Cell-Permeable Succinate Rescues Mitochondrial Respiration in Cellular Models of Statin Toxicity

Statins are the cornerstone of lipid-lowering therapy. Although generally well tolerated, statin-associated muscle symptoms (SAMS) represent the main reason for treatment discontinuation. Mitochondrial dysfunction of complex I has been implicated in the pathophysiology of SAMS. The present study proposed to assess the concentration-dependent ex vivo effects of three statins on mitochondrial respiration in viable human platelets and to investigate whether a cell-permeable prodrug of succinate (complex II substrate) can compensate for statin-induced mitochondrial dysfunction. Mitochondrial respiration was assessed by high-resolution respirometry in human platelets, acutely exposed to statins in the presence/absence of the prodrug NV118. Statins concentration-dependently inhibited mitochondrial respiration in both intact and permeabilized cells. Further, statins caused an increase in non-ATP generating oxygen consumption (uncoupling), severely limiting the OXPHOS coupling efficiency, a measure of the ATP generating capacity. Cerivastatin (commercially withdrawn due to muscle toxicity) displayed a similar inhibitory capacity compared with the widely prescribed and tolerable atorvastatin, but did not elicit direct complex I inhibition. NV118 increased succinate-supported mitochondrial oxygen consumption in atorvastatin/cerivastatin-exposed platelets leading to normalization of coupled (ATP generating) respiration. The results acquired in isolated human platelets were validated in a limited set of experiments using atorvastatin in HepG2 cells, reinforcing the generalizability of the findings.     

Reduced Order Observer for Linear Time-Invariant Multivariable Systems with Unknown Inputs

This paper presents the design of a new reduced order observer to estimate the state for a class of linear time-invariant multivariable systems with unknown inputs. The proposed design approach is a combination of the approaches proposed by Hou and Muller (IEEE Trans. Autom. Control 37:871–875, 1992) and Boubaker (Int. J. Autom. Control Syst. Eng. 5:45–51, 2005); matrix decompositions, state transformations, and substitutions based on coordinate changes are used. It is shown that the problem of reduced order observers for linear systems with unknown inputs can be reduced to a standard one (the unknown input vector will not interfere in the observer equations). The effectiveness of the suggested design algorithm is illustrated by a numerical example (aircraft lateral motion), and, for the same aircraft dynamics, we compare our new observer with other already existing observers from the existence conditions and dynamic characteristics point of view; the superiority of the new designed observer is demonstrated.     

Facile Microwave Assisted Synthesis of Silver Nanostars for Ultrasensitive Detection of Biological Analytes by SERS

We report a very simple, rapid and reproducible method for the fabrication of anisotropic silver nanostars (AgNS) that can be successfully used as highly efficient SERS substrates for different bioanalytes, even in the case of a near-infra-red (NIR) excitation laser. The nanostars have been synthesized using the chemical reduction of Ag⁺ ions by trisodium citrate. This is the first research reporting the synthesis of AgNS using only trisodium citrate as a reducing and stabilizing agent. The key elements of this original synthesis procedure are rapid hydrothermal synthesis of silver nanostars followed by a cooling down procedure by immersion in a water bath. The synthesis was performed in a sealed bottom flask homogenously heated and brought to a boil in a microwave oven. After 60 s, the colloidal solution was cooled down to room temperature by immersion in a water bath at 35 °C. The as-synthesized AgNS were washed by centrifugation and used for SERS analysis of test molecules (methylene blue) as well as biological analytes: pharmaceutical compounds with various Raman cross sections (doxorubicin, atenolol & metoprolol), cell lysates and amino acids (methionine & cysteine). UV-Vis absorption spectroscopy, (Scanning) Transmission Electron Microscopy ((S)TEM) and Atomic Force Microscopy (AFM) have been employed for investigating nanostars’ physical properties.     

New Machine Learning Ensemble for Flood Susceptibility Estimation

Water Resources Management - Floods are among the most severe natural hazard phenomena that affect people around the world. Due to this fact, the identification of zones highly susceptible to...     

Flood Susceptibility Assessment by Using Bivariate Statistics and Machine Learning Models - A Useful Tool for Flood Risk Management

In Romania, as in the rest of the world, the flood frequency has increased considerably. Prahova river basin is among the most exposed catchments of the country to flood risk. It also represents the area of the present study for which the identification of surfaces with high susceptibility to flood phenomena was attempted by applying 2 hybrid models (adaptive neuro-fuzzy inference system and fuzzy support vector machine hybrid) and 2 bivariate statistical models (certainty factor and statistical index). The computation of Flood Potential Index (FPI) was possible by considering a number of 10 flood conditioning factors together with a number of 158 flood pixels and 158 non-flood pixels. Generally, the high and very high flood potential appears on around 25% of the upper and middle basin of Prahova river. The validation of the results was made through the ROC Curve model. One of the novelties of this research is related to the application of Fuzzy Support Vector Machine ensemble for the first time in a study concerning the evaluation of the susceptibility to a certain natural hazard.

