporal rate of heat release prescribed by thermodynamic, mechanic and acoustic requirements; the paths for ‘clean combustion’, i.e. the limitation of exhaust components such as nitric oxide, carbon monoxide or unburned hydrocarbons at lowest possible levels; and the cycle-to-cycle stability of the entire combustion process.

The engineering tasks to influence and control these processes create the permanent need to provide and improve diagnostic tools in order to understand the fluid dynamic and thermo-chemical phenomena governing the combustion in engines. It is the purpose of this article to describe the application of optical methods such as laser-inducedfluorescence and combustion photography for the investigation of cylinder filling, mixture formation and flame propagation in gasoline engines.

First, some diagnostic requirements for combustion analysis will be addressed. Optical techniques and experimental procedures are then derived and finally the application of these techniques in the analysis and development of gasoline engine combustion systems is demonstrated.     

Synthesis of Indomorphan Pseudo‐Natural Product Inhibitors of Glucose Transporters GLUT‐1 and ‐3

Bioactive compound design based on natural product (NP) structure may be limited because of partial coverage of NP‐like chemical space and biological target space. These limitations can be overcome by combining NP‐centered strategies with fragment‐based compound design through combination of NP‐derived fragments to afford structurally unprecedented “pseudo‐natural products” (pseudo‐NPs). The design, synthesis, and biological evaluation of a collection of indomorphan pseudo‐NPs that combine biosynthetically unrelated indole‐ and morphan‐alkaloid fragments are described. Indomorphane derivative Glupin was identified as a potent inhibitor of glucose uptake by selectively targeting and upregulating glucose transporters GLUT‐1 and GLUT‐3. Glupin suppresses glycolysis, reduces the levels of glucose‐derived metabolites, and attenuates the growth of various cancer cell lines. Our findings underscore the importance of dual GLUT‐1 and GLUT‐3 inhibition to efficiently suppress tumor cell growth and the cellular rescue mechanism, which counteracts glucose scarcity.     

Tests for specific nonparametric relations between two distribution functions with applications

Let (X,Y) be a random vector and let G and H be the marginal distributions of X and Y, respectively. In this paper, we propose two tests, one of Kolmogorov‐Smirnov type and the other of Wilcoxon type, for the null hypothesis Ψ(G) = H against the alternative Ψ(G) < H, where Ψ() is a function such that Ψ(G) is a distribution function. The tests are based on the empirical distribution functions of the observations on X and Y, which are dependent. We obtain their asymptotic null distributions. A suspected relationship between the distribution functions of two dependent outcomes can be specified as a hypothesis to be tested in examples like the load sharing models, record values, and auction bidding models. As an application, we consider in detail the problem of testing the effect of load sharing in two component parallel systems.