Determination of the sticking coefficient of energetic hydrocarbon molecules by molecular dynamics

The sticking coefficient of hydrocarbon species is a key quantity that influences the growth process of amorphous hydrocarbon layers. To extend the very limited database for low impact energies, classical molecular dynamics simulations were performed, determining the sticking coefficients of CH_x (x = 0 … 4) with kinetic energies between 5 and 100 eV. Similar simulations are performed with hydrogen substituted by deuterium. Additionally, analytical formulas are presented that fit the data very well and can be used to interpolate the simulation results.     

Improved 10Be and 26Al-AMS with a 5 MV spectrometer

Detector and ion source changes have increased Be and Al count rates and reduced measurement background at SUERC. Low energy 16 MeV ²⁶Al³⁺ ions can be separated from interferences by adopting thin silicon nitride membrane detector windows. In contrast, a thick Havar detector window is used to preferentially slow boron ions for simplified ¹⁰Be vs. ¹⁰B separation without an additional gas cell.     

Alzheimer’s Disease—Rationales for Potential Treatment with the Thrombin Inhibitor Dabigatran

Alzheimer’s disease (AD) is caused by neurodegenerative, but also vascular and hemostatic changes in the brain. The oral thrombin inhibitor dabigatran, which has been used for over a decade in preventing thromboembolism and has a well-known pharmacokinetic, safety and antidote profile, can be an option to treat vascular dysfunction in early AD, a condition known as cerebral amyloid angiopathy (CAA). Recent results have revealed that amyloid-β proteins (Aβ), thrombin and fibrin play a crucial role in triggering vascular and parenchymal brain abnormalities in CAA. Dabigatran blocks soluble thrombin, thrombin-mediated formation of fibrin and Aβ-containing fibrin clots. These clots are deposited in brain parenchyma and blood vessels in areas of CAA. Fibrin-Aβ deposition causes microvascular constriction, occlusion and hemorrhage, leading to vascular and blood–brain barrier dysfunction. As a result, blood flow, perfusion and oxygen and nutrient supply are chronically reduced, mainly in hippocampal and neocortical brain areas. Dabigatran has the potential to preserve perfusion and oxygen delivery to the brain, and to prevent parenchymal Aβ-, thrombin- and fibrin-triggered inflammatory and neurodegenerative processes, leading to synapse and neuron death, and cognitive decline. Beneficial effects of dabigatran on CAA and AD have recently been shown in preclinical studies and in retrospective observer studies on patients. Therefore, clinical studies are warranted, in order to possibly expand dabigatran approval for repositioning for AD treatment.     

Leucine Reconstitutes Phagocytosis-Induced Cell Death in E. coli-Infected Neonatal Monocytes—Effects on Energy Metabolism and mTOR Signaling

MΦ differentiate from circulating monocytes (Mo). The reduced ability of neonatal Mo to undergo apoptosis after E. coli infection (phagocytosis-induced cell death (PICD)) could contribute to sustained inflammatory processes. The objective of our study was to investigate whether immune metabolism in Mo can be modified to gain access to pro-apoptotic signaling. To this end, we supplemented Mo from neonates and from adults with the branched amino acid leucine. In neonatal Mo, we observed increased energy production via oxidative phosphorylation (Oxphos) after E. coli infection via Seahorse assay. Leucine did not change phagocytic properties. In neonatal Mo, we detected temporal activation of the AKT and mTOR pathways, accompanied with subsequent activation of downstream targets S6 Kinase (S6K) and S6. FACS analyses showed that once mTOR activation was terminated, the level of anti-apoptotic BCL-2 family proteins (BCL-2; BCL-X_L) decreased. Release of cytochrome C and cleavage of caspase-3 indicated involvement of the intrinsic apoptotic pathway. Concomitantly, the PICD of neonatal Mo was initiated, as detected by hypodiploid DNA. This process was sensitive to rapamycin and metformin, suggesting a functional link between AKT, mTOR and the control of intrinsic apoptotic signaling. These features were unique to neonatal Mo and could not be observed in adult Mo. Supplementation with leucine therefore could be beneficial to reduce sustained inflammation in septic neonates.     

