Pharmacological doses of melatonin impede cognitive decline in tau‐related Alzheimer models,once tauopathy is initiated,by restoring the autophagic flux

Alterations in autophagy are increasingly being recognized in the pathogenesis of proteinopathies like Alzheimer's disease (AD). This study was conducted to evaluate whether melatonin treatment could provide beneficial effects in an Alzheimer model related to tauopathy by improving the autophagic flux and, thereby, prevent cognitive decline. The injection of AAV‐hTau^P301L viral vectors and treatment/injection with okadaic acid were used to achieve mouse and human ex vivo, and in vivo tau‐related models. Melatonin (10 μmol/L) impeded oxidative stress, tau hyperphosphorylation, and cell death by restoring autophagy flux in the ex vivo models. In the in vivo studies, intracerebroventricular injection of AAV‐hTau^P301L increased oxidative stress, neuroinflammation, and tau hyperphosphorylation in the hippocampus 7 days after the injection, without inducing cognitive impairment; however, when animals were maintained for 28 days, cognitive decline was apparent. Interestingly, late melatonin treatment (10 mg/kg), starting once the alterations mentioned above were established (from day 7 to day 28), reduced oxidative stress, neuroinflammation, tau hyperphosphorylation, and caspase‐3 activation; these observations correlated with restoration of the autophagy flux and memory improvement. This study highlights the importance of autophagic dysregulation in tauopathy and how administration of pharmacological doses of melatonin, once tauopathy is initiated, can restore the autophagy flux, reduce proteinopathy, and prevent cognitive decline. We therefore propose exogenous melatonin supplementation or the development of melatonin derivatives to improve autophagy flux for the treatment of proteinopathies like AD.     

Residual cholesterol synthesis and simvastatin induction of cholesterol synthesis in Smith-Lemli-Opitz syndrome fibroblasts

Smith-Lemli-Opitz syndrome (RSH/SLOS) is an autosomal recessive, malformation syndrome caused by mutations in the 3beta-hydroxysterol delta7-reductase gene (DHCR7). DHCR7 catalyzes the reduction of 7-dehydrocholesterol (7DHC) to cholesterol. We report the mutation analysis and determination of residual cholesterol synthesis in 47 SLOS patients, and the effects of treatment of SLOS skin fibroblasts with simvastatin. Using deuterium labeling we have quantified the amount of synthesized cholesterol and 7DHC in homozygote, heterozygote, and control fibroblast cell lines. In SLOS fibroblasts, the fraction of synthesized cholesterol to total sterol synthesis ranged from undetectable to over 50%. This establishes that different mutant alleles encode enzymes with varying degrees of residual activity. There was a correlation between increased phenotypic severity and decreased residual cholesterol synthesis (r(2)=0.45, p<0.0001). Simvastatin treatment of SLOS fibroblasts with residual DHCR7 enzymatic activity decreased 7DHC levels and increased cholesterol synthesis. This increase in cholesterol synthesis is due to increased expression of a mutant allele with residual function. Determination of residual enzymatic activity for specific DHCR7 mutant alleles will help in understanding the processes underlying the broad phenotypic spectrum found in this disorder and will be useful in identifying patients who may benefit from simvastatin therapy.     

Spatial and seasonal variability of the mass concentration and chemical composition of PM2.5 in Poland

The seasonal changes in ambient mass concentrations and chemical composition of fine particulate matter (PM_2.5) were investigated in three locations in Poland. The analyses included PM_2.5-bound hazardous benzo(a)pyrene (BaP), As, Ni, Cd, and Pb. The samples of PM_2.5 were collected daily in Katowice (southern Poland, urban background site), Gdańsk, and Diabla Góra (northern Poland, urban and regional background sites, respectively) during 1-year-long campaign in 2010. Based on monthly ambient concentrations of PM_2.5-bound carbon (organic and elemental), water-soluble ions (Na⁺, NH₄ ⁺, K⁺, Mg²⁺, Ca²⁺, Cl^?, NO₃ ^?, SO₄ ^2?), and elements As, Ni, Cd, Pb, Ti, Al, Fe, the chemical mass closure of PM_2.5 was checked for each of the four seasons of the year and for the heating and non-heating periods at each site. Also, the annual concentrations of PM_2.5 were determined and the annual PM_2.5 mass closure checked. At each measuring point, the PM_2.5 concentrations were high compared to its Polish yearly permissible value, 25 μg/m³, and its concentrations elsewhere in Europe. The highest annual PM_2.5 concentration, 43 μg/m³, occurred in Katowice; it was twice the annual PM_2.5 concentration in Gdańsk, and thrice the one in Diabla Góra. The high annual averages were due to very high monthly concentrations in the heating period, which were highest in the winter. PM_2.5 consisted mainly of carbonaceous matter (elemental carbon (EC) + organic matter (OM), the sum of elemental carbon, EC, and organic matter, OM; its annual mass contributions to PM_2.5 were 43, 31, and 33 % in Katowice, Gdansk, and Diabla Góra, respectively), secondary inorganic aerosol (SIA), the Na_Cl group, and crustal matter (CM)—in the decreasing order of their yearly mass contributions to PM_2.5. OM, EC, SIA, Na_Cl, and CM accounted for almost 81 % of the PM_2.5 mass in Katowice, 74 % in Gdańsk, and 90 % in Diabla Góra. The annual average toxic metal contribution to the PM_2.5 mass was not greater than 0.2 % at each site. In Katowice and Gdańsk, the yearly ambient BaP concentrations were high (15.4 and 3.2 ng/m³, respectively); in rural Diabla Góra, the concentrations of BaP were almost equal to 1 ng/m³, the Polish BaP annual limit. The great seasonal fluctuations of the shares of the component groups in PM_2.5 and of the concentrations of PM_2.5 and its components are due to the seasonal fluctuations of the emissions of PM and its precursors from hard and brown coal combustion for energy production, growing in a heating season, reaching maximum in winter, and decreasing in a non-heating period. In Gdańsk, northern Poland, especially in the spring and autumn, sea spray might have affected the chemical composition of PM_2.5. The greatest hazard from PM_2.5 occurs in Katowice, southern Poland, in winter, when very high concentrations of PM_2.5 and PM_2.5-related carbonaceous matter, including BaP, are maintained by poor natural ventilation in cities, weather conditions, and the highest level of industrialization in Poland. In less industrialized northern Poland, where the aeration in cities is better and rather gaseous than solid fuels are used, the health hazard from ambient PM_2.5 is much lower.     

