In silico, NMR and pharmacological evaluation of an hydroxyoxindole cholinesterase inhibitor.

From a screening study of various potential inhibitors for cholinesterases (ChEs), compound (rac)-1 (4-((3-hydroxy-2-oxo-3-phenylindolin-1-yl) methyl) piperidin-1-ium chloride) showed an IC50 of 18 µM for butyrylcholinesterase (BuChE). Herein we present a toxicological and pharmacological evaluation of (rac)-1 to determine its potential for use as an alternative ChE inhibitor for the treatment of Alzheimer's disease. The strategy adopted included in vivo and ex vivo studies with mouse models, Molecular Modelling and Saturation Transfer Difference (STD) NMR studies. Preliminary molecular docking studies were conducted with both (R) and (S)-1 with acetylcholinesterase (AChE) and BuChE, prior to advancing to the mouse model, and indeed favorable interactions were observed, with (R)-1 showing the best binding with AChE and (S)-1 with BuChE. STD-NMR studies were used to successfully validate these results. Toxicological studies were also conducted using the Artemia salina model, with donepezil as reference. It was found that in the in vivo mouse studies that (rac)-1 presented a slightly better inhibition of AChE (0.096 µmol.min-1.mg-1) than donepezil (0.112 µmol.min-1.mg-1) and the same level of inhibition for BuChE as donepezil (0.014 µmol.min-1.mg-1).

Measurements of nanoresonator-qubit interactions in a hybrid quantum electromechanical system.

Experiments to probe the basic quantum properties of motional degrees of freedom of mechanical systems have developed rapidly over the last decade. One promising approach is to use hybrid electromechanical systems incorporating superconducting qubits and microwave circuitry. However, a critical challenge facing the development of these systems is to achieve strong coupling between mechanics and qubits while simultaneously reducing coupling of both the qubit and mechanical mode to the environment. Here we report measurements of a qubit-coupled mechanical resonator system consisting of an ultra-high-frequency nanoresonator and a long coherence-time superconducting transmon qubit, embedded in a superconducting coplanar waveguide cavity. It is demonstrated that the nanoresonator and transmon have commensurate energies and transmon coherence times are one order of magnitude larger than for all previously reported qubit-coupled nanoresonators. Moreover, we show that numerical simulations of this new hybrid quantum system are in good agreement with spectroscopic measurements and suggest that the nanoresonator in our device resides at low thermal occupation number, near its ground state, acting as a dissipative bath seen by the qubit. We also outline how this system could soon be developed as a platform for implementing more advanced experiments with direct relevance to quantum information processing and quantum thermodynamics, including the study of nanoresonator quantum noise properties, reservoir engineering, and nanomechanical quantum state generation and detection.

Insights into (S)-rivastigmine inhibition of butyrylcholinesterase (BuChE): Molecular docking and saturation transfer difference NMR (STD-NMR).

Rivastigmine is a very important drug prescribed for the treatment of Alzheimer's disease (AD) symptoms. It is a dual inhibitor, in that it inhibits both acetylcholinesterase (AChE) and butyrylcholinesterase (BuChE). For our screening program on the discovery of new rivastigmine analogue hits for human butyrylcholinesterase (hBuChE) inhibition, we investigated the interaction of this inhibitor with BuChE using the complimentary approach of the biophysical method, saturation transfer difference (STD)-NMR and molecular docking. This allowed us to obtain essential information on the key binding interactions between the inhibitor and the enzyme to be used for screening of hit compounds. The main conclusions obtained from this integrated study was that the most dominant interactions were (a) H-bonding between the carbamate carbonyl of the inhibitor and the NH group of the imidazole unit of H434, (b) stacking of the aromatic unit of the inhibitor and the W82 aromatic unit in the choline binding pocket via π-π interactions and (c) possible CH/π interactions between the benzylic methyl group and the N-methyl groups of the inhibitor and W82 of the enzyme.

New cholinesterase inhibitors for Alzheimer's disease: Structure Activity Studies (SARs) and molecular docking of isoquinolone and azepanone derivatives.

