Novel Design of Neuropeptide-Based Drugs with β-Sheet Breaking Potential in Amyloid-Beta Cascade: Molecular and Structural Deciphers

Our work discusses the investigation of 75 peptide-based drugs with the potential ability to break the β-sheet structures of amyloid-beta peptides from senile plaques. Hence, this study offers a unique insight into the design of neuropeptide-based drugs with β-sheet breaker potential in the amyloid-beta cascade for Alzheimer’s disease (AD). We started with five peptides (¹⁵QKLVFF²⁰, ¹⁶KLVFF²⁰, ¹⁷LVFF²⁰, ¹⁶KLVF¹⁹ and ¹⁵QKLV¹⁸), to which 14 different organic acids were attached at the N-terminal. It was necessary to evaluate the physiochemical features of these sequences due to the biological correlation with our proposal. Hence, the preliminary analysis of different pharmacological features provided the necessary data to select the peptides with the best biocompatibility for administration purposes. Our approaches demonstrated that the peptides ¹⁷LVFF²⁰, NA-¹⁷LVFF²⁰, ¹⁶KLVF¹⁹ and NA-¹⁶KLVF¹⁹ (NA-nicotinic acid) have the ability to interfere with fibril formation and hence improve the neuro and cognitive functions. Moreover, the peptide conjugate NA-¹⁶KLVF¹⁹ possesses attractive pharmacological properties, demonstrated by in silico and in vitro studies. Tandem mass spectrometry showed no fragmentation for the spectra of ¹⁶KLVF¹⁹. Such important results suggest that under the action of protease, the peptide cleavage does not occur at all. Additionally, circular dichroism confirmed docking simulations and showed that NA-¹⁶KLVF¹⁹ may improve the β-sheet breaker mechanism, and thus the entanglement process of amyloid-beta peptides can be more effective.     

Intergenerational Metabolomic Analysis of Mothers with a History of Gestational Diabetes Mellitus and Their Offspring

Shared metabolomic patterns at delivery have been suggested to underlie the mother-to-child transmission of adverse metabolic health. This study aimed to investigate whether mothers with gestational diabetes mellitus (GDM) and their offspring show similar metabolomic patterns several years postpartum. Targeted metabolomics (including 137 metabolites) was performed in plasma samples obtained during an oral glucose tolerance test from 48 mothers with GDM and their offspring at a cross-sectional study visit 8 years after delivery. Partial Pearson’s correlations between the area under the curve (AUC) of maternal and offspring metabolites were calculated, yielding so-called Gaussian graphical models. Spearman’s correlations were applied to investigate correlations of body mass index (BMI), Matsuda insulin sensitivity index (ISI-M), dietary intake, and physical activity between generations, and correlations of metabolite AUCs with lifestyle variables. This study revealed that BMI, ISI-M, and the AUC of six metabolites (carnitine, taurine, proline, SM(-OH) C14:1, creatinine, and PC ae C34:3) were significantly correlated between mothers and offspring several years postpartum. Intergenerational metabolite correlations were independent of shared BMI, ISI-M, age, sex, and all other metabolites. Furthermore, creatinine was correlated with physical activity in mothers. This study suggests that there is long-term metabolic programming in the offspring of mothers with GDM and informs us about targets that could be addressed by future intervention studies.     

Six-layer lamination of a new dry film negative-tone photoresist for fabricating complex 3D microfluidic devices

We present a new epoxy-based negative-tone dry film photoresist (DFR) for fabricating multilayer microfluidic devices using a lamination process combined with a standard photolithography technology. As proof-of-concept, a complex 3D-hydrodynamic focusing device was produced via a six-layer lamination process of 33 µm-thick DFR layers. The bonding strength of the new DFR was tested on silicon, glass, and titanium substrates, respectively. A maximum bonding strength of 37 MPa was obtained for the dry film photoresist laminated on glass. No leakage was found, and burst tests proved excellent robustness and sealing reliability of the microchannels.     