     

Prognostic significance of 25‐hydroxivitamin D entirely explained by a higher comorbidity burden: Experience from a South‐Eastern European Dialysis Cohort

Vitamin D deficiency is still a common problem particularly in the elderly and in individuals with various degrees of renal impairment. The present study aimed to evaluate the association between plasma concentrations of 25(OH)D and death in a large cohort of prevalent patients on hemodialysis (HD) from south‐east Romania, a typical Balkan region. This is an observational prospective study that included a total of 570 patients on maintenance HD. Study patients were classified into three groups by baseline 25(OH)D levels: (1) sufficient 25(OH)D—i.e., >30 ng/mL; (2) insufficient 25(OH)D—i.e., between 10 and 29 ng/mL; and (3) deficient 25(OH)D—i.e., <10 ng/mL. During the follow‐up period of 14 months, 68 patients (11.9%) died, the Kaplan–Meier analysis showing significant differences in all‐cause mortality for chronic kidney disease patients in different 25(OH)D groups (P = 0.002). Unadjusted Cox regression analysis also showed significant differences in survival. The multivariate Cox regression model showed no significant differences in survival according to vitamin D levels. Hazard ratio for death in the “<10 ng/mL” group was 1.619 (P = 0.190) and in the “10–30 ng/mL” group was 0.837 (P = 0.609). In our dialysis population with a high comorbidity burden, low 25(OH)D concentration was not associated with mortality in the adjusted Cox model, suggesting that vitamin D deficiency could represent only a non‐specific marker for a poor health status, with less impact on mortality.     

Synthesis, structural and magnetic characterization of iron-zinc-borate glass ceramics containing nanocrystalline zinc ferrite

Two different glass ceramics with the composition of the (Fe₂O₃)_x·(B₂O₃)_(60−x)·(ZnO)₄₀, where x = 12.5 and 15 mol%, have been synthesized using the melt-quench method. The X-ray diffraction (XRD) patterns show the presence of nanometric zinc ferrite (ZnFe₂O₄) crystals, with spinel structure, in a glassy matrix after cooling from melting temperature. The estimated amount of crystallized zinc ferrite varies between 16 and 35%, as a function of the chemical composition. Glass transition (T_g), crystallization (T_p) and melting (T_m) temperatures were determined by differential thermal analysis (DTA) investigations. Fourier transform infrared (FTIR) data revealed that the BO₃ and BO₄ are the main structural units of these glass ceramics network. FTIR spectra of these samples show features at characteristic vibration frequencies of ZnFe₂O₄. Electron paramagnetic resonance (EPR) measurements show the presence of isolated Fe³⁺ ions predominantly situated in rhombic vicinities and as well as the Fe³⁺ species interacting by dipole–dipole interaction or to their superexchange coupled pairs in clustered formations. The magnetic properties of the studied glass ceramics were investigated by vibrating sample magnetometer (VSM). From the magnetization curves for glass ceramic containing 15 mol% Fe₂O₃ it was found that the nanoparticles exhibit ferromagnetic interactions combined with superparamagnetism with a blocking temperature, T_B. For studied samples the hysteresis is present. The coercive field is dependent on composition and magnetic field being around 0.05 μ_B/f.u for measurements performed in maximum 0.4 T.     

NiO/YSZ nanoparticles obtained by new sol–gel route

This paper discusses the production in one single synthesis step of a binary mixture of YSZ particles and NiO particles as precursor powder for the manufacture of SOFC anodes. Three parameters were varied, each over two levels: (i) the temperature of the calcination step involved in the production process, (ii) the proportions of the two organic precursors: sucrose and pectin and (iii) the proportions of YSZ and NiO. The particles, and the calcination process involved in their production, are analyzed by TGA, TEM, SEM, XRD and BET adsorption. It is shown that the relative particle sizes are near-optimal for the production of SOFC anodes and that the particles consist either of pure cubic YSZ or pure cubic NiO. The particle sizes indicated by the various analysis methods are consistent. The particle size and the degree of crystallinity of the particles increase with increasing calcination temperature, while it appears that the process is rather forgiving for changes in the sucrose:pectin ratio. SEM studies show that the powder produced already has good connectivity between the YSZ and the NiO particles, respectively, which is good for the functionality of the resulting anode.     

Landing Auto‐Pilots for Aircraft Motion in Longitudinal Plane using Adaptive Control Laws Based on Neural Networks and Dynamic Inversion

This paper presents two new automatic landing systems (ALSs) for aircraft motion in longitudinal plane; the model of the landing geometry determines the flight trajectory and the aircraft calculated altitude; the flight trajectory during landing consists of two parts: the glide slope and the flare. Both designed ALSs have an adaptive system (ACS) for the aircraft output's control; for the first ALS, the output vector consists of the flying altitude and the longitudinal velocity, while, for the second ALS, the output variables are the pitch angle and the longitudinal velocity of aircraft. The second variant of ALS also contains an altitude controller providing the calculated pitch angle. The calculated altitude (for the first ALS), the calculated pitch angle (for the second ALS), and the desired flight velocity are provided to the ACS by means of a block consisting of two reference models. ACS is based on the dynamic inversion concept and contains an adaptive controller which includes a linear dynamic compensator, a state observer, a neural network, and a Pseudo Control Hedging block. The paper is focused both on the design of the two ALSs and on their complex software implementation and validation.