A library of isoquinolinone and azepanone derivatives were screened for both acetylcholinesterase (AChE) and butyrylcholinesterase (BuChE) activity. The strategy adopted included (a) in vitro biological assays, against eel AChE (EeAChE) and equine serum BuChE (EqBuChE) in order to determine the compounds IC50 and their dose-response activity, consolidated by (b) molecular docking studies to evaluate the docking poses and interatomic interactions in the case of the hit compounds, validated by STD-NMR studies. Compound (1f) was identified as one of these hits with an IC50 of 89.5µM for EeAChE and 153.8µM for EqBuChE, (2a) was identified as a second hit with an IC50 of 108.4µM (EeAChE) and 277.8µM (EqBuChE). In order to gain insights into the binding mode and principle active site interactions of these molecules, (R)-(1f) along with 3 other analogues (also as the R-enantiomer) were docked into both RhAChE and hBuChE models. Galantamine was used as the benchmark. The docking study was validated by performing an STD-NMR study of (1f) with EeAChE using galantamine as the benchmark.

Microanalysis characterization of bioactive protein-bound polysaccharides produced by Amanita ponderosa cultures.

Different compounds of edible mushrooms are responsible for their bioactivity. The ability to synthesize polysaccharides, namely protein-polysaccharide (PPS) complexes, is related to the antioxidant capacity of these compounds and present great interest in preventing a number of diseases, including cancer, cardiovascular and auto-immune diseases, and accelerated aging. Amanita ponderosa are wild edible mushrooms that grow in Mediterranean "montado" areas [Portuguese name given to cork oak (Quercus suber) and holm oak (Quercus ilex) forests]. The aim of this study was to evaluate the production of PPS complexes obtained from A. ponderosa cultures using a new microanalytical approach to quickly and easily monitor the production process. Microanalysis using Fourier-transform infrared using attenuated total reflection and Raman spectroscopy of PPS samples showed spectra compatible with identification of this type of compound in culture extracts. PPS separated by size-exclusion chromatography showed seven main complexes. Molecular weights of the main PPS complexes isolated from cultures ranged between 1.5 and 20 kDa and did not present toxicity against Artemia salina, demonstrating the potential of A. ponderosa as a source of biologically active compounds with nutraceutical value. Application of this microanalytical approach to monitoring the production of PPS compounds can be successfully applied in biotechnological processes.

Microbial communities analysis assessed by pyrosequencing--a new approach applied to conservation state studies of mural paintings.

The knowledge about the microbial communities present in mural paintings is of utmost importance to develop effective conservation and mitigation strategies. The present paper describes a methodological approach for the detailed characterisation of microorganisms thriving in mural paintings by combining culture-dependent methods that allow the identification of microorganisms capable of growing in the laboratory conditions and to obtain high cell densities for further studies, and culture independent methods, such as denaturing gradient gel electrophoresis (DGGE) and pyrosequencing. The coupled use of culture-dependent methods and DGGE does not give enough information to investigate the diversity and abundance of microorganisms present in wall paintings. Pyrosequencing, a novel molecular technique, used here for the first time in this area of research, allowed the identification of a large number of microorganisms, confirming some already identified by the cultivation-dependent methods such as fungi of the genera Penicillium and Cladosporium, but also providing a great contribution in the identification of several genera and species, not previously identified in these artworks, giving also a detailed overview of contaminants which was not possible with the other approaches. The results obtained on several mural painting samples show a strong relationship between the most deteriorated areas of the paintings and higher microbial contamination.

Analysis of acyclovir in vitreous humor by a validated HPLC method.

An HPLC-UV method was developed and validated for the determination of acyclovir in vitreous humor. The method was carried out in isocratic mode using 0.02 mol/L acetic acid/methanol (95:5) as mobile phase, a C18 column at 25 degrees C and UV detection at 254 nm. The method was linear (r2> 0.99) over the range of 35-700 microg/mL, precise (RSD <5%), accurate (recovery ranged from 98.18 to 99.64%), robust, selective regarding of the vitreous humor, and robust remaining unaffected by deliberate variations in relevant parameters. The validated HPLC-UV method can be successfully applied to determine acyclovir directly injected into the vitreous cavity of rabbits' eye.

Emergence of the pointer basis through the dynamics of correlations.

We use the classical correlation between a quantum system being measured and its measurement apparatus to analyze the amount of information being retrieved in a quantum measurement process. Accounting for decoherence of the apparatus, we show that these correlations may have a sudden transition from a decay regime to a constant level. This transition characterizes a nonasymptotic emergence of the pointer basis, while the system apparatus can still be quantum correlated. We provide a formalization of the concept of emergence of a pointer basis in an apparatus subject to decoherence. This contrast of the pointer basis emergence to the quantum to classical transition is demonstrated in an experiment with polarization entangled photon pairs.

Social exclusion and myiasis of the upper lip in a Brazilian rural resident.