Assessment of mechanical and microstructural properties of geopolymers produced from metakaolin,silica fume,and red mud

Geopolymers have been studied as viable alternative to traditional Portland cement-based products, given the use of industrial by-products as raw materials. This work evaluated the mechanical and microstructural properties of geopolymeric mortars produced with sodium hydroxide solution, metakaolin, silica fume, and red mud. The mixtures were produced by means of dosages with different molar ratios and curing conditions. The raw materials were characterized by granulometry, chemical, mineralogical, and thermal analysis. The characterization of mortars was performed by scanning electron microscopy (SEM) and axial compressive strength tests. The precalcination at 850°C of the red mud was sufficient to make it more reactive and suitable for use in geopolymers. Noteworthy, the best mechanical strengths of metakaolin mortars for curing at 50°C, and with the lowest SiO₂/Al₂O₃ ratios. In the mortars with incorporated red mud, there was a decrease of strength at thermal curing conditions and with the increase of residue content, whose microstructure indicates the formation of more pores in the geopolymer matrix. The thermal curing promoted the formation of sodalite crystals, and the significant presence of Na particles on the surface suggests that part of the added NaOH did not react with the precursors.     

Getting a Grip on the Undrugged: Targeting β-Catenin with Fragment-Based Methods

Aberrant WNT pathway activation, leading to nuclear accumulation of β-catenin, is a key oncogenic driver event. Mutations in the tumor suppressor gene APC lead to impaired proteasomal degradation of β-catenin and subsequent nuclear translocation. Restoring cellular degradation of β-catenin represents a potential therapeutic strategy. Here, we report the fragment-based discovery of a small molecule binder to β-catenin, including the structural elucidation of the binding mode by X-ray crystallography. The difficulty in drugging β-catenin was confirmed as the primary screening campaigns identified only few and very weak hits. Iterative virtual and NMR screening techniques were required to discover a compound with sufficient potency to be able to obtain an X-ray co-crystal structure. The binding site is located between armadillo repeats two and three, adjacent to the BCL9 and TCF4 binding sites. Genetic studies show that it is unlikely to be useful for the development of protein–protein interaction inhibitors but structural information and established assays provide a solid basis for a prospective optimization towards β-catenin proteolysis targeting chimeras (PROTACs) as alternative modality.     

Lipoprotein (a) metabolism estimated by nonsteady-state kinetics

Lipoprotein (a) [Lp(a)] is a low-density lipoprotein (LDL) particle with an additional apolipoprotein named apo(a). The concentration of Lp(a) in plasma is determined to a large extent by the size of the apo(a) isoform. Because elevated Lp(a) concentrations in plasma are associated with risk for premature coronary heart disease it is important to determine whether variations in production or catabolism mediate differences in Lp(a) concentration. We determined metabolic parameters of Lp(a) in 17 patients with heterozygous familial hypercholesterolemia or severe mixed hyperlipidemia by fitting a monoexponential function to the rebound of Lp(a) plasma concentration following LDL-apheresis. In 8 of those 17 patients this was done twice following two different aphereses. Although this approach allows one to estimate metabolic parameters without the use of a tracer, it requires several major assumptions such as that apheresis itself does not change production or catabolism of Lp(a) and that Lp(a) metabolism can be described by a single compartment. One apheresis decreased Lp(a) concentration by 59.1±8.3%. The fractional catabolic rate (FCR) was 0.16±0.12 d⁻¹ and production rate 6.27±5.26 mg·kg⁻¹·d⁻¹. However, observed (concentration before first apheresis) and predicted steady-state concentrations differed considerably (more than 20%) in 9 of 17 patients, indicating that not all assumptions were fulfille in all patients. Production rate but not FCR was correlated with Lp(a) plasma concentration (r ²=0.43. P=0.004) and molecular weight of apo(a) (r ²=0.48, P=0.011), which confirms radiotracer experiments showing that variations in Lp(a) plasma concentrations are due to differences in production not catabolism. When parameters were estimated tiwce in a subgroup of eight patients, satisfactory reproducibility was observed in six patients. Although parameters determined on two occasions correlated well, only FCR was concordant (intraclass correiation coefficient). Thus, despite the limitations arising from the assumptions implicit to this method, metabolic parameters of Lp(a) can be estimated from the rebound of plasma concentration following apheresis. Parts of this study were presented at the meeting of the International Atherosclerosis Society, Paris, October 5–9, 1997.