Variation in the human lipidome associated with coffee consumption as revealed by quantitative targeted metabolomics

The effect of coffee consumption on human health is still discussed controversially. Here, we report results from a metabolomics study of coffee consumption, where we measured 363 metabolites in blood serum of 284 male participants of the Cooperative Health Research in the Region of Augsburg study population, aged between 55 and 79 years. A statistical analysis of the association of metabolite concentrations and the number of cups of coffee consumed per day showed that coffee intake is positively associated with two classes of sphingomyelins, one containing a hydroxy‐group (SM(OH)) and the other having an additional carboxy‐group (SM(OH,COOH)). In contrast, long‐ and medium‐chain acylcarnitines were found to decrease with increasing coffee consumption. It is noteworthy that the concentration of total cholesterol also rises with an increased coffee intake in this study group. The association observed here between these hydroxylated and carboxylated sphingolipid species and coffee intake may be induced by changes in the cholesterol levels. Alternatively, these molecules may act as scavengers of oxidative species, which decrease with higher coffee intake. In summary, we demonstrate strong positive associations between coffee consumption and two classes of sphingomyelins and a negative association between coffee consumption and long‐ and medium‐chain acylcarnitines.     

Fluorinated FeF3 catalyst interactions in three different oil formulations using design of experiment optimization and chemistry characterization of tribofilms

The influence of fluorinated FeF₃ catalyst on the formation and properties of tribofilms was examined using design of experiment (DOE) under extreme boundary lubrication (385 N or maximum Hertzian contact pressure of 2.72 GPa). A closed loop boundary condition test was developed to examine the behaviour of lubricants under boundary conditions. The reduction of phosphorus in engine oil was examined using two different plain oils and one fully formulated oil. Results indicate the formation of a thicker tribofilm in plain fluorinated oil when compared with fluorinated fully formulated oils. Several chemistry combinations were prepared and tested. Wear and frictional properties were evaluated using DOE, and the interactions of fluorinated FeF₃ catalyst with minimum phosphorus were studied and compared with respect to fully formulated and plain zinc dialkyl dithiophosphate oils. Tribofilms with thickness ranging from 150 to 350 nm were developed during wear tests and were analysed for fluorinated plain and fully formulated oils that target reducing phosphorus. Three specific tests with optimised 0.6% FeF₃ catalyst concentrations were used with 0.05% phosphorus in plain and fully formulated oil to verify the model optimised conditions with respect to wear and time to full break down. Scanning electron microscopy, hardness of the tribofilms and Auger spectroscopy confirm the presence of fluorine and phosphorus. These tests confirm the optimised prediction of the DOE model. Copyright © 2011 John Wiley & Sons, Ltd.     

Numerical investigation of the flow inside the combustion chamber of a plant oil stove

Recently a low cost cooking device for developing and emerging countries was developed at KIT in cooperation with the company Bosch und Siemens Hausger te GmbH.After constructing an innovative basic design further development was required.Numerical investigations were conducted in order to investigate the flow inside the combustion chamber of the stove under variation of different geometrical parameters.Beyond the performance improvement a further reason of the investigations was to rate the effects of manufacturing tolerance problems.In this paper the numerical investigation of a plant oil stove by means of RANS simulation will be presented.In order to reduce the computational costs different model reduction steps were necessary.The simulation results of the basic configuration compare very well with experimental measurements and problematic behaviors of the actual stove design could be explained by the investigation.     