CONTEXT: People living in rural or remote Brazil, as in other sub-tropical or tropical nations, are vulnerable to infections that would not normally occur in urban areas or wealthier nations. Brazil is a geographically extensive nation, historically marked by vast socioeconomic inequalities. Approximately 16% of the population live in rural areas. ISSUE: This clinical case report demonstrates the vulnerability of rural residents who are underserved by Brazil's 'universal' public healthcare system, despite social and economic challenges that increase their risk for disease. Myiasis (especially oral myiasis) is a rare health condition in humans caused by fly larvae. Oral myiasis usually appears in periodontal pockets and open wounds, such as after dental extractions. It is associated with poverty, lack of access to health care, and very poor overall health status. While myiasis has a worldwide distribution, it is particularly associated with the tropical and sub-tropical regions of North and South America. LESSONS LEARNED: This article describes a rare case of myiasis in the upper lip of a rural male patient. The case report demonstrate that rural and remote residents can be socially excluded from the benefits of technology and biomedicine, making them vulnerable to rare infections.

von Neumann entropy and entropy production of a damped harmonic oscillator.

In this paper we analyze the entropy and entropy production of a nonisolated quantum system described within the quantum Brownian motion framework. This is a very general and paradigmatic framework for describing nonisolated quantum systems and can be used in any kind of coupling regime. We start by considering the application of von Neumann entropy to an arbitrarily damped quantum system making use of its reduced density operator. We argue that this application is formally valid and develop a path-integral method to evaluate that quantity analytically. We apply this technique to a harmonic oscillator in contact with a heat bath and obtain an exact form for its entropy. Then we study the entropy production of this system and enlighten important characteristics of its thermodynamical behavior on the pure quantum realm and also address their transition to the classical limit.

Toxicological and pharmacological properties of essential oils of Calamintha nepeta, Origanum virens and Thymus mastichina of Alentejo (Portugal).

Three autochthonous flavouring herbs from Alentejo (Portugal), Calamintha nepeta (syn. Clinopodium nepeta), Origanun virens and Thymus mastichina, were selected to evaluate toxicological, antioxidant, antiproliferative and antimicrobial potential of their essential oils (EOs). C. nepeta and T. mastichina EOs showed a high content of oxygenated monoterpenes (86-91%) while O. virens had similar content of oxygenated and hydrocarbon monoterpenes (45%). Toxicological assessment suggests high activity against A. salina (31.8 < CL50 < 128.4 mg/L) and very low toxicity in Swiss mice (DL50 ≥ 1500 mg/kg). EOs showed high antioxidant ability by DPPH radical scavenging assay (0.1-0.6 mg QE/mL EO), total reducing power method (0.2-1.7 mg QE/mL EO) and ß-carotene/linoleic acid system (11-501 mg QE/mL EO). An important antiproliferative effect against human breast tumour cell line was observed (88.9 < EC50 < 108.5 mg/L). Moreover, EOs presented a large antibacterial spectrum. Results point out the low toxicity and high antioxidant, antiproliferative and antimicrobial activities of EOs of these endemic aromatic plants, suggesting their potential use in biotechnological, food and/or pharmaceutical industries.

Environmental dynamics of Bacillus amyloliquefaciens CCMI 1051 antifungal activity under different nitrogen patterns.

AIMS: The aim of this study was to evaluate the influence of environmental conditions on the antifungal activity of the Bacillus sp. CCMI 1053 cultures. METHODS AND RESULTS: The electrospray ionization mass spectra (ESI-MS) analysis was used to detect the active peptides produced by Bacillus amyloliquefaciens CCMI 1051 cultures in a glucose-containing medium to which four different nitrogen sources were added. The cultures produced different patterns of Bacillus sporulation and distinct antifungal activity of the cell-free culture broths. CONCLUSIONS: The highest sporulation obtained corresponds to higher antifungal activity when it is formed after 3 days of microbial growth. The antifungal activity against Trichoderma harzianum CCMI 783 is more influenced by the concentration on the nitrogen source than the culture time of incubation. The association of nitrogen concentration and the time of incubation is particularly relevant in the expression of the antifungal activity. SIGNIFICANCE AND IMPACT OF THE STUDY: The present findings allow the reduction of the use of chemical pesticides and to limit some plant diseases. The association of the nitrogen source and the time of incubation is a novelty, which would improve the production of secondary metabolites. Both economical and environmental benefits arise from the study.

A Data Mining Approach to Improve Inorganic Characterization of Amanita ponderosa Mushrooms.

Amanita ponderosa are wild edible mushrooms that grow in some microclimates of Iberian Peninsula. Gastronomically this species is very relevant, due to not only the traditional consumption by the rural populations but also its commercial value in gourmet markets. Mineral characterisation of edible mushrooms is extremely important for certification and commercialization processes. In this study, we evaluate the inorganic composition of Amanita ponderosa fruiting bodies (Ca, K, Mg, Na, P, Ag, Al, Ba, Cd, Cr, Cu, Fe, Mn, Pb, and Zn) and their respective soil substrates from 24 different sampling sites of the southwest Iberian Peninsula (e.g., Alentejo, Andalusia, and Extremadura). Mineral composition revealed high content in macroelements, namely, potassium, phosphorus, and magnesium. Mushrooms showed presence of important trace elements and low contents of heavy metals within the limits of RDI. Bioconcentration was observed for some macro- and microelements, such as K, Cu, Zn, Mg, P, Ag, and Cd. A. ponderosa fruiting bodies showed different inorganic profiles according to their location and results pointed out that it is possible to generate an explanatory model of segmentation, performed with data based on the inorganic composition of mushrooms and soil mineral content, showing the possibility of relating these two types of data.

Behavior of oxidation in the radiochromic gel dosimeter through photoacoustic technique measurements.

Natural oxidation is an undesirable process suffered by gel dosimetry systems as it changes the values and spatial distribution of absorbed doses. Natural oxidation of Fricke xylenol gel (FXG) dosimeter was inferred from optical absorbance values measured for the first time using the photoacoustic technique. An acoustic detector measures the intensity of the light transmitted by the FXG, which is directly proportional to the ionizing radiation dose absorbed by the samples. In this work, we demonstrated the behavior, the rates, and the dependence of natural oxidation on storage temperature, time, and active components through measurements by photoacoustic technique.

Antioxidant activity and cholinesterase inhibition studies of four flavouring herbs from Alentejo.

Essential oils (EOs) and aqueous extracts of aerial parts of four aromatic species, Calamintha nepeta, Foeniculum vulgare, Mentha spicata and Thymus mastichina, from southwest of Portugal were characterised chemically and analysed in order to evaluate their antioxidant potential and cholinesterase inhibitory activities. The main components of EOs were oxygenated monoterpenes, and aqueous extracts were rich in phenol and flavonoid compounds. EOs and aqueous extracts presented a high antioxidant potential, with ability to protect the lipid substrate, free radical scavenging and iron reducing power. Furthermore, EOs and extracts showed AChE and BChE inhibitory activities higher than rivastigmine, the standard drug. Results suggested the potential use of EOs and aqueous extracts of these flavouring herbs as nutraceutical or pharmaceutical preparations to minimise the oxidative stress and the progression of degenerative diseases.

INVESTIGATION OF THE INFLUENCE OF THE POSITION INSIDE A SMALL AIRCRAFT ON THE COSMIC-RADIATION-INDUCED DOSE.

This article report the measurements on-board a small aircraft at the same altitude and around the same geographic coordinates. The measurements of Ambient Dose Equivalent Rate (H*(10)) were performed in several positions inside the aircraft, close and far from the pilot location and the discrimination between neutron and non-neutron components. The results show that the neutrons are attenuated close to fuel depots and the non-neutron component appears to have the opposite behavior inside the aircraft. These experimental results are also confronted with results from Monte Carlo simulation, obtained with the MCNPX code, using a simplified model of the Learjet-type aircraft and a modeling of the standard atmosphere, which reproduces the real energy and angular distribution of the particles. The Monte Carlo simulation agreed with the experimental measurements and shows that the total H*(10) presents small variation (around 1%) between the positions inside aircraft, although the neutron spectra present significant variations.

Statistical entropy of open quantum systems.

Dissipative quantum systems are frequently described within the framework of the so-called "system-plus-reservoir" approach. In this work we assign their description to the Maximum Entropy Formalism and compare the resulting thermodynamic properties with those of the well-established approaches. Due to the non-negligible coupling to the heat reservoir, these systems are nonextensive by nature, and the former task may require the use of nonextensive parameter dependent informational entropies. In doing so, we address the problem of choosing appropriate forms of those entropies in order to describe a consistent thermodynamics for dissipative quantum systems. Nevertheless, even having chosen the most successful and popular forms of those entropies, we have proven our model to be a counterexample where this sort of approach leads us to wrong results.