The chicken chorioallantoic membrane model in biology,medicine and bioengineering

The chicken chorioallantoic membrane (CAM) is a simple, highly vascularized extraembryonic membrane, which performs multiple functions during embryonic development, including but not restricted to gas exchange. Over the last two decades, interest in the CAM as a robust experimental platform to study blood vessels has been shared by specialists working in bioengineering, development, morphology, biochemistry, transplant biology, cancer research and drug development. The tissue composition and accessibility of the CAM for experimental manipulation, makes it an attractive preclinical in vivo model for drug screening and/or for studies of vascular growth. In this article we provide a detailed review of the use of the CAM to study vascular biology and response of blood vessels to a variety of agonists. We also present distinct cultivation protocols discussing their advantages and limitations and provide a summarized update on the use of the CAM in vascular imaging, drug delivery, pharmacokinetics and toxicology.     

Functionalization of α-hydroxyphosphonates as a convenient route to N-tosyl-α-aminophosphonates

Direct conversion of the α-hydroxyl group by para-toluenesulfonamide to yield α-(N-tosyl)aminophosphonates is reported. α-Aminophosphonates 23a,b–37a,b were obtained from the corresponding α-hydroxyphosphonates 6a,b–21a,b in the presence of K₂CO₃, via the retro-Abramov reaction of the appropriate aldehydes, 1–5. The subsequent formation of imines with simultaneous addition of diethyl phosphite provided access to the α-sulfonamide phosphonates 23a,b–37a,b with better diastereoselectivity than in the case of the Pudovik reaction. The mechanism for this transformation is proposed herein. When Cbz N-protected aziridine 9a,b and phenylalanine analogue 12a,b were exploited, intramolecular substitution was observed, leading to the corresponding epoxide 38 as the sole product, or oxazolidin-2-one 39 as a minor product. Analogous substitution was not observed in the case of proline 18a,b and serine 21a,b derivatives.

The reaction mechanism and diastereoselectivity of the direct transformation of α-hydroxyphosphonates 6a,b–21a,b by para-toluenesulfonamide, yielding α-(N-tosyl)aminophosphonates 23a,b–37a,b under K₂CO₃ conditions are presented.     

Application of Mössbauer Spectroscopy for Identification of Iron-Containing Components in Upper Silesian Topsoil Being under Industrial Anthropopressure

The main objective of the presented preliminary study was the identification of iron-containing phases. Iron-containing phases had accumulated in organic topsoil horizons collected from an area that has long been affected by the steel industry and emissions from power plants. X-ray diffraction and Mössbauer spectroscopy methods were used for the determination of the iron-containing mineral phases in topsoil subsamples which, after two-staged separation, varied in terms of magnetic susceptibility and granulometry. The Mössbauer spectra were recorded using paramagnetic and magnetic components, although the latter occurred only in the strongly magnetic fraction. The central part of spectra was fitted by two doublets (D1 and D2), which were identified as aluminosilicates. Simultaneously, the experimental spectra were described using several Zeeman sextets (Z1, Z2, and Z3) corresponding to the occurrence of hematite and magnetite-like phases with iron in tetrahedral and octahedral sites. Identification of magnetic phases in the tested material, including hematite, led to the conclusion that soil contamination in the studied area was presumably caused by emissions from a nearby power plant. Magnetite-like phases with a different iron content detected in topsoil samples could be related to metallurgical and coking processes, reflecting the specificity of the industrial area from which the samples were taken. The specific composition of the iron-containing aluminosilicates also illustrated the intense and long-lasting impact of the steel and coking industries on the studied area.     

Evaluation of Hybrid Melamine and Steel Fiber Reinforced Geopolymers Composites

This study investigated the influence of the steel and melamine fibers hybridization on the flexural and compressive strength of a fly ash-based geopolymer. The applied reinforcement reduced the geopolymer brittleness. Currently, there are several types of polymer fibers available on the market. However, the authors did not come across information on the use of melamine fibers in geopolymer composites. Two systems of reinforcement for the composites were investigated in this work. Reinforcement with a single type of fiber and a hybrid system, i.e., two types of fibers. Both systems strengthened the base material. The research results showed the addition of melamine fibers as well as steel fibers increased the compressive and flexural strength in comparison to the plain matrix. In the case of a hybrid system, the achieved results showed a synergistic effect of the introduced fibers, which provided better strength results in relation to composites reinforced with a single type of fiber in the same amount by weight.