Numerical noise prediction in fluid machinery

Introduction Today’s design and optimization of fluid machinery is more and more based on numerical methods. With such methods it becomes possible to recognize and limit technical problems in advance. In this way expensive experiments can be reduced. An important issue is the reduction and prevention of noise radiation. In this context sufficiently sound numerical methods are required to detect noise sources and to describe the propagation mechanisms and their effects. However, presently, n…     

The Importance of Variable Speeds under Extreme Pressure Loading in Molybdenum Disulfide Greases Using Four-Ball Wear Tests

There is recent concern regarding grease behavior in extreme pressure applications. The research described here is aimed at providing good friction and wear performance while optimizing rotational speeds under extreme loading conditions. A design of experiment (DOE) was used to analyze molybdenum disulfide (MoS₂) greases and their importance in reducing wear under extreme loading and various speeds conditions (schedule 1 and schedule 2 speeds). The lamellar structure of MoS₂ provides very good weld protection by forming a layer that can be easily sheared under the applications of extreme pressures. An extreme load of 785 N was used in conjunction with different schedules of various rotational speeds to examine lithium-based grease with and without MoS₂ for an equal number of revolutions. A four-ball wear tester was utilized to run a large number of experiments randomly selected by the DOE software. The grease was heated to 75°C and the wear scar diameters were collected at the end of each test.

The results indicated that wear was largely dependent on the speed condition under extreme pressure loading, and thus a lower MoS₂ concentration is needed to improve the wear resistance of lithium-based greases. The response surface diagram showed that the developed molybdenum disulfide greases exhibited both extreme pressure as well as good wear properties under various rotational speeds when compared to steady-state speed. It is believed that MoS₂ greases under schedule 1 speeds perform better and provide an antiwear film that can resist extreme pressure loadings.     

Friction and wear reductions in fluorinated plain and fully formulated oils through enhanced heating time using moderate loading under boundary lubrication conditions

The use of fluorinated mix catalyst (titanium fluoride: TiF₃ + iron fluoride: FeF₃) with polytetrafluoroethylene: PTFE in engine oil is increasingly a strategy to improve fuel economy and component durability to simultaneously provide low friction and excellent wear protection. The influence of these additives shows promising results during load bearing capacity testing and long‐term durability experiments. This paper addresses the enhancement of friction and wear performances of 0.1% and 0.05% phosphorus plain zinc dialkyl dithiophosphate (ZDDP) oil and fully formulated engine oil when heated to 100°C for specific time under thermal and tribological conditions for moderate pressure loading (1.9 GPa Hertzian pressure or 180 N) which simulate the cold start of a car under 700 rpm rotational speed or the valve trains loading where most of the ZDDP are applied. Tests were performed in a ball on cylinder tribometer under boundary lubrication conditions. Surface analyses were carried out using scanning electron microscopy (SEM) and transmission electron microscopy (TEM). Results showed that the anti‐wear additives (2 wt. % PTFE + 0.5 wt. % FeF₃ + .5 wt. % TiF₃) provided excellent wear protection to 0.1% phosphorus plain and fully formulated oil when cylinder is immersed in the desired lubricant and heated for a predetermined time but performed poorly in 0.05% phosphorus fully formulated oil under the same conditions. The transform of anti‐wear coated material to the worn surfaces, which was a function of the anti‐wear performance of additives, was shown to have an influence on friction performance. The wear reducing effect, which was observed in fluorinated additives tribological tests, indicated a positive contribution and good tribofilm formations. Copyright © 2016 John Wiley & Sons, Ltd.     

Threat and selective exposure: The moderating role of threat and decision context on confirmatory information search after decisions.

Previous studies on the impact of perceived threat on confirmatory information search (selective exposure) in the context of decision making have yielded mixed results. Some studies have suggested that confirmatory information search is reduced, yet others have found contradictory effects. The present series of 5 studies consistently found that the crucial moderator for these inconsistent findings was whether the induced threat was contextually related to the subsequent decision and information search tasks. Contextual incongruence (e.g., an induction of terrorist threat followed by an economic decision case) results in reduced levels of confirmatory information search, whereas a congruent threat (e.g., an induction of terrorist threat followed by a decision case on terrorism) results in increased levels of confirmatory information search. Analyses of the underlying psychological processes revealed that decision-unrelated threat inductions increase decision makers' experienced decision uncertainty, thus reducing confirmatory information search. (PsycINFO Database Record (c) 2010 APA, all rights